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Qu H, Yu Q, Ye L, Zheng J. SLC39A14 promotes the development of esophageal squamous cell carcinoma through PI3K/Akt/mTOR signaling pathway. Int Immunopharmacol 2025; 146:113831. [PMID: 39700956 DOI: 10.1016/j.intimp.2024.113831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 11/25/2024] [Accepted: 12/08/2024] [Indexed: 12/21/2024]
Abstract
OBJECTIVES This study aims to investigate the expression of solute carrier family 39 member 14 (SLC39A14) in esophageal squamous cell carcinoma (ESCC) tissues and its prognosis, as well as the impact of SLC39A14 expression on the biological behavior of ESCC cells and associated mechanisms. METHODS Bioinformatics analysis was utilized to compare the differential expression of SLC39A14 mRNA between esophageal cancer tissues and adjacent non-cancerous tissues. Immunohistochemistry was employed to evaluate SLC39A14 protein expression in human ESCC tissues and normal esophageal tissues, followed by an analysis of its association with clinicopathological parameters in esophageal cancer patients. Through cell proliferation, migration, invasion, and Western blot assays, we deeply evaluated the specific effects of SLC39A14 gene knockdown (or overexpression) on ESCC cells and explored its potential biological functions in ESCC. Subsequently, we validated the role of SLC39A14 in ESCC in a xenograft model. Furthermore, LY294002 drug intervention was used to verify the regulatory effect of SLC39A14 on PI3K/Akt/mTOR signaling pathway. RESULTS Both mRNA and protein levels of SLC39A14 were significantly elevated in tumor tissues from ESCC patients compared to adjacent normal tissues. Notably, higher levels of SLC39A14 expression positively correlated with ESCC tumor size (p = 0.010) and clinical T stage (p = 0.025), while exhibiting a negative correlation with overall patient survival rates (p = 0.023). In vitro experiments demonstrated that knocking down SLC39A14 significantly inhibited cell proliferation, migration and invasion. In vivo study showed that SLC39A14 facilitated progression within murine models bearing ESCC tumors. Mechanistic analyses suggested that pro-carcinogenic effects exerted by SLC39A14 are mediated through activation of the PI3K/Akt/mTOR signaling pathway. CONCLUSIONS Our findings suggest that SLC39A14 may serve as a potential biomarker for ESCC due to its pro-oncogenic role during ESCC progression.
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Affiliation(s)
- Hangshuai Qu
- Department of Public Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang Province, China
| | - Qingxin Yu
- Department of pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo City, Zhejiang Province, China
| | - Luxia Ye
- Department of Public Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang Province, China
| | - Jingmin Zheng
- Department of Public Laboratory, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang Province, China.
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Jahan I, Islam MA, Harun-Ur-Rashid M, Sultana GNN. Cancer prevention at the microscopic level with the potent power of micronutrients. Heliyon 2024; 10:e39680. [PMID: 39553634 PMCID: PMC11564030 DOI: 10.1016/j.heliyon.2024.e39680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 10/13/2024] [Accepted: 10/21/2024] [Indexed: 11/19/2024] Open
Abstract
Cancer remains a leading cause of morbidity and mortality worldwide, necessitating ongoing exploration of effective prevention strategies. Micronutrients, vital for maintaining cellular health, offer promising avenues for cancer prevention. This review delineates the critical roles of micronutrients in cancer prevention, elucidating their mechanisms at the cellular level. Focusing on essential vitamins and minerals like Vitamins A, C, D, E, selenium, and zinc, we explore their profound effects on fundamental cellular processes such as DNA repair, oxidative stress regulation, cellular proliferation, and immune surveillance. These nutrients, characterized by their antioxidative, anti-inflammatory, and immune-enhancing properties, have shown potential in reducing the risk of cancer. The article synthesizes outcomes from a broad spectrum of clinical trials, epidemiological studies, and systematic reviews to evaluate the efficacy of micronutrients in thwarting cancer development. This critical analysis explores significant trials, addresses controversies in nutrient efficacy, and highlights the implications for clinical practice and public health policy. The review underscores the importance of integrating nutritional strategies into comprehensive cancer prevention frameworks and suggests directions for future research to optimize the preventive potentials of micronutrients.
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Affiliation(s)
- Israt Jahan
- Genetic Engineering and Biotechnology Research Laboratory (GEBRL), Centre for Advanced Research in Sciences (CARS), University of Dhaka, Dhaka, 1000, Bangladesh
| | - Md Aminul Islam
- Genetic Engineering and Biotechnology Research Laboratory (GEBRL), Centre for Advanced Research in Sciences (CARS), University of Dhaka, Dhaka, 1000, Bangladesh
| | - Mohammad Harun-Ur-Rashid
- Department of Chemistry, International University of Business Agriculture and Technology (IUBAT), Dhaka, 1230, Bangladesh
| | - Gazi Nurun Nahar Sultana
- Genetic Engineering and Biotechnology Research Laboratory (GEBRL), Centre for Advanced Research in Sciences (CARS), University of Dhaka, Dhaka, 1000, Bangladesh
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Lima FDS, Gonçalves CEDS, Fock RA. Zinc and aging: a narrative review of the effects on hematopoiesis and its link with diseases. Nutr Rev 2024; 82:1125-1137. [PMID: 37717139 DOI: 10.1093/nutrit/nuad115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/18/2023] Open
Abstract
There has been a global increase in the older population in recent decades and, as age advances, complex metabolic and epigenetic changes occur in the organism, and these may trigger some health complications commonly found among this population. Additionally, several changes occur in older people that can reduce the dietary intake or the process of nutrient absorption. In this way, tissues with high nutrient requirements are more affected. Hematopoiesis is the process of formation, development, and maturation of blood cells and is a process with a high turnover. This high demand makes the integrity of the hematopoietic process susceptible to various factors that impair physiological function, such as aging and micronutrient bioavailability. Among these micronutrients, Zinc is considered an important micronutrient, playing diverse roles across various tissues and cell types. Some of the alterations in hematopoiesis that appear as a consequence of aging and due to insufficient micronutrient intake are well described in the literature; however, not much is known about how zinc deficiency contributes towards the development of diseases seen in aging. Considering the importance of zinc to act on several biological processes, this narrative review discusses several studies related to the physiological requirements, deficiency, or excess of zinc, including studies in experimental models and humans, and aimed to shed light on the relationship between zinc and the regulation of hematopoietic tissue, exploring possible links between this mineral with common disorders that appear during aging.
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Affiliation(s)
- Fabiana Da Silva Lima
- Department of Food and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Ricardo Ambrósio Fock
- Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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4
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Kubo Y, Igaue S, Utsunomiya D, Kubo K, Kurita D, Ishiyama K, Oguma J, Daiko H. Association between preoperative serum zinc level and prognosis in patients with advanced esophageal cancer in the neoadjuvant treatment era. Ann Gastroenterol Surg 2024; 8:595-603. [PMID: 38957556 PMCID: PMC11216781 DOI: 10.1002/ags3.12781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 07/04/2024] Open
Abstract
Background Zinc (Zn), an essential trace element, has an adverse influence on the prognosis of several cancers. However, the association between the preoperative serum Zn level and outcomes in patients with advanced esophageal cancer in the current neoadjuvant treatment era remains unclear. Methods This study involved 185 patients with esophageal cancer who underwent R0 surgery after neoadjuvant chemotherapy from August 2017 to February 2021. We retrospectively investigated the relationship between the preoperative serum Zn level and the patients' outcomes. Results The patients were divided into a low Zn group (<64 μg/dL) and a high Zn group (≤64 μg/dL) according to the mean preoperative serum Zn level. Low Zn had significantly worse overall survival (OS) (2-year OS rate: 76.2% vs. 83.3% in low vs. high Zn; p = 0.044). A low Zn in pathological non-responders (Grade ≤ 1a) was significantly associated with a shorter 2-year recurrence-free survival (RFS) rate (39.6% vs. 64.1% in low vs. high Zn; p = 0.032). The multivariate analysis identified low BMI and Zn level among preoperative nutritional status indices as an independent risk factor for worse RFS in non-responders. Compared with responders, pathological non-responders comprised significantly more males and a performance status of ≥1, and there was no difference in Zn level according to pathological response. Conclusion A preoperative low Zn level had a negative impact on early recurrence in esophageal cancer patients who underwent neoadjuvant chemotherapy. This suggests the need to administer Zn supplementation to patients with esophageal cancer who have preoperative Zn deficiency.
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Affiliation(s)
- Yuto Kubo
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Shota Igaue
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Daichi Utsunomiya
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Kentaro Kubo
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Daisuke Kurita
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Koshiro Ishiyama
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Junya Oguma
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Hiroyuki Daiko
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
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Sugimoto R, Lee L, Tanaka Y, Morita Y, Hijioka M, Hisano T, Furukawa M. Zinc Deficiency as a General Feature of Cancer: a Review of the Literature. Biol Trace Elem Res 2024; 202:1937-1947. [PMID: 37658952 PMCID: PMC10955002 DOI: 10.1007/s12011-023-03818-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/16/2023] [Indexed: 09/05/2023]
Abstract
Trace elements are minerals that are present in very low concentrations in the human body and yet are crucial for a wide range of physiological functions. Zinc, the second most abundant trace element, is obtained primarily from the diet. After being taken up in the intestine, zinc is distributed to various target organs, where it plays key roles in processes such as immunity, protein folding, apoptosis, and antioxidant activity. Given the important role of zinc in a wide range of enzymatic reactions and physiological processes, zinc deficiency has been identified in a variety of diseases, notably cancer. In recent years, multiple meta-analyses and reviews looking at zinc levels in individual cancer types have been published, as have a plethora of primary studies demonstrating a link between low zinc levels and specific types of cancer. In this review, we summarize recent evidence implicating low zinc concentrations in serum or tissues as a characteristic in a wide range of cancers. We also discuss preliminary findings indicating that zinc level measurement could ultimately become a useful clinical tool for cancer diagnosis and predicting outcomes in patients with cancer. Finally, we suggest future directions for further elucidating the role of zinc deficiency in cancer development and progression.
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Affiliation(s)
- Rie Sugimoto
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-Ku, Fukuoka, 811-1395, Japan.
| | - Lingaku Lee
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-Ku, Fukuoka, 811-1395, Japan
| | - Yuki Tanaka
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-Ku, Fukuoka, 811-1395, Japan
| | - Yusuke Morita
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-Ku, Fukuoka, 811-1395, Japan
| | - Masayuki Hijioka
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-Ku, Fukuoka, 811-1395, Japan
| | - Terumasa Hisano
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-Ku, Fukuoka, 811-1395, Japan
| | - Masayuki Furukawa
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-Ku, Fukuoka, 811-1395, Japan
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6
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Yang P, Li H, Sun M, Guo X, Liao Y, Hu M, Ye P, Liu R. Zinc deficiency drives ferroptosis resistance by lactate production in esophageal squamous cell carcinoma. Free Radic Biol Med 2024; 213:512-522. [PMID: 38301975 DOI: 10.1016/j.freeradbiomed.2024.01.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/18/2024] [Accepted: 01/23/2024] [Indexed: 02/03/2024]
Abstract
Trace metal zinc is involved in key processes of solid tumors by its antioxidant properties, while the role of zinc at the onset of esophageal squamous cell carcinoma (ESCC) remains controversial. This study aimed to determine whether zinc is associated with the ESCC and underlying molecular events involving malignant progression. Based on a case-control study, we found serum and urine zinc were decreased and correlated with ESCC progression. Thus, an in vitro model for zinc deficiency (ZD) was established, and we found that ZD contributed to the proliferation, migration, and invasion of EC109 cells. Untargeted metabolomics identified 59 upregulated metabolites and 6 downregulated metabolites, among which glycolysis and ferroptosis-related oxidation of chain fatty acids might play crucial steps in ZD-treated molecular events. Interestingly, ZD disrupted redox homeostasis and enhanced cytosolic Fe2+ of EC109 cells, while lipid peroxidation, the key marker of ferroptosis occurrence, was decreased after ZD treatment. The mechanism underlying these changes may involve ZD-enhanced ESCC glycolysis and lactate production, which confer ferroptosis resistance by inhibiting of p-AMPK and leading to the upregulation of SREBP1 and SCD1 to enhance the production of anti-ferroptosis monounsaturated fatty acids.
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Affiliation(s)
- Peiyan Yang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Hui Li
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Mingjun Sun
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Xinxin Guo
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Yinghao Liao
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Mohan Hu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Ping Ye
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China
| | - Ran Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China.
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7
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Wang T, Xu F, Lin X, Lv Y, Zhang X, Cheng W, Wang L, Wang M, Zhang M, Xia T, Qian S, Tang M, Yang W, Zhang Y, Zhang D, Hu A, Zhao Q. Co-exposure to iron, copper, zinc, selenium and titanium is associated with the prevention of gastric precancerous lesions. Biometals 2023; 36:1141-1156. [PMID: 37351758 DOI: 10.1007/s10534-023-00509-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/08/2023] [Indexed: 06/24/2023]
Abstract
Gastric cancer is the third leading cause of cancer death, and gastric precancerous lesions (GPLs) are an important stage in the transformation of normal gastric mucosa to gastric cancer. Matched for age and sex, a total of 316 subjects were eventually included from our prospective observation population (including 1007 patients with GPLs and 762 normal controls), and a questionnaire survey was conducted. In total, 10 plasma elements (iron, copper, zinc, selenium, rubidium, strontium, titanium, aluminum, vanadium and arsenic) were measured by applying inductively coupled plasma‒mass spectrometry (ICP‒MS). A multivariate conditional logistic regression model and Bayesian kernel logistic regression model (BKMR) were used to analyze the association between plasma element concentrations and GPLs. In the multimetal model, plasma titanium concentrations were significantly and positively associated with the prevalence of GPLs, with a fourth-quartile OR of 11.56 ([95% CI]: [2.78-48.13]). Plasma selenium and copper were negatively correlated with GPLs, with the highest quartiles of selenium and copper having an OR of 0.03 ([95% CI]: [0.01-0.15]; P < 0.001) and 0.24 ([95% CI]: [0.07-0.82]), respectively. In the BKMR model, there was a significant negative combined correlation of five metals on GPLs: iron, copper, zinc, selenium, and titanium. The results of this study showed that plasma concentrations of selenium and copper were negatively correlated with GPLs, while plasma concentrations of titanium were positively correlated with GPLs, and the combined action of the five elements was negatively correlated with GPLs.
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Affiliation(s)
- Tingting Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Fang Xu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Xiao Lin
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Yaning Lv
- Anhui Province, Hefei Customs Technology Center, Hefei, China
| | - Xiaohui Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Wenli Cheng
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Li Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Min Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Meng Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Tao Xia
- Department of Gastroenterology, Anhui Province, Lujiang County People's Hospital, Hefei, China
| | - Shiqing Qian
- Department of Pathology, Anhui Province, Lujiang County People's Hospital, Hefei, China
| | - Min Tang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Wanshui Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China
| | - Ying Zhang
- Department of Gastroenterology and Hepatology, Anhui Province, Tongling Municipal Hospital, Tongling, China.
| | - Daoming Zhang
- Department of Gastroenterology, Anhui Province, Lujiang County People's Hospital, Hefei, China.
| | - Anla Hu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China.
| | - Qihong Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, China.
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Chen H, Zhao T, Fan J, Yu Z, Ge Y, Zhu H, Dong P, Zhang F, Zhang L, Xue X, Lin X. Construction of a prognostic model for colorectal adenocarcinoma based on Zn transport-related genes identified by single-cell sequencing and weighted co-expression network analysis. Front Oncol 2023; 13:1207499. [PMID: 37829346 PMCID: PMC10565862 DOI: 10.3389/fonc.2023.1207499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/25/2023] [Indexed: 10/14/2023] Open
Abstract
Background Colorectal cancer (CRC) is one of the most prevalent malignancies and the third most lethal cancer globally. The most reported histological subtype of CRC is colon adenocarcinoma (COAD). The zinc transport pathway is critically involved in various tumors, and its anti-tumor effect may be through improving immune function. However, the Zn transport pathway in COAD has not been reported. Methods The determination of Zn transport-related genes in COAD was carried out through single-cell analysis of the GSE 161277 obtained from the GEO dataset. Subsequently, a weighted co-expression network analysis of the TCGA cohort was performed. Then, the prognostic model was conducted utilizing univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Functional enrichment, immune microenvironment, and survival analyses were also carried out. Consensus clustering analysis was utilized to verify the validity of the prognostic model and explore the immune microenvironment. Ultimately, cell experiments, including CCK-8,transwell and scratch assays, were performed to identify the function of LRRC59 in COAD. Results According to the Zn transport-related prognostic model, the individuals with COAD in TCGA and GEO databases were classified into high- and low-risk groups. The group with low risk had a comparatively more favorable prognosis. Two groups had significant variations in the immune infiltration, MHC, and the expression of genes related to the immune checkpoint. The cell experiments indicated that the proliferation, migration, and invasion of the HCT-116, DLD-1, and RKO cell lines were considerably increased after LRRC59 knockdown. It proved that LRRC59 was indeed a protective factor for COAD. Conclusion A prognostic model for COAD was developed using zinc transport-related genes. This model can efficiently assess the immune microenvironment and prognosis of individuals with COAD. Subsequently, the function of LRRC59 in COAD was validated via cell experiments, highlighting its potential as a biomarker.
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Affiliation(s)
- Hua Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ting Zhao
- Department of Microbiology and Immunology, School of Basic Medical Science, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianing Fan
- School of Second Clinical Medical, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhiqiang Yu
- Department of General Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yiwen Ge
- School of Second Clinical Medical, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - He Zhu
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Pingping Dong
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Fu Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liang Zhang
- Department of General Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangyang Xue
- Department of Microbiology and Immunology, School of Basic Medical Science, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaoming Lin
- Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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9
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Alotaibi A, Gadekar VP, Gundla PS, Mandarthi S, Jayendra N, Tungekar A, Lavanya BV, Bhagavath AK, Cordero MAW, Pitkaniemi J, Niazi SK, Upadhya R, Bepari A, Hebbar P. Global comparative transcriptomes uncover novel and population-specific gene expression in esophageal squamous cell carcinoma. Infect Agent Cancer 2023; 18:47. [PMID: 37641095 PMCID: PMC10463703 DOI: 10.1186/s13027-023-00525-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and is one of the deadliest gastrointestinal malignancies. Despite numerous transcriptomics studies to understand its molecular basis, the impact of population-specific differences on this disease remains unexplored. AIMS This study aimed to investigate the population-specific differences in gene expression patterns among ESCC samples obtained from six distinct global populations, identify differentially expressed genes (DEGs) and their associated pathways, and identify potential biomarkers for ESCC diagnosis and prognosis. In addition, this study deciphers population specific microbial and chemical risk factors in ESCC. METHODS We compared the gene expression patterns of ESCC samples from six different global populations by analyzing microarray datasets. To identify DEGs, we conducted stringent quality control and employed linear modeling. We cross-compared the resulting DEG lists of each populations along with ESCC ATLAS to identify known and novel DEGs. We performed a survival analysis using The Cancer Genome Atlas Program (TCGA) data to identify potential biomarkers for ESCC diagnosis and prognosis among the novel DEGs. Finally, we performed comparative functional enrichment and toxicogenomic analysis. RESULTS Here we report 19 genes with distinct expression patterns among populations, indicating population-specific variations in ESCC. Additionally, we discovered 166 novel DEGs, such as ENDOU, SLCO1B3, KCNS3, IFI35, among others. The survival analysis identified three novel genes (CHRM3, CREG2, H2AC6) critical for ESCC survival. Notably, our findings showed that ECM-related gene ontology terms and pathways were significantly enriched among the DEGs in ESCC. We also found population-specific variations in immune response and microbial infection-related pathways which included genes enriched for HPV, Ameobiosis, Leishmaniosis, and Human Cytomegaloviruses. Our toxicogenomic analysis identified tobacco smoking as the primary risk factor and cisplatin as the main drug chemical interacting with the maximum number of DEGs across populations. CONCLUSION This study provides new insights into population-specific differences in gene expression patterns and their associated pathways in ESCC. Our findings suggest that changes in extracellular matrix (ECM) organization may be crucial to the development and progression of this cancer, and that environmental and genetic factors play important roles in the disease. The novel DEGs identified may serve as potential biomarkers for diagnosis, prognosis and treatment.
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Grants
- 43- PRFA-P-8 the Deanship of Scientific Research, Princess Nourah bint Abdulrahman University, through the Program of Research Project Funding After Publication
- 43- PRFA-P-8 the Deanship of Scientific Research, Princess Nourah bint Abdulrahman University, through the Program of Research Project Funding After Publication
- 43- PRFA-P-8 the Deanship of Scientific Research, Princess Nourah bint Abdulrahman University, through the Program of Research Project Funding After Publication
- 43- PRFA-P-8 the Deanship of Scientific Research, Princess Nourah bint Abdulrahman University, through the Program of Research Project Funding After Publication
- 43- PRFA-P-8 the Deanship of Scientific Research, Princess Nourah bint Abdulrahman University, through the Program of Research Project Funding After Publication
- 43- PRFA-P-8 the Deanship of Scientific Research, Princess Nourah bint Abdulrahman University, through the Program of Research Project Funding After Publication
- 43- PRFA-P-8 the Deanship of Scientific Research, Princess Nourah bint Abdulrahman University, through the Program of Research Project Funding After Publication
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Affiliation(s)
- Amal Alotaibi
- Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | | | | | - Sumana Mandarthi
- Mbiomics LLC, 16192 Coastal Highway, Lewes, DE, 19958, USA
- Meta Biosciences Pvt Ltd, Manipal-GOK Bioincubator, Manipal, India
| | - Nidhi Jayendra
- Mbiomics LLC, 16192 Coastal Highway, Lewes, DE, 19958, USA
| | - Asna Tungekar
- Mbiomics LLC, 16192 Coastal Highway, Lewes, DE, 19958, USA
| | - B V Lavanya
- Mbiomics LLC, 16192 Coastal Highway, Lewes, DE, 19958, USA
| | - Ashok Kumar Bhagavath
- Department of Cellular and Molecular Biology, University of Texas Health Science Center, Tyler, TX, USA
| | - Mary Anne Wong Cordero
- Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Janne Pitkaniemi
- Finnish Cancer Registry, Unioninkatu 22, 00130, Helsinki, Finland
- Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Shaik Kalimulla Niazi
- Department of Preparatory Health Sciences, Riyadh Elm University, Riyadh, Saudi Arabia
| | - Raghavendra Upadhya
- Manipal Center for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal, India
| | - Asmatanzeem Bepari
- Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
| | - Prashantha Hebbar
- Mbiomics LLC, 16192 Coastal Highway, Lewes, DE, 19958, USA.
- Manipal Center for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal, India.
- Meta Biosciences Pvt Ltd, Manipal-GOK Bioincubator, Manipal, India.
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10
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Fong L, Huebner K, Jing R, Smalley K, Brydges C, Fiehn O, Farber J, Croce C. Zinc treatment reverses and anti-Zn-regulated miRs suppress esophageal carcinomas in vivo. Proc Natl Acad Sci U S A 2023; 120:e2220334120. [PMID: 37155893 PMCID: PMC10193985 DOI: 10.1073/pnas.2220334120] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 04/04/2023] [Indexed: 05/10/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB-controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% decrease in ESCC incidence vs. Zn-untreated controls. Zn treatment eliminated ESCCs by affecting a spectrum of biological processes that included downregulation of expression of the two miRs and miR-31-controlled inflammatory pathway, stimulation of miR-21-PDCD4 axis apoptosis, and reversal of the ESCC metabolome: with decrease in putrescine, increase in glucose, accompanied by downregulation of metabolite enzymes ODC and HK2. Thus, Zn treatment or miR-31/21 silencing are effective therapeutic strategies for ESCC in this rodent model and should be examined in the human counterpart exhibiting the same biological processes.
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Affiliation(s)
- Louise Y. Fong
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA19107
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA19107
| | - Kay Huebner
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH43210
| | - Ruiyan Jing
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA19107
| | - Karl J. Smalley
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA19107
| | - Christopher R. Brydges
- NIH West Coast Metabolomics Center, The Genome Center, University of California, Davis, CA95616
| | - Oliver Fiehn
- NIH West Coast Metabolomics Center, The Genome Center, University of California, Davis, CA95616
| | - John L. Farber
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA19107
| | - Carlo M. Croce
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH43210
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11
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Alotaibi A, Gadekar VP, Gundla PS, Mandarthi S, Ravi S, Mallya D, Tungekar A, Lavanya BV, Bhagavath AK, Cordero MW, Pitkaniemi J, Seetharam RN, Bepari A, Hebbar P. A comprehensive analysis of mRNA expression profiles of Esophageal Squamous Cell Carcinoma reveals downregulation of Desmoglein 1 and crucial genomic targets. Cancer Biomark 2023; 38:465-487. [PMID: 38073377 DOI: 10.3233/cbm-230145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2023]
Abstract
AIM Esophageal Squamous Cell Carcinoma (ESCC) is a histological subtype of esophageal cancer that begins in the squamous cells in the esophagus. In only 19% of the ESCC-diagnosed patients, a five-year survival rate has been seen. This necessitates the identification of high-confidence biomarkers for early diagnosis, prognosis, and potential therapeutic targets for the mitigation of ESCC. METHOD We performed a meta-analysis of 10 mRNA datasets and identified consistently perturbed genes across the studies. Then, integrated with ESCC ATLAS to segregate 'core' genes to identify consequences of primary gene perturbation events leading to gene-gene interactions and dysregulated molecular signaling pathways. Further, by integrating with toxicogenomics data, inferences were drawn for gene interaction with environmental exposures, trace elements, chemical carcinogens, and drug chemicals. We also deduce the clinical outcomes of candidate genes based on survival analysis using the ESCC related dataset in The Cancer Genome Atlas. RESULT We identified 237 known and 18 novel perturbed candidate genes. Desmoglein 1 (DSG1) is one such gene that we found significantly downregulated (Fold Change =-1.89, p-value = 8.2e-06) in ESCC across six different datasets. Further, we identified 31 'core' genes (that either harbor genetic variants or are regulated by epigenetic modifications) and found regulating key biological pathways via adjoining genes in gene-gene interaction networks. Functional enrichment analysis showed dysregulated biological processes and pathways including "Extracellular matrix", "Collagen trimmer" and "HPV infection" are significantly overrepresented in our candidate genes. Based on the toxicogenomic inferences from Comparative Toxicogenomics Database we report the key genes that interacted with risk factors such as tobacco smoking, zinc, nitroso benzylmethylamine, and drug chemicals such as cisplatin, Fluorouracil, and Mitomycin in relation to ESCC. We also point to the STC2 gene that shows a high risk for mortality in ESCC patients. CONCLUSION We identified novel perturbed genes in relation to ESCC and explored their interaction network. DSG1 is one such gene, its association with microbiota and a clinical presentation seen commonly with ESCC hints that it is a good candidate for early diagnostic marker. Besides, in this study we highlight candidate genes and their molecular connections to risk factors, biological pathways, drug chemicals, and the survival probability of ESCC patients.
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Affiliation(s)
- Amal Alotaibi
- Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
- Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Veerendra P Gadekar
- Mbiomics LLC, Lewes DE, USA
- Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | | | | | | | | | | | | | - Ashok Kumar Bhagavath
- Department of Cellular and Molecular Biology, University of Texas Health Science Center, Tyler, Texas, TX, USA
| | - MaryAnne Wong Cordero
- Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Janne Pitkaniemi
- Finnish Cancer Registry, Helsinki, Finland
- Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Raviraja N Seetharam
- Manipal Center for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal, India
| | - Asmatanzeem Bepari
- Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Prashantha Hebbar
- Mbiomics LLC, Lewes DE, USA
- Manipal Center for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal, India
- Meta Biosciences Pvt Ltd., Manipal - GOK Bioincubator, Advanced Research Center, Manipal, India
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12
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Yang X, Tang Z, Li J, Jiang J. Esophagus cancer and essential trace elements. Front Public Health 2022; 10:1038153. [PMID: 36466456 PMCID: PMC9709130 DOI: 10.3389/fpubh.2022.1038153] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Numerous epidemiological and laboratory studies on essential trace elements have reported protective associations in developing various cancer types, including esophagus cancer (EC). However, the results are not always consistent. Some essential trace elements could play a vital role in preventing esophagus cancer. Some showed no association with esophageal cancer risk, while others harmed individuals. This article reviews the association between the intake or supplementation of essential trace elements (especially zinc, copper, iron, and selenium) and the risk of esophageal cancer. Generally, zinc intake may decrease the risk of esophageal cancer (EC), especially in high esophageal squamous cell carcinoma (ESCC) prevalence regions. The association between copper supplementation and EC remains uncertain. Total iron consumption is thought to be associated with lower EC risk, while heme iron intake may be associated with higher EC risk. Selenium intake showed a protective effect against EC, especially for those individuals with a low baseline selenium level. This review also prospects the research direction of the association between EC and essential trace elements.
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Affiliation(s)
- Xin Yang
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhe Tang
- Department of Thoracic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Li
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jizong Jiang
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Jizong Jiang
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13
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Renteria M, Belkin O, Aickareth J, Jang D, Hawwar M, Zhang J. Zinc's Association with the CmPn/CmP Signaling Network in Breast Cancer Tumorigenesis. Biomolecules 2022; 12:1672. [PMID: 36421686 PMCID: PMC9687477 DOI: 10.3390/biom12111672] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/05/2022] [Accepted: 11/09/2022] [Indexed: 08/24/2023] Open
Abstract
It is well-known that serum and cellular concentrations of zinc are altered in breast cancer patients. Specifically, there are notable zinc hyper-aggregates in breast tumor cells when compared to normal mammary epithelial cells. However, the mechanisms responsible for zinc accumulation and the consequences of zinc dysregulation are poorly understood. In this review, we detailed cellular zinc regulation/dysregulation under the influence of varying levels of sex steroids and breast cancer tumorigenesis to try to better understand the intricate relationship between these factors based on our current understanding of the CmPn/CmP signaling network. We also made some efforts to propose a relationship between zinc signaling and the CmPn/CmP signaling network.
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Affiliation(s)
| | | | | | | | | | - Jun Zhang
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
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14
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Zhang J, Wang G, Huang A, Cao K, Tan W, Geng H, Lin X, Zhan F, Wu K, Zheng S, Liu C. Association between Serum Level of Multiple Trace Elements and Esophageal Squamous Cell Carcinoma Risk: A Case-Control Study in China. Cancers (Basel) 2022; 14:4239. [PMID: 36077776 PMCID: PMC9455051 DOI: 10.3390/cancers14174239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/21/2022] [Accepted: 08/29/2022] [Indexed: 02/07/2023] Open
Abstract
We investigated the associations between multiple serum trace element levels and risk for esophageal squamous cell carcinoma (ESCC). A total of 185 ESCC patients and 191 healthy individuals were recruited in our study. The concentration of 13 trace elements (Al, V, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Sr, Cd and Pb) in serum was determined with inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression and the Probit extension of Bayesian Kernel Machine Regression (BKMR) models was established to explore the associations and the cumulative and mixed effects of multiple trace elements on ESCC. Three elements (Zn, Se and Sr) displayed a negative trend with risk for ESCC, and a significant overall effect of the mixture of Al, V, Mn, Ni, Zn, Se and Sr on ESCC was found, with the effects of V, Ni and Sr being nonlinear. Bivariate exposure-response interactions among these trace elements indicated a synergistic effect between Zn and Se, and an impactful difference of V combined with Ni, Sr or Zn. Our results indicate that Ni, V, Al, Mn, Zn, Se and Sr are associated with ESCC risk, providing additional evidence of the complex effects of trace elements disorder during the etiology of EC development.
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Affiliation(s)
- Jingbing Zhang
- Department of Preventive Medicine, Shantou University Medical College, Shantou 515041, China
| | - Geng Wang
- Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou 515041, China
| | - Anyan Huang
- Mental Health Center, Shantou University Medical College, Shantou 515065, China
| | - Kexin Cao
- Department of Preventive Medicine, Shantou University Medical College, Shantou 515041, China
| | - Wei Tan
- Department of Preventive Medicine, Shantou University Medical College, Shantou 515041, China
| | - Hui Geng
- Department of Preventive Medicine, Shantou University Medical College, Shantou 515041, China
| | - Xiaosheng Lin
- Health Management Center, The People’s Hospital of Jieyang, Jieyang 522000, China
| | - Fulan Zhan
- Department of Ultrasound, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Kusheng Wu
- Department of Preventive Medicine, Shantou University Medical College, Shantou 515041, China
| | - Shukai Zheng
- Department of Burns and Plastic Surgery, and Cleft Lip and Palate Treatment Center, Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Caixia Liu
- Department of Preventive Medicine, Shantou University Medical College, Shantou 515041, China
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15
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Cheng Y, Chen H. Aberrance of Zinc Metalloenzymes-Induced Human Diseases and Its Potential Mechanisms. Nutrients 2021; 13:nu13124456. [PMID: 34960004 PMCID: PMC8707169 DOI: 10.3390/nu13124456] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/06/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
Zinc, an essential micronutrient in the human body, is a component in over 300 enzymes and participates in regulating enzymatic activity. Zinc metalloenzymes play a crucial role in physiological processes including antioxidant, anti-inflammatory, and immune responses, as well as apoptosis. Aberrant enzyme activity can lead to various human diseases. In this review, we summarize zinc homeostasis, the roles of zinc in zinc metalloenzymes, the physiological processes of zinc metalloenzymes, and aberrant zinc metalloenzymes in human diseases. In addition, potential mechanisms of action are also discussed. This comprehensive understanding of the mechanisms of action of the regulatory functions of zinc in enzyme activity could inform novel zinc-micronutrient-supply strategies for the treatment of diseases.
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Affiliation(s)
- Yunqi Cheng
- Queen Mary School, Medical College, Nanchang University, Nanchang 330006, China;
- Department of Histology and Embryology, Medical College, Nanchang University, Nanchang 330006, China
| | - Hongping Chen
- Department of Histology and Embryology, Medical College, Nanchang University, Nanchang 330006, China
- Correspondence:
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16
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Microarray Analysis of the Chemoprophylaxis Effect of Zinc Gluconate: Inspiring but Caution Required. Dig Dis Sci 2021; 66:4570-4571. [PMID: 34655013 DOI: 10.1007/s10620-021-07238-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/21/2021] [Indexed: 12/09/2022]
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17
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Chen Y, Liu FX, Liu H. Effects of dietary zinc deficiency on esophageal squamous cell proliferation and the mechanisms involved. World J Gastrointest Oncol 2021; 13:1755-1765. [PMID: 34853648 PMCID: PMC8603456 DOI: 10.4251/wjgo.v13.i11.1755] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/30/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Dietary zinc deficiency has been shown to be associated with the development of esophageal cancer in humans, but the exact mechanism of action is not known
AIM To observe the effects of dietary zinc deficiency on esophageal squamous cell proliferation.
METHODS Thirty C57BL/6 mice were randomly divided into three groups: A zinc-sufficient (ZS) group, zinc-deficient (ZD) group, and zinc-replenished (ZR) group. For weeks 1–10, zinc levels in the mice diets were 30.66–30.89 mg/kg in the ZS group and 0.66–0.89 mg/kg in the ZD and ZR groups. During weeks 10–12, the ZR group was switched to the ZS diet; the other two groups had no changes in their diets. Changes in body weight, serum, and esophageal tissue zinc concentrations were assessed as well as differences in the expression of proliferating cell nuclear antigen (PCNA), mitogen-activated protein kinase p38 (p38MAPK), nuclear factor kappa B (NF-κB) p105, NF-κB p65, and cyclooxygenase (COX)-2 proteins in the esophageal mucosa.
RESULTS The body weight and zinc concentration in the serum and esophageal mucosa were significantly lower in the ZD and ZR groups than in the ZS group (P < 0.05). In ZD mice, there was a marked proliferation of basal cells in the esophageal mucosa, resulting in a disturbance in the arrangement of basal cells in layers 2–4, a thickening of the squamous layer, and a significant increase in the expression of the above-mentioned five proteins involved in proliferation and inflammation in the esophageal mucosa. Two weeks after switching to the ZS diet, the serum zinc concentration in the ZR group increased, and the expression of PCNA, NF-κB p105, and COX-2 decreased, but the concentration of zinc in the esophageal mucosa and the structure of the esophageal mucosa did not display any significant changes
CONCLUSION The ZD diet decreased the growth rate and promoted the proliferation of esophageal squamous cells in mice. The mechanism of proliferation was related to the induced overexpression of COX-2, P38, PCNA, and NF-κB (p105 and p65), and the ZR diet reduced the expression of PCNA, NF-κB p105, and COX-2, thereby reversing this process.
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Affiliation(s)
- Yao Chen
- Department of Traditional Chinese Medicine, Peking University International Hospital, Beijing 102206, China
| | - Fang-Xun Liu
- International Medical Center, Peking University International Hospital, Beijing 102206, China
| | - Hong Liu
- Department of Gastroenterology, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, China
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18
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Lan T, Xue X, Dunmall LC, Miao J, Wang Y. Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers. Aging (Albany NY) 2021; 13:12273-12293. [PMID: 33903283 PMCID: PMC8109069 DOI: 10.18632/aging.202934] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 03/23/2021] [Indexed: 04/15/2023]
Abstract
Esophageal cancer (EC) represents a human malignancy, diagnosed often at the advanced stage of cancer and resulting in high morbidity and mortality. The development of precision medicine allows for the identification of more personalized therapeutic strategies to improve cancer treatment. By implanting primary cancer tissues into immunodeficient mice for expansion, patient-derived xenograft (PDX) models largely maintain similar histological and genetic representations naturally found in patients' tumor cells. PDX models of EC (EC-PDX) provide fine platforms to investigate the tumor microenvironment, tumor genomic heterogeneity, and tumor response to chemoradiotherapy, which are necessary for new drug discovery to combat EC in addition to optimization of current therapeutic strategies for EC. In this review, we summarize the methods used for establishing EC-PDX models and investigate the utilities of EC-PDX in screening predictive biomarkers and potential therapeutic targets. The challenge of this promising research tool is also discussed.
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Affiliation(s)
- Tianfeng Lan
- Sino-British Research Center for Molecular Oncology, National Center for the International Research in Cell and Gene Therapy, School of Basic Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China
| | - Xia Xue
- Sino-British Research Center for Molecular Oncology, National Center for the International Research in Cell and Gene Therapy, School of Basic Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China
- The Academy of Medical Science, Precision Medicine Center of the Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Henan, P.R. China
| | - Louisa Chard Dunmall
- Centre for Cancer Biomarkers and Biotherapeuitcs, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Jinxin Miao
- Sino-British Research Center for Molecular Oncology, National Center for the International Research in Cell and Gene Therapy, School of Basic Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China
- Academy of Chinese Medicine Science, Henan University of Chinese Medicine, Zhengzhou, Henan, P.R. China
| | - Yaohe Wang
- Sino-British Research Center for Molecular Oncology, National Center for the International Research in Cell and Gene Therapy, School of Basic Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China
- Centre for Cancer Biomarkers and Biotherapeuitcs, Barts Cancer Institute, Queen Mary University of London, London, UK
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19
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Celecoxib alleviates zinc deficiency-promoted colon tumorigenesis through suppressing inflammation. Aging (Albany NY) 2021; 13:8320-8334. [PMID: 33686969 PMCID: PMC8034938 DOI: 10.18632/aging.202642] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 12/09/2020] [Indexed: 01/26/2023]
Abstract
Accumulating evidence has shown that dietary zinc deficiency (ZD) increases the risk of various cancers including esophageal and gastric cancer. However, the role of ZD in colon tumorigenesis is unknown and the related mechanisms need to be investigated. Apcmin/+ mice, widely used to mimic the spontaneous process of human intestinal tumor, were used to construct a ZD mice model in this study. Inflammatory mediators such as COX-2, TNF-α, CCL, CXCL, and IL chemokines families were evaluated using real-time PCR and Enzyme-linked immunosorbent assay (ELISA). Besides, the immunoreactivities of cyclin D1, PCNA, and COX-2 in the colon were detected by immunohistochemistry. We found that zinc deficiency could promote colon tumorigenesis in Apcmin/+ mice. The mechanisms are involved in the upregulation of inflammatory mediators: COX-2, TNF-α, CCL, CXCL, and IL chemokines families. Administration of celecoxib, a selective COX-2 inhibitor, decreased colon tumorigenesis in Apcmin/+ mice via inhibiting the inflammatory mediators. ZD plays an important role in the process of colon cancers of Apcmin/+ mice. Celecoxib attenuates ZD-induced colon tumorigenesis in Apcmin/+ mice by inhibiting the inflammatory mediators. Our novel finding would provide potential prevention of colorectal tumor-induced by ZD.
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20
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Zhang Y, Tian Y, Zhang H, Xu B, Chen H. Potential pathways of zinc deficiency-promoted tumorigenesis. Biomed Pharmacother 2020; 133:110983. [PMID: 33190036 DOI: 10.1016/j.biopha.2020.110983] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/21/2020] [Accepted: 11/03/2020] [Indexed: 12/11/2022] Open
Abstract
Zinc (Zn) is the second most abundant necessary trace element in the human body. It is reported that zinc deficiency (ZD) promotes many types of cancer progression through multiple signal pathways. It is well known that oxidative stress, DNA damage, DNA repair, cell cycle, cell apoptosis, metabolic alterations, microRNAs abnormal expression, and inflammation level are closely related to cancer development. Cumulative evidence suggests that ZD influences these biological functions. This review explores the latest advances in understanding the role of ZD in tumorigenesis. Fully comprehending the potential mechanisms of ZD-induced tumors may provide novel clues for prevention and clinical treatment of cancers.
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Affiliation(s)
- Yuting Zhang
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Yuyang Tian
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi, 330006, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Haowen Zhang
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi, 330006, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Baohua Xu
- Department of Experimental Animals, Medical College of Nanchang University, Nanchang, Jiangxi, 330006, PR China; Jiangxi Key Laboratory of Experimental Animals, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Hongping Chen
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi, 330006, PR China; Jiangxi Key Laboratory of Experimental Animals, Nanchang University, Nanchang, Jiangxi, 330006, PR China.
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21
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Natural Agents Targeting Mitochondria in Cancer. Int J Mol Sci 2020; 21:ijms21196992. [PMID: 32977472 PMCID: PMC7582837 DOI: 10.3390/ijms21196992] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 02/07/2023] Open
Abstract
Mitochondria are the key energy provider to highly proliferating cancer cells, and are subsequently considered one of the critical targets in cancer therapeutics. Several compounds have been studied for their mitochondria-targeting ability in cancer cells. These studies’ outcomes have led to the invention of “mitocans”, a category of drug known to precisely target the cancer cells’ mitochondria. Based upon their mode of action, mitocans have been divided into eight classes. To date, different synthetic compounds have been suggested to be potential mitocans, but unfortunately, they are observed to exert adverse effects. Many studies have been published justifying the medicinal significance of large numbers of natural agents for their mitochondria-targeting ability and anticancer activities with minimal or no side effects. However, these natural agents have never been critically analyzed for their mitochondria-targeting activity. This review aims to evaluate the various natural agents affecting mitochondria and categorize them in different classes. Henceforth, our study may further support the potential mitocan behavior of various natural agents and highlight their significance in formulating novel potential anticancer therapeutics.
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22
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Fong LY, Taccioli C, Palamarchuk A, Tagliazucchi GM, Jing R, Smalley KJ, Fan S, Altemus J, Fiehn O, Huebner K, Farber JL, Croce CM. Abrogation of esophageal carcinoma development in miR-31 knockout rats. Proc Natl Acad Sci U S A 2020; 117:6075-6085. [PMID: 32123074 PMCID: PMC7084137 DOI: 10.1073/pnas.1920333117] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 × 10-6). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB-controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31-associated EGLN3/NF-κB-controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31-/- rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development.
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Affiliation(s)
- Louise Y Fong
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107;
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Cristian Taccioli
- Department of Animal Medicine, Production and Health, University of Padova, 35020 Legnaro (PD), Italy
| | - Alexey Palamarchuk
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
| | | | - Ruiyan Jing
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Karl J Smalley
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Sili Fan
- NIH West Coast Metabolomics Center, UC Davis Genome Center, University of California, Davis, CA 95616
| | - Joseph Altemus
- Office of Animal Resources, Thomas Jefferson University, Philadelphia, PA 19107
| | - Oliver Fiehn
- NIH West Coast Metabolomics Center, UC Davis Genome Center, University of California, Davis, CA 95616
| | - Kay Huebner
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
| | - John L Farber
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107
| | - Carlo M Croce
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;
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Wang J, Zhao H, Xu Z, Cheng X. Zinc dysregulation in cancers and its potential as a therapeutic target. Cancer Biol Med 2020; 17:612-625. [PMID: 32944394 PMCID: PMC7476080 DOI: 10.20892/j.issn.2095-3941.2020.0106] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022] Open
Abstract
Zinc is an essential element and serves as a structural or catalytic component in many proteins. Two families of transporters are involved in maintaining cellular zinc homeostasis: the ZIP (SLC39A) family that facilitates zinc influx into the cytoplasm, and the ZnT (SLC30A) family that facilitates zinc efflux from the cytoplasm. Zinc dyshomeostasis caused by the dysfunction of zinc transporters can contribute to the initiation or progression of various cancers, including prostate cancer, breast cancer, and pancreatic cancer. In addition, intracellular zinc fluctuations lead to the disturbance of certain signaling pathways involved in the malignant properties of cancer cells. This review briefly summarizes our current understanding of zinc dyshomeostasis in cancer, and discusses the potential roles of zinc or zinc transporters in cancer therapy.
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Affiliation(s)
- Jie Wang
- Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China
| | - Huanhuan Zhao
- Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China
| | - Zhelong Xu
- Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China
| | - Xinxin Cheng
- Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China
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24
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Wang KL, Chen XL, Lei L, Li P, Hong LL, Huang XC, Mao WM, Mukaisho K, Ling ZQ. Validation study of susceptibility loci for esophageal squamous cell carcinoma identified by GWAS in a Han Chinese subgroup from Eastern China. J Cancer 2019; 10:3624-3631. [PMID: 31333779 PMCID: PMC6636302 DOI: 10.7150/jca.32810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 05/04/2019] [Indexed: 11/05/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) occurs at a relatively high frequency in China and is one of the most prevalent cancers in the world. Genome-wide association studies (GWAS) have identified 24 single-nucleotide polymorphisms (SNPs) that could be associated with ESCC in Chinese patients. This retrospective study aimed to validate the association between these 24 SNPs and ESCC in a Han Chinese subgroup from East China. A total of 2280 and 1900 patients with ESCC (case group) and non-esophageal cancer (control group) were included from a single center. Genotyping of the 24 polymorphisms was performed using the Sequenom MassARRAY system. Unconditional logistic regression analyses were conducted for every polymorphism. It was found that rs12188136 (P=0.027, OR=1.158, 95% CI=1.016-1.319 for AG/AA) was associated with ESCC. Binary logistic regression analyses revealed a significant negative association of rs875339 in RORA (P=0.014, OR=0.762, 95% CI=0.613-0.947 for TT/CC). Under the dominant model, rs6854472 was slightly associated with ESCC risk (P=0.048, OR=1.192, 95% CI=1.002-1.418). Under the recessive model, a significant negative association was observed for rs875339 (P=0.010, OR=0.758, 95% CI=0.615-0.935). In a word, this large-scale replication study validated that rs12188136 and rs6854472 are associated with ESCC in a Han Chinese subgroup from Eastern China, and that rs875339 is negative associated with ESCC.
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Affiliation(s)
- Kai-Lai Wang
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Xiang-Liu Chen
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Lan Lei
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Pei Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Lian-Lian Hong
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Xian-Chong Huang
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China
| | - Wei-Min Mao
- Department of Thoracic Tumor Surgery, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China.,Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Hangzhou 310022, China
| | - Kenichi Mukaisho
- Department of Pathology, Division of Molecular Diagnostic Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Zhi-Qiang Ling
- Zhejiang Cancer Institute, Zhejiang Cancer Hospital, No.1 Banshan East Rd., Gongshu District, Hangzhou 310022, P.R.China.,Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Hangzhou 310022, China
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25
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He G, Zhu H, Yao Y, Chai H, Wang Y, Zhao W, Fu S, Wang Y. Cysteine-rich intestinal protein 1 silencing alleviates the migration and invasive capability enhancement induced by excessive zinc supplementation in colorectal cancer cells. Am J Transl Res 2019; 11:3578-3588. [PMID: 31312368 PMCID: PMC6614615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 05/05/2019] [Indexed: 06/10/2023]
Abstract
Cysteine-rich intestinal protein 1 (CRIP1) is overexpressed in colorectal cancer (CRC) tissues and functions as an oncogene in regulating the migration and invasion of CRC cells. However, the underlying mechanism is unclear. CRIP1 has a role in zinc absorption and functions as an intracellular zinc transport protein. Here, we aimed to focus on the function of zinc and its underlying mechanism in CRC and determine whether CRIP1 promotes invasion and CRC metastasis through excessive zinc-induced epithelial-mesenchymal transition (EMT) by affecting the phosphorylated glycogen synthase kinase (GSK)-3beta. The results showed that ZnSO4 (Zn2+) supplementation in medium increased the labile intracellular zinc content. Furthermore, excessive Zn2+ supplementation activated the GSK3/mTOR signaling pathway in both SW620 and LoVo cells, and excessive Zn2+ supplementation promoted migration, invasion, and EMT of SW620 and LoVo cells. This migration promotion was alleviated by the specific mTOR inhibitor rapamycin, indicating that the GSK3/mTOR signaling pathway was involved in this process. CRIP1 silencing increased the labile intracellular zinc content and inhibited EMT and GSK3/mTOR signaling pathway. CRIP1 silencing alleviated the zinc supplementation effects on migration, invasion, EMT, and GSK3/mTOR signaling pathway. In conclusion, excessive Zn2+ promotes migration and invasion capabilities of SW620 and LoVo cells through GSK3/mTOR signaling pathway-induced EMT.
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Affiliation(s)
- Guoyang He
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
- Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Southern Medical UniversityGuangzhou 510000, Guangdong Province, China
| | - Huifang Zhu
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Yakun Yao
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Huanran Chai
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Yongqiang Wang
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Wenli Zhao
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Suzhen Fu
- The First Affiliated Hospital of Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
| | - Yongxia Wang
- Department of Pathology, Xinxiang Medical UniversityXinxiang 453000, Henan Province, China
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26
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Bai Y, Wang G, Fu W, Lu Y, Wei W, Chen W, Wu X, Meng H, Feng Y, Liu Y, Li G, Wang S, Wang K, Dai J, Li H, Li M, Huang J, Li Y, Wei S, Yuan J, Yao P, Miao X, He M, Zhang X, Yang H, Wu T, Guo H. Circulating essential metals and lung cancer: Risk assessment and potential molecular effects. ENVIRONMENT INTERNATIONAL 2019; 127:685-693. [PMID: 30991224 DOI: 10.1016/j.envint.2019.04.021] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 04/03/2019] [Accepted: 04/08/2019] [Indexed: 06/09/2023]
Abstract
OBJECTIVE Essential metals play important roles in the carcinogenic process. However, seldom longitudinal investigations have evaluated their roles in lung cancer development. We aimed to investigate the associations between multiple essential metals and lung cancer incidence and to explore the potential mechanisms. METHODS A nested case-control study of 440 incident lung cancer cases and 1:3 frequency matched 1320 healthy controls from the Dongfeng-Tongji Cohort was conducted. The baseline plasma concentrations of 11 essential metals (cobalt, copper, iron, manganese, molybdenum, rubidium, selenium, strontium, stannum, vanadium, and zinc) were measured, and their associations with lung cancer incidence were estimated. Effect of positive metal (zinc) on 4-year telomere attrition was then evaluated among an occupational cohort of 724 workers. We also assessed the transcriptional regulation effects of plasma zinc on mRNA expression profiles, and the expressions of zinc-related genes were further compared in pair-wised lung tumor and normal tissues. RESULTS Elevated plasma level of zinc was associated with lower incident risk of lung cancer [OR (95% CI) = 0.89 (0.79, 0.99)] and decreased 4-year telomere attrition [β (95% CI) = -0.73 (-1.27, -0.19)]. These effects were pronounced among males. In particularly, zinc could regulate the expressions of 8 cancer-related genes, including SOD1, APE, TP53BP1, WDR33, LAPTM4B, TRIT1, HUWE1, and ZNF813, which were over-expressed in lung tumor tissues. CONCLUSIONS We propose that high plasma zinc could prevent incident lung cancer, probably by slowing down telomere attrition and regulating the expressions of cancer-related genes. These results provided a new insight into lung cancer prevention.
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Affiliation(s)
- Yansen Bai
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gege Wang
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenshan Fu
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanjun Lu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
| | - Wei Wei
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weilin Chen
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiulong Wu
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Meng
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yue Feng
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhang Liu
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guyanan Li
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suhan Wang
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ke Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juanxiu Dai
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hang Li
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengying Li
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiao Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yangkai Li
- Department of Thoracic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng Wei
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Yuan
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Yao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Miao
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meian He
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaomin Zhang
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Handong Yang
- Department of Cardiovascular Disease, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, China
| | - Tangchun Wu
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Guo
- Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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27
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Olaiya DO, Alatise OI, Oketayo OO, Abiye OE, Obianjunwa EI, Balogun FA. Trace Element Analysis of Cancerous and Non-cancerous Breast Tissues of African Women in Southwest Nigeria Using Particle-Induced X-ray Emission Technique. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2019; 13:1178223419840694. [PMID: 31037030 PMCID: PMC6475852 DOI: 10.1177/1178223419840694] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 02/14/2019] [Indexed: 11/21/2022]
Abstract
In this study, we applied particle-induced X-ray emission (PIXE) spectroscopy to investigate the levels of trace elements in breast tissues and whole blood (cancerous and non-cancerous) of selected African women in Ile-Ife, Southwest Nigeria. Freeze-dried and homogenized specimens obtained through mastectomy from clinically diagnosed patients were made into 11-mm-diameter pellets. The pellets were irradiated with 2.5 MeV proton beam energy from a 1.7 MV 5SDH Tandem accelerator. The PIXE analytical system was calibrated with certified reference matrices of Bovine Liver and Animal Blood: NIST 1577a and IAEA-A-13, respectively. A total of 23 elements: Na, K, Ca, Cl, S, Al, P, Si, Zn, Pb, Br, Rb, Zr, Se, Sr, Mn, V, Ti, Cu, Fe, Ni, Cr, and Mg were detected. The results indicated that the levels were within 0.9-5288 and 0.6-2320 ppm in breast tissues and 0.3-17228 and 2.0-2475 ppm in the whole blood of cancerous and non-cancerous subjects, respectively. At the .05 level of significance, significant differences exist between these levels in the cancerous and non-cancerous breast tissues (t = 0.008) as well as the whole blood (t = 0.041). The results gave the baseline concentration of the observed trace elements in the normal and malignant subjects and indicated PIXE as a powerful tool for such investigation.
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Affiliation(s)
- David O Olaiya
- Department of Physics and Engineering Physics, Obafemi Awolowo University, Ile Ife, Nigeria
| | - Olusegun I Alatise
- General Surgery Department, Obafemi Awolowo University Teaching Hospital Complex (OAUTHC), Ile Ife, Nigeria
| | | | - Olawale E Abiye
- Center for Energy Research and Development, Obafemi Awolowo University, Ile Ife, Nigeria
| | - Eusebius I Obianjunwa
- Center for Energy Research and Development, Obafemi Awolowo University, Ile Ife, Nigeria
| | - Fatai A Balogun
- Center for Energy Research and Development, Obafemi Awolowo University, Ile Ife, Nigeria
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Pan F, Chen Y, He JZ, Long L, Chen Y, Luo HJ, Xu YW, Pang XX, Yang Q, Wang JJ, Xu XE, Wang SH, Li EM, Xu LY. Dietary riboflavin deficiency promotes N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats by inducing chronic inflammation. Am J Cancer Res 2019; 9:2469-2481. [PMID: 31815047 PMCID: PMC6895446 DOI: pmid/31815047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 10/18/2019] [Indexed: 02/05/2023] Open
Abstract
Epidemiological studies in high-incidence areas of esophageal cancer in China suggest that environmental carcinogen N-nitrosomethylbenzylamine (NMBA) and riboflavin (RBF) deficiency may be the main risk factors for esophageal cancer. However, it is not clear that the combination induces cancer. Here, experiment (Exp) 1 evaluated the effects of NMBA and RBF deficiency individually or in combination on esophageal tumorigenesis. Male F344 rats were randomly assigned to 4 groups into a 2 (no NMBA vs. NMBA) × 2 (normal RBF vs. RBF-deficient) factorial design, including normal RBF (6 mg/kg, R6), RBF-deficient (0 mg/kg, R0), normal RBF combined with NMBA (R6N), and RBF-deficient combined with NMBA (R0N) groups. The Exp 2 explored the effects of RBF deficiency at different doses combined with NMBA (0.6 mg/kg, R0.6N; 0.06 mg/kg, R0.06N) on esophageal tumorigenesis. Results showed that R0N enhanced the incidence of esophageal intraepithelial neoplasia (EIN, 53.3%, P = 0.06), including carcinoma in situ, whereas R6N mainly induced the occurrence of esophageal benign hyperplasia (38.9%) and EIN (16.7%). RBF deficiency promotes EIN in a dose-dependent manner, and R0.06N significantly increases the incidence of EIN (57.9%, P < 0.05). Gene expression profiling demonstrated that inflammatory cytokines were highly expressed in R0N EIN tissues, whereas R6N EIN tissues had a proliferation and differentiation gene signature (fold-change > 1.5). Furthermore, RBF deficiency aggravated oxidative DNA damage (8-OHdG) and double-strand breaks (γH2AX) (P < 0.05). Our results suggest that RBF deficiency causes chronic inflammation-associated genomic instability contributes to NMBA-induced esophageal tumorigenesis.
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Affiliation(s)
- Feng Pan
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Department of Biochemistry and Molecular Biology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Ye Chen
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Institute of Oncologic Pathology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Jian-Zhong He
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Institute of Oncologic Pathology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Lin Long
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Department of Biochemistry and Molecular Biology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Yang Chen
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Department of Biochemistry and Molecular Biology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Hong-Jun Luo
- Bioanalytical Laboratory, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Yi-Wei Xu
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical CollegeShantou 515041, Guangdong, China
| | - Xiao-Xiao Pang
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Institute of Oncologic Pathology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Qian Yang
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Institute of Oncologic Pathology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Juan-Juan Wang
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Institute of Oncologic Pathology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Xiu-E Xu
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Institute of Oncologic Pathology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Shao-Hong Wang
- Department of Pathology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen UniversityShantou 515041, Guangdong, China
| | - En-Min Li
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Department of Biochemistry and Molecular Biology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
| | - Li-Yan Xu
- Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Medical College of Shantou UniversityShantou 515041, Guangdong, China
- Institute of Oncologic Pathology, Medical College of Shantou UniversityShantou 515041, Guangdong, China
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Chetwood JD, Garg P, Finch P, Gordon M. Systematic review: the etiology of esophageal squamous cell carcinoma in low-income settings. Expert Rev Gastroenterol Hepatol 2019; 13:71-88. [PMID: 30791842 DOI: 10.1080/17474124.2019.1543024] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Esophageal carcinoma causes over 380 000 deaths per year, ranking sixth worldwide in mortality amongst all malignancies. Globally, the squamous cell subtype is most common and accounts for 80% of esophageal cancers. Nonetheless, esophageal squamous cell carcinoma is much more poorly understood than esophageal adenocarcinoma, including what is driving such high prevalences, why it often presents in young patients, and shows such marked geographical delineations Areas covered: The current literature was searched for articles focusing on aetiopathogenesis of squamous cell esophageal carcinoma via a systematic review, particularly in low-resource settings. This was supplemented by papers of interest known to the authors. Expert commentary: Current putative mechanisms include polycyclic aromatic hydrocarbons, nitrosamines, acetaldehyde, cyclo-oxygenase-2 pathways, androgen and their receptor levels, as well as smoking & alcohol, micronutrient deficiencies and diet, mycotoxins, thermal damage, oral hygiene and microbiotal factors, inhaled smoke, viral infections such as HPV, and chronic irritative states. Etiology is likely multifactorial and varies geographically. Though smoking and alcohol play a predominant role in high-income settings, there is strong evidence that mycotoxins, diet and temperature effects may play an under-recognized role in low and middle-income settings.
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Affiliation(s)
- John David Chetwood
- a Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi
| | - Priya Garg
- a Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi
| | | | - Melita Gordon
- a Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi.,b College of Medicine , Blantyre , Malawi.,c Institute of Infection and Global Health , University of Liverpool , Liverpool , UK
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30
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Pan P, Dombkowski AA, Wang LS, Stoner GD. A nutrigenetic approach for investigating the chemopreventive effects of black raspberries during the development of preneoplastic esophagi in rats. JOURNAL OF BERRY RESEARCH 2018; 8:263-274. [PMID: 30613310 PMCID: PMC6319902 DOI: 10.3233/jbr-180346] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
BACKGROUND Large epidemiological studies have shown that diets high in fruits reduce the risk of esophageal squamous cell carcinoma (ESCC). OBJECTIVE The current study investigated the effects of black raspberries (BRBs) on gene expression during the development of preneoplastic esophagi in rats. METHODS Using a post-initiation protocol, F344 rats were injected with N-nitrosomethylbenzylamine (NMBA) and then fed either a control diet or 5% BRBs. At weeks 9, 15, and 35, we euthanized subgroups of the rats and collected preneoplastic esophagi to isolate RNA samples for DNA microarray. RESULTS Along the development of NMBA-induced preneoplastic esophagi, NMBA injections led to differential expression of 1181 genes comparing to control rats, and dietary BRBs modulated 428 genes in esophagi from NMBA-treated rats. There are 137 common genes between 1181 and 428 gene sets, and BRBs significantly reversed the expression of 133 genes. These genes are associated with multiple gene oncology functions. BRBs induced an 8.8-fold gene enrichment on the pathway of inflammatory response and regulated 10 genes involved in this pathway. Among them, BRBs significantly reversed the expression of pro-inflammatory cytokines, such as CCL2, S100A8, and IL19. CONCLUSIONS BRBs exhibit strong anti-inflammatory effects against NMBA-induced rat esophageal tumorigenesis.
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Affiliation(s)
- Pan Pan
- Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Alan A. Dombkowski
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Li-Shu Wang
- Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Gary D. Stoner
- Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
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31
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Jin J, Guo T, Guo Y, Liu J, Qu F, He Y. Methylation‑associated silencing of miR‑128 promotes the development of esophageal cancer by targeting COX‑2 in areas with a high incidence of esophageal cancer. Int J Oncol 2018; 54:644-654. [PMID: 30535495 DOI: 10.3892/ijo.2018.4653] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/05/2018] [Indexed: 01/10/2023] Open
Abstract
Esophageal cancer is one of the most common cancer types in the world, with a widely varying incidence between different regions. Zinc deficiency (ZD) is very common in high‑risk areas for esophageal cancer. Dietary ZD is reported to be associated with esophageal squamous cell carcinoma (ESCC). In the current study, the effects of ZD on tumorigenesis and expression of inflammatory factors were investigated in mice. It was identified that a ZD diet advanced ESCC and increased the expression of cyclooxygenase‑2 (COX‑2) prior to the occurrence of ESCC in mice. ZD significantly enhanced DNA methyltransferase (DNMT) activity and increased the expression of DNMT1 and DNMT3B. Furthermore, the expression of miR‑128 was downregulated by methylation, and COX‑2, a direct target of miR‑128, was upregulated with the reduction in miR‑128. Upregulation of miR‑128 inhibited the cell cycle, proliferation and metastasis, and the expression of COX‑2, cyclin D1 and retinoblastoma protein (Rb). Furthermore, the relative expression level of miR‑128 was negatively associated with COX‑2 in ESCC tissues. Collectively, these findings indicate that methylation‑associated silencing of miR‑128 promotes the development of esophageal cancer through upregulation of the expression of cyclin D1 and Rb by targeting COX‑2 in ZD regions with a high incidence of esophageal cancer.
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Affiliation(s)
- Jing Jin
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Tiantian Guo
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yongdong Guo
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Jianghui Liu
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Feng Qu
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yutong He
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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32
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Doi H, Kuribayashi K, Kijima T. Utility of polaprezinc in reducing toxicities during radiotherapy: a literature review. Future Oncol 2018; 14:1977-1988. [PMID: 30074413 DOI: 10.2217/fon-2018-0021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 03/21/2018] [Indexed: 01/22/2023] Open
Abstract
Chemoradiotherapy is important for treating malignancies. However, radiation-induced toxicities develop as chemoradiotherapy-related complications. Various agents reduce or prevent toxicities, but there are no standard treatments. Polaprezinc (PZ), a chelating compound used for gastric ulcers, has antioxidant and free radical scavenging effects. Although few studies have evaluated PZ and radiation-induced normal tissue damage, several clinical studies have shown the efficacy of PZ for oral mucositis, esophagitis, proctitis and taste alterations during and after radiotherapy. Moreover, preclinical data support the clinical data, indicating good potential of testing PZ in future trials. However, as there are only few well-documented review articles on PZ use in cancer treatment, we conducted this literature review. PZ reduced several radiation-induced toxicities and improved the quality of life.
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Affiliation(s)
- Hiroshi Doi
- Department of Radiation Oncology, Meiwa Cancer Clinic, Nishinomiya, Hyogo, Japan
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
- Department of Radiation Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kozo Kuribayashi
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Takashi Kijima
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
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33
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Abstract
Cancer is a major cause of death. The diversity of cancer types and the propensity of cancers to acquire resistance to therapies, including new molecularly targeted and immune-based therapies, drives the search for new ways to understand cancer progression. The remodelling of calcium (Ca2+) signalling and the role of the Ca2+ signal in controlling key events in cancer cells such as proliferation, invasion and the acquisition of resistance to cell death pathways is well established. Most of the work defining such changes has focused on Ca2+ permeable Transient Receptor Potential (TRP) Channels and some voltage gated Ca2+ channels. However, the identification of ORAI channels, a little more than a decade ago, has added a new dimension to how a Ca2+ influx pathway can be remodelled in some cancers and also how calcium signalling could contribute to tumour progression. ORAI Ca2+ channels are now an exemplar for how changes in the expression of specific isoforms of a Ca2+ channel component can occur in cancer, and how such changes can vary between cancer types (e.g. breast cancer versus prostate cancer), and even subtypes (e.g. oestrogen receptor positive versus oestrogen receptor negative breast cancers). ORAI channels and store operated Ca2+ entry are also highlighting the diverse roles of Ca2+ influx pathways in events such as the growth and metastasis of cancers, the development of therapeutic resistance and the contribution of tumour microenvironmental factors in cancer progression. In this review we will highlight some of the studies that have provided evidence for the need to deepen our understanding of ORAI Ca2+ channels in cancer. Many of these studies have also suggested new ways on how we can exploit the role of ORAI channels in cancer relevant processes to develop or inform new therapeutic strategies.
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34
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Argyris PP, Slama ZM, Ross KF, Khammanivong A, Herzberg MC. Calprotectin and the Initiation and Progression of Head and Neck Cancer. J Dent Res 2018; 97:674-682. [PMID: 29443623 DOI: 10.1177/0022034518756330] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Calprotectin (S100A8/A9), a heterodimeric complex of calcium-binding proteins S100A8 and S100A9, is encoded by genes mapping to the chromosomal locus 1q21.3 of the epidermal differentiation complex. Whereas extracellular calprotectin shows proinflammatory and antimicrobial properties by signaling through RAGE and TLR4, intracytoplasmic S100A8/A9 appears to be important for cellular development, maintenance, and survival. S100A8/A9 is constitutively expressed in myeloid cells and the stratified mucosal epithelia lining the oropharyngeal and genitourinary mucosae. While upregulated in adenocarcinomas and other cancers, calprotectin mRNA and protein levels decline in head and neck squamous cell carcinoma (HNSCC). S100A8/A9 is also lost during head and neck preneoplasia (dysplasia). Calprotectin decrease does not correlate with the clinical stage (TNM) of HNSCC. When expressed in carcinoma cells, S100A8/A9 downregulates matrix metalloproteinase 2 expression and inhibits invasion and migration in vitro. S100A8/A9 regulates cell cycle progression and decelerates cancer cell proliferation by arresting at the G2/M checkpoint in a protein phosphatase 2α-dependent manner. In HNSCC, S100A8 and S100A9 coregulate with gene networks controlling cellular development and differentiation, cell-to-cell signaling, and cell morphology, while S100A8/A9 appears to downregulate expression of invasion- and tumorigenesis-associated genes. Indeed, tumor formation capacity is attenuated in S100A8/A9-expressing carcinoma cells in vivo. Hence, intracellular calprotectin appears to function as a tumor suppressor in head and neck carcinogenesis. When compared with S100A8/A9-low HNSCC based on analysis of TCGA, S100A8/A9-high HNSCC shows significant upregulation of apoptosis-related genes, including multiple caspases. Accordingly, S100A8/A9 facilitates DNA damage responses in HNSCC, promotes apoptotic cell death, and confers sensitivity to cisplatin and X-radiation in vitro. In the tumor milieu, loss of S100A8/A9 strongly associates with poor squamous differentiation and higher tumor grading, EGFR upregulation, increased DNA methylation, and, finally, poorer overall survival for patients with HNSCC. Hence, intracellular calprotectin shows a multifaceted protective role against the development of HNSCC.
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Affiliation(s)
- P P Argyris
- 1 Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
| | - Z M Slama
- 1 Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
| | - K F Ross
- 1 Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
| | - A Khammanivong
- 2 Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN, USA.,3 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - M C Herzberg
- 1 Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
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35
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Fong LY, Taccioli C, Jing R, Smalley KJ, Alder H, Jiang Y, Fadda P, Farber JL, Croce CM. MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency. Oncotarget 2017; 7:10723-38. [PMID: 26918602 PMCID: PMC4905434 DOI: 10.18632/oncotarget.7561] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 02/08/2016] [Indexed: 12/21/2022] Open
Abstract
Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC), and marginal ZD is prevalent in humans. In rats, marked-ZD (3 mg Zn/kg diet) induces a proliferative esophagus with a 5-microRNA signature (miR-31, -223, -21, -146b, -146a) and promotes ESCC. Here we report that moderate and mild-ZD (6 and 12 mg Zn/kg diet) also induced esophageal hyperplasia, albeit less pronounced than induced by marked-ZD, with a 2-microRNA signature (miR-31, -146a). On exposure to an environmental carcinogen, ∼16% of moderate/mild-ZD rats developed ESCC, a cancer incidence significantly greater than for Zn-sufficient rats (0%) (P ≤ 0.05), but lower than marked-ZD rats (68%) (P < 0.001). Importantly, the high ESCC, marked-ZD esophagus had a 15-microRNA signature, resembling the human ESCC miRNAome, with miR-223, miR-21, and miR-31 as the top-up-regulated species. This signature discriminated it from the low ESCC, moderate/mild-ZD esophagus, with a 2-microRNA signature (miR-31, miR-223). Additionally, Fbxw7, Pdcd4, and Stk40 (tumor-suppressor targets of miR-223, -21, and -31) were downregulated in marked-ZD cohort. Bioinformatics analysis predicted functional relationships of the 3 tumor-suppressors with other cancer-related genes. Thus, microRNA dysregulation and ESCC progression depend on the extent of dietary Zn deficiency. Our findings suggest that even moderate ZD may promote esophageal cancer and dietary Zn has preventive properties against ESCC. Additionally, the deficiency-associated miR-223, miR-21, and miR-31 may be useful therapeutic targets in ESCC.
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Affiliation(s)
- Louise Y Fong
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Cristian Taccioli
- Animal Medicine, Production and Health Department, University of Padua, Padua, Italy
| | - Ruiyan Jing
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Karl J Smalley
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Hansjuerg Alder
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Yubao Jiang
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Paolo Fadda
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - John L Farber
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Carlo M Croce
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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36
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Fong LY, Jing R, Smalley KJ, Taccioli C, Fahrmann J, Barupal DK, Alder H, Farber JL, Fiehn O, Croce CM. Integration of metabolomics, transcriptomics, and microRNA expression profiling reveals a miR-143-HK2-glucose network underlying zinc-deficiency-associated esophageal neoplasia. Oncotarget 2017; 8:81910-81925. [PMID: 29137232 PMCID: PMC5669858 DOI: 10.18632/oncotarget.18434] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 05/29/2017] [Indexed: 01/01/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) in humans is a deadly disease associated with dietary zinc (Zn)-deficiency. In the rat esophagus, Zn-deficiency induces cell proliferation, alters mRNA and microRNA gene expression, and promotes ESCC. We investigated whether Zn-deficiency alters cell metabolism by evaluating metabolomic profiles of esophageal epithelia from Zn-deficient and replenished rats vs sufficient rats, using untargeted gas chromatography time-of-flight mass spectrometry (n = 8/group). The Zn-deficient proliferative esophagus exhibits a distinct metabolic profile with glucose down 153-fold and lactic acid up 1.7-fold (P < 0.0001), indicating aerobic glycolysis (the "Warburg effect"), a hallmark of cancer cells. Zn-replenishment rapidly increases glucose content, restores deregulated metabolites to control levels, and reverses the hyperplastic phenotype. Integration of metabolomics and our reported transcriptomic data for this tissue unveils a link between glucose down-regulation and overexpression of HK2, an enzyme that catalyzes the first step of glycolysis and is overexpressed in cancer cells. Searching our published microRNA profile, we find that the tumor-suppressor miR-143, a negative regulator of HK2, is down-regulated in Zn-deficient esophagus. Using in situ hybridization and immunohistochemical analysis, the inverse correlation between miR-143 down-regulation and HK2 overexpression is documented in hyperplastic Zn-deficient esophagus, archived ESCC-bearing Zn-deficient esophagus, and human ESCC tissues. Thus, to sustain uncontrolled cell proliferation, Zn-deficiency reprograms glucose metabolism by modulating expression of miR-143 and its target HK2. Our work provides new insight into critical roles of Zn in ESCC development and prevention.
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Affiliation(s)
- Louise Y. Fong
- Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
- Center for Molecular Carcinogenesis, Thomas Jefferson University, Philadelphia, PA, USA
| | - Ruiyan Jing
- Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Karl J. Smalley
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Cristian Taccioli
- Animal Medicine, Production and Health Department, University of Padua, Padua, Italy
| | - Johannes Fahrmann
- University of California, Davis, West Coast Metabolomics Center, Davis, CA, USA
| | - Dinesh K. Barupal
- University of California, Davis, West Coast Metabolomics Center, Davis, CA, USA
| | - Hansjuerg Alder
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - John L. Farber
- Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Oliver Fiehn
- University of California, Davis, West Coast Metabolomics Center, Davis, CA, USA
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Carlo M. Croce
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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37
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Choi S, Cui C, Luo Y, Kim SH, Ko JK, Huo X, Ma J, Fu LW, Souza RF, Korichneva I, Pan Z. Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1. FASEB J 2017; 32:404-416. [PMID: 28928244 DOI: 10.1096/fj.201700227rrr] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 09/05/2017] [Indexed: 12/15/2022]
Abstract
Zinc, an essential micronutrient, has a cancer preventive role. Zinc deficiency has been shown to contribute to the progression of esophageal cancer. Orai1, a store-operated Ca2+ entry (SOCE) channel, was previously reported to be highly expressed in tumor tissues removed from patients with esophageal squamous cell carcinoma (ESCC) with poor prognosis, and elevation of its expression contributes to both hyperactive intracellular Ca2+ oscillations and fast cell proliferation in human ESCC cells. However, the molecular basis of cancer preventive functions of zinc and its association with Orai1-mediated cell proliferation remains unknown. The present study shows that zinc supplementation significantly inhibits proliferation of ESCC cell lines and that the effect of zinc is reversible with N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine, a specific Zn2+ chelator, whereas nontumorigenic esophageal epithelial cells are significantly less sensitive to zinc treatment. Fluorescence live cell imaging revealed that extracellular Zn2+ exerted rapid inhibitory effects on Orai1-mediated SOCE and on intracellular Ca2+ oscillations in the ESCC cells. Knockdown of Orai1 or expression of Orai1 mutants with compromised zinc binding significantly diminished sensitivity of the cancer cells to zinc treatment in both SOCE and cell proliferation analyses. These data suggest that zinc may inhibit cell proliferation of esophageal cancer cells through Orai1-mediated intracellular Ca2+ oscillations and reveal a possible molecular basis for zinc-induced cancer prevention and Orai1-SOCE signaling pathway in cancer cells.-Choi, S., Cui, C., Luo, Y., Kim, S.-H., Ko, J.-K., Huo, X., Ma, J., Fu, L.-W., Souza, R. F., Korichneva, I., Pan, Z. Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1.
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Affiliation(s)
- Sangyong Choi
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, Texas, USA.,Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Chaochu Cui
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, Texas, USA.,Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yanhong Luo
- Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.,Department of Endocrinology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Sun-Hee Kim
- Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | | | - Xiaofang Huo
- Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott and White Research Institute, Dallas, Texas, USA
| | - Jianjie Ma
- Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.,Department of Surgery, Ohio State University Wexner Medical Center, Columbus, Ohio, USA; and
| | - Li-Wu Fu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Rhonda F Souza
- Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott and White Research Institute, Dallas, Texas, USA
| | - Irina Korichneva
- Department of Pharmacology, University of Picardie Jules Verne, Amiens, France
| | - Zui Pan
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, Texas, USA; .,Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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38
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Liu CM, Liang D, Jin J, Li DJ, Zhang YC, Gao ZY, He YT. Research progress on the relationship between zinc deficiency, related microRNAs, and esophageal carcinoma. Thorac Cancer 2017; 8:549-557. [PMID: 28892299 PMCID: PMC5668500 DOI: 10.1111/1759-7714.12493] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/20/2017] [Accepted: 07/21/2017] [Indexed: 01/06/2023] Open
Abstract
Esophageal cancer (EC) is a common malignant tumor of the gastrointestinal tract with a high incidence in China. Zinc (Zn) deficiency is a key risk factor for the occurrence and development of EC and affects progression by regulating microRNA (miRNA, miR) expression. In addition, the dysregulation of miRNAs is accompanied by the dysregulation of their target genes in EC. In this paper, we review the potential molecular mechanisms between Zn deficiency and EC with the aim of providing new strategies and methods for early diagnosis, targeted therapy, and prognostic evaluation.
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Affiliation(s)
- Cong-Min Liu
- Cancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, China
| | - Di Liang
- Cancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, China
| | - Jing Jin
- Cancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, China
| | - Dao-Juan Li
- Cancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, China
| | - Ya-Chen Zhang
- Cancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, China
| | - Zhao-Yu Gao
- Cancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, China
| | - Yu-Tong He
- Cancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, China
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39
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40
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Li Q, Jin J, Liu J, Wang L, He Y. Knockdown of Zinc Transporter ZIP5 by RNA Interference Inhibits Esophageal Cancer Growth In Vivo. Oncol Res 2017; 24:205-14. [PMID: 27458102 PMCID: PMC7838672 DOI: 10.3727/096504016x14648701447896] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
We recently found that SLC39A5 (ZIP5), a zinc transporter, is overexpressed in esophageal cancer. Downregulation of ZIP5 inhibited the proliferation, migration, and invasion of the esophageal cancer cell line KYSE170 in vitro. In this study, we found that downregulation of SLC39A5 (ZIP5) by interference resulted in a significant reduction in esophageal cancer tumor volume and weight in vivo. COX2 (cyclooxygenase 2) expression was decreased and E-cadherin expression was increased in the KYSE170K xenografts, which was caused by the downregulation of ZIP5. However, we did not find that the downregulation of ZIP5 caused a change in the relative expressions of cyclin D1, VEGF (vascular endothelial growth factor), MMP9 (matrix metalloprotein 9), and Bcl-2 (B-cell lymphoma/leukmia-2) mRNA or an alteration in the average level of zinc in the peripheral blood and xenografts in vivo. Collectively, these findings indicate that knocking down ZIP5 by small interfering RNA (siRNA) might be a novel treatment strategy for esophageal cancer with ZIP5 overexpression.
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Affiliation(s)
- Qian Li
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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41
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Xu YM, Gao YM, Wu DD, Yu FY, Zang ZS, Yang L, Yao Y, Cai NL, Zhou Y, Chiu JF, Ching YP, Lau ATY. Aberrant cytokine secretion and zinc uptake in chronic cadmium-exposed lung epithelial cells. Proteomics Clin Appl 2017; 11. [PMID: 27801555 DOI: 10.1002/prca.201600059] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 09/30/2016] [Accepted: 10/26/2016] [Indexed: 02/05/2023]
Abstract
PURPOSE Our previous results showed that cadmium (Cd)-adapted lung epithelial cells (LECs) developed resistance to apoptosis due to non-responsiveness of the c-Jun N-terminal kinase pathway and augmented expression of cytokeratin 8. Since cellular Cd entry is a prerequisite in order for Cd to elicit its cytotoxicity, therefore, we wonder if there are differential metal ion transport ability and also other phenotypic changes that occurred in these Cd-resistant LECs. EXPERIMENTAL DESIGN AND RESULTS Here, we explored further and found that the zinc (Zn) importer Zip8 was stably abolished in these cells along with a marked decrease of Cd and Zn accumulation. Moreover, by cell migration assays and cytokine antibody array analysis, we found that Cd-adapted cells exhibit enhanced migratory ability possibly due to elevated secretions of vascular endothelial growth factor and macrophage inflammatory protein-3 alpha (MIP-3α). CONCLUSION AND CLINICAL RELEVANCE Taken together, our results show that during chronic Cd exposure, lung cells antagonize excessive cellular Cd-influx by abolishing Zip8 expression to reduce Cd-toxicity; however, this also renders cells with a diminished Zn uptake. The imbalance of Zn homeostasis and elevation of angiogenic and epithelial-mesenchymal transition-promoting cytokines in Cd-adapted cells might thus likely promote Zn deficiency, angiogenesis, and cell invasion.
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Affiliation(s)
- Yan-Ming Xu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China
| | - Yang-Min Gao
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China
| | - Dan-Dan Wu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China
| | - Fei-Yuan Yu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China
| | - Zhong-Sheng Zang
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China
| | - Lei Yang
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China
| | - Yue Yao
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China
| | - Na-Li Cai
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China
| | - Yuan Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, P. R. China
| | - Jen-Fu Chiu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, P. R. China
| | - Yick-Pang Ching
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, P. R. China
| | - Andy T Y Lau
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, P. R. China
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Nasef NA, Mehta S, Ferguson LR. Susceptibility to chronic inflammation: an update. Arch Toxicol 2017; 91:1131-1141. [PMID: 28130581 DOI: 10.1007/s00204-016-1914-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 12/13/2016] [Indexed: 12/25/2022]
Abstract
Chronic inflammation is defined by the persistence of inflammatory processes beyond their physiological function, resulting in tissue destruction. Chronic inflammation is implicated in the progression of many chronic diseases and plays a central role in chronic inflammatory and autoimmune disease. As such, this review aims to collate some of the latest research in relation to genetic and environmental susceptibilities to chronic inflammation. In the genetic section, we discuss some of the updates in cytokine research and current treatments that are being developed. We also discuss newly identified canonical and non-canonical genes associated with chronic inflammation. In the environmental section, we highlight some of the latest updates and evidence in relation to the role that infection, diet and stress play in promoting inflammation. The aim of this review is to provide an overview of the latest research to build on our current understanding of chronic inflammation. It highlights the complexity associated with chronic inflammation, as well as provides insights into potential new targets for therapies that could be used to treat chronic inflammation and consequently prevent disease progression.
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Affiliation(s)
- Noha Ahmed Nasef
- Discipline of Nutrition and Dietetics, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Sunali Mehta
- Department of Pathology, University of Otago, Dunedin, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, Dunedin, New Zealand
| | - Lynnette R Ferguson
- Discipline of Nutrition and Dietetics, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
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Pan Z, Choi S, Ouadid-Ahidouch H, Yang JM, Beattie JH, Korichneva I. Zinc transporters and dysregulated channels in cancers. Front Biosci (Landmark Ed) 2017; 22:623-643. [PMID: 27814637 DOI: 10.2741/4507] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
As a nutritionally essential metal ion, zinc (Zn) not only constitutes a structural element for more than 3000 proteins but also plays important regulatory functions in cellular signal transduction. Zn homeostasis is tightly controlled by regulating the flux of Zn across cell membranes through specific transporters, i.e. ZnT and ZIP family proteins. Zn deficiency and malfunction of Zn transporters have been associated with many chronic diseases including cancer. However, the mechanisms underlying Zn regulatory functions in cellular signaling and their impact on the pathogenesis and progression of cancers remain largely unknown. In addition to these acknowledged multifunctions, Zn modulates a wide range of ion channels that in turn may also play an important role in cancer biology. The goal of this review is to propose how zinc deficiency, through modified Zn homeostasis, transporter activity and the putative regulatory function of Zn can influence ion channel activity, and thereby contribute to carcinogenesis and tumorigenesis. This review intends to stimulate interest in, and support for research into the understanding of Zn-modulated channels in cancers, and to search for novel biomarkers facilitating effective clinical stratification of high risk cancer patients as well as improved prevention and therapy in this emerging field.
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Affiliation(s)
- Zui Pan
- The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA,
| | - Sangyong Choi
- Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Halima Ouadid-Ahidouch
- University of Picardie Jules Verne, UFR Sciences, EA 4667, Laboratory of Cell and Molecular Physiology, SFR CAP-SANTE (FED 4231), Amiens, France
| | - Jin-Ming Yang
- Department of Pharmacology, College of Medicine, Penn State University, 500 University Drive Hershey, PA 17033, USA
| | - John H Beattie
- Rowett Institute of Nutrition and Health, University of Aberdeen, Foresterhill, Bucksburn, Aberdeen AB25 2ZD, Scotland, UK
| | - Irina Korichneva
- University of Picardie Jules Verne, UFR Sciences, EA 4667, Laboratory of Cell and Molecular Physiology, SFR CAP-SANTE (FED 4231), Amiens, France
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Romualdo GR, Goto RL, Henrique Fernandes AA, Cogliati B, Barbisan LF. Dietary zinc deficiency predisposes mice to the development of preneoplastic lesions in chemically-induced hepatocarcinogenesis. Food Chem Toxicol 2016; 96:280-9. [DOI: 10.1016/j.fct.2016.08.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 08/10/2016] [Accepted: 08/16/2016] [Indexed: 12/25/2022]
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45
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Nariman-Saleh-Fam Z, Bastami M, Somi MH, Samadi N, Abbaszadegan MR, Behjati F, Ghaedi H, Tavakkoly-Bazzaz J, Masotti A. In silico dissection of miRNA targetome polymorphisms and their role in regulating miRNA-mediated gene expression in esophageal cancer. Cell Biochem Biophys 2016; 74:483-497. [PMID: 27518186 DOI: 10.1007/s12013-016-0754-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 07/09/2016] [Indexed: 12/14/2022]
Abstract
Esophageal cancer is the eighth most common cancer worldwide. Also middle-aged obese adults with higher body mass index during childhood have a greater risk to develop esophageal cancer. The contribution of microRNAs to esophageal cancer has been extensively studied and it became clear that these noncoding RNAs may play crucial roles in pathogenesis, diagnosis and prognosis of the disease. Increasing evidences have suggested that polymorphisms perturbing microRNA targetome (i.e., the compendium of all microRNA target sites) are associated with cancers including esophageal cancer. However, the extent to which such variants contribute to esophageal cancer is still unclear. In this study, we applied an in silico approach to systematically identify polymorphisms perturbing microRNA targetome in esophageal cancer and performed various analyses to predict the functional consequences of the occurrence of these variants. The computational results were integrated to provide a prioritized list of the most potentially disrupting esophageal cancer-implicated microRNA targetome polymorphisms along with the in silico insight into the mechanisms with which such variations may modulate microRNA-mediated regulation. The results of this study will be valuable for future functional experiments aimed at dissecting the roles of microRNA targetome polymorphisms in the onset and progression of esophageal cancer.
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Affiliation(s)
- Ziba Nariman-Saleh-Fam
- Medical Genetics Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Milad Bastami
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Naser Samadi
- Faculty of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry and Medical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Abbaszadegan
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, 9196773117, Iran
| | - Farkhondeh Behjati
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Hamid Ghaedi
- Medical Genetics Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Javad Tavakkoly-Bazzaz
- Medical Genetics Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Andrea Masotti
- Bambino Gesù Children's Hospital-IRCCS, Gene Expression - Microarrays Laboratory, Viale di San Paolo 15, Rome, 00146, Italy.
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Lu Y, Shivappa N, Lin Y, Lagergren J, Hébert JR. Diet-related inflammation and oesophageal cancer by histological type: a nationwide case-control study in Sweden. Eur J Nutr 2016; 55:1683-1694. [PMID: 26189130 DOI: 10.1007/s00394-015-0987-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 07/03/2015] [Indexed: 12/29/2022]
Abstract
PURPOSE This project sought to test the role of diet-related inflammation in modulating the risk of oesophageal cancer. METHODS A nationwide population-based case-control study was conducted from 1 December 1994 through 31 December 1997 in Sweden. All newly diagnosed patients with adenocarcinoma of the oesophagus or gastroesophageal junction and a randomly selected half of patients with oesophageal squamous cell carcinoma were eligible as cases. Using the Swedish Registry of the Total Population, the control group was randomly selected from the entire Swedish population and frequency-matched on age (within 10 years) and sex. The literature-derived dietary inflammatory index (DII) was developed to describe the inflammatory potential of diet. DII scores were computed based on a food frequency questionnaire. Higher DII scores indicate more pro-inflammatory diets. Odds ratios and 95 % confidence intervals (CI) were computed to assess risk associated between DII scores and oesophageal cancer using logistic regression adjusted by potential confounders. RESULTS In total, 189 oesophageal adenocarcinomas, 262 gastroesophageal junctional adenocarcinomas, 167 oesophageal squamous cell carcinomas, and 820 control subjects were recruited into the study. Significant associations with DII were observed for oesophageal squamous cell carcinoma (ORQuartile4vs1 4.35, 95 % CI 2.24, 8.43), oesophageal adenocarcinoma (ORQuartile4vs1 3.59, 95 % CI 1.87, 6.89), and gastroesophageal junctional adenocarcinoma (ORQuartile4vs1 2.04, 95 % CI 1.24, 3.36). Significant trends across quartiles of DII were observed for all subtypes of oesophageal cancer. CONCLUSIONS Diet-related inflammation appears to be associated with an increased risk of oesophageal cancer, regardless of histological type.
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Affiliation(s)
- Yunxia Lu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden.
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
| | - Nitin Shivappa
- Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Yulan Lin
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden
- European Palliative Care Research Centre, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden
- Division of Cancer Studies, King's College London, London, UK
| | - James R Hébert
- Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
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47
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The tumor microenvironment in esophageal cancer. Oncogene 2016; 35:5337-5349. [PMID: 26923327 PMCID: PMC5003768 DOI: 10.1038/onc.2016.34] [Citation(s) in RCA: 238] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 01/15/2016] [Accepted: 01/21/2016] [Indexed: 02/08/2023]
Abstract
Esophageal cancer is a deadly disease, ranking sixth among all cancers in mortality. Despite incremental advances in diagnostics and therapeutics, esophageal cancer still carries a poor prognosis, and thus there remains a need to elucidate the molecular mechanisms underlying this disease. There is accumulating evidence that a comprehensive understanding of the molecular composition of esophageal cancer requires attention to not only tumor cells but also the tumor microenvironment, which contains diverse cell populations, signaling factors, and structural molecules that interact with tumor cells and support all stages of tumorigenesis. In esophageal cancer, environmental exposures can trigger chronic inflammation, which leads to constitutive activation of pro-inflammatory signaling pathways that promote survival and proliferation. Anti-tumor immunity is attenuated by cell populations such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), as well as immune checkpoints like programmed death-1 (PD-1). Other immune cells such as tumor-associated macrophages can have other pro-tumorigenic functions, including the induction of angiogenesis and tumor cell invasion. Cancer-associated fibroblasts secrete growth factors and alter the extracellular matrix (ECM) to create a tumor niche and enhance tumor cell migration and metastasis. Further study of how these TME components relate to the different stages of tumor progression in each esophageal cancer subtype will lead to development of novel and specific TME-targeting therapeutic strategies, which offer considerable potential especially in the setting of combination therapy.
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Pawar H, Srikanth SM, Kashyap MK, Sathe G, Chavan S, Singal M, Manju HC, Kumar KVV, Vijayakumar M, Sirdeshmukh R, Pandey A, Prasad TSK, Gowda H, Kumar RV. Downregulation of S100 Calcium Binding Protein A9 in Esophageal Squamous Cell Carcinoma. ScientificWorldJournal 2015; 2015:325721. [PMID: 26788548 PMCID: PMC4691646 DOI: 10.1155/2015/325721] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 11/16/2015] [Indexed: 02/07/2023] Open
Abstract
The development of esophageal squamous cell carcinoma (ESCC) is poorly understood and the major regulatory molecules involved in the process of tumorigenesis have not yet been identified. We had previously employed a quantitative proteomic approach to identify differentially expressed proteins in ESCC tumors. A total of 238 differentially expressed proteins were identified in that study including S100 calcium binding protein A9 (S100A9) as one of the major downregulated proteins. In the present study, we carried out immunohistochemical validation of S100A9 in a large cohort of ESCC patients to determine the expression and subcellular localization of S100A9 in tumors and adjacent normal esophageal epithelia. Downregulation of S100A9 was observed in 67% (n = 192) of 288 different ESCC tumors, with the most dramatic downregulation observed in the poorly differentiated tumors (99/111). Expression of S100A9 was restricted to the prickle and functional layers of normal esophageal mucosa and localized predominantly in the cytoplasm and nucleus whereas virtually no expression was observed in the tumor and stromal cells. This suggests the important role that S100A9 plays in maintaining the differentiated state of epithelium and suggests that its downregulation may be associated with increased susceptibility to tumor formation.
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Affiliation(s)
- Harsh Pawar
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
- Rajiv Gandhi University of Health Sciences, Bangalore 560041, India
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore 560029, India
- Department of Zoology, Savitribai Phule Pune University, Ganeshkhind, Pune, Maharashtra 411007, India
| | - Srinivas M. Srikanth
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
- Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry 605014, India
| | - Manoj Kumar Kashyap
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0960, USA
| | - Gajanan Sathe
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
| | - Sandip Chavan
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
| | - Mukul Singal
- Government Medical College and Hospital, Sector 32, Chandigarh 160030, India
| | - H. C. Manju
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore 560029, India
| | | | - M. Vijayakumar
- Department of Surgical Oncology, Kidwai Memorial Institute of Oncology, Bangalore 560029, India
| | - Ravi Sirdeshmukh
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
| | - Akhilesh Pandey
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - T. S. Keshava Prasad
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
- Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry 605014, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
| | - Rekha V. Kumar
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore 560029, India
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Peiffer DS, Wang LS, Zimmerman NP, Ransom BWS, Carmella SG, Kuo CT, Chen JH, Oshima K, Huang YW, Hecht SS, Stoner GD. Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer. Cancer Immunol Res 2015; 4:72-82. [PMID: 26603620 DOI: 10.1158/2326-6066.cir-15-0091] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 09/06/2015] [Indexed: 11/16/2022]
Abstract
Freeze-dried black raspberries (BRB), their component anthocyanins (AC), and a metabolite of BRB ACs, protocatechuic acid (PCA), inhibit the development of esophageal cancer in rats induced by the carcinogen, N-nitrosomethylbenzylamine (NMBA). All three components reduce inflammation in the esophagus and in plasma. The present study determined the relation of changes in inflammatory markers to infiltration of innate immune cells into NMBA-treated esophagus. Rats were injected with NMBA (0.35 mg/kg) for 5 weeks while on control diet. Following NMBA treatment, rats were fed diets containing 6.1% BRB powder, an AC-rich fraction of BRBs (3.8 μmol/g), or 500 ppm PCA. At weeks 15, 25, and 35, inflammatory biomarker expression in the plasma and esophagus was quantified, and infiltration of immune cells in the esophagus was examined. At all three time points, BRB, AC, and PCA similarly affected cytokine production in the esophagus and plasma of NMBA-treated rats, relative to the NMBA-only control. These included decreased expression of the proinflammatory cytokine IL1β and increased expression of the anti-inflammatory cytokine IL10. Moreover, all three diets also increased the expression of IL12, a cytokine that activates both cytolytic natural killer and CD8(+) T cells. In addition, the three diets also decreased infiltration of both macrophages and neutrophils into the esophagus. Overall, our results suggest that another mechanism by which BRBs, ACs, and PCA inhibit NMBA-induced esophageal tumorigenesis is by altering cytokine expression and innate immune cell trafficking into tumor tissues.
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Affiliation(s)
- Daniel S Peiffer
- Department of Medicine, Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin
| | - Li-Shu Wang
- Department of Medicine, Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin
| | | | | | - Steven G Carmella
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Chieh-Ti Kuo
- Department of Medicine, Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin
| | - Jo-Hsin Chen
- Department of Medicine, Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin
| | - Kiyoko Oshima
- Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Yi-Wen Huang
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Stephen S Hecht
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Gary D Stoner
- Department of Medicine, Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin.
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50
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Taccioli C, Garofalo M, Chen H, Jiang Y, Tagliazucchi GM, Di Leva G, Alder H, Fadda P, Middleton J, Smalley KJ, Selmi T, Naidu S, Farber JL, Croce CM, Fong LY. Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo. J Natl Cancer Inst 2015; 107:djv220. [PMID: 26286729 PMCID: PMC4675101 DOI: 10.1093/jnci/djv220] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 01/31/2015] [Accepted: 07/20/2015] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined. METHODS To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter assay. Cellular proliferation, apoptosis, and expression of inflammation genes were determined by immunoblotting, caspase assays, and immunohistochemistry. The miR-31 promoter in Zn-deficient esophagus was identified by ChIP-seq using an antibody for histone mark H3K4me3. Data were analyzed with t test and analysis of variance. All statistical tests were two-sided. RESULTS In vivo, anti-miR-31 reduced miR-31 overexpression (P = .002) and suppressed the esophageal preneoplasia in Zn-deficient rats. At the same time, the miR-31 target Stk40 was derepressed, thereby inhibiting the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis (caspase 3/7 activities, fold change = 10.7, P = .005). This same connection between miR-31 overexpression and STK40/NF-κΒ expression was also documented in human ESCC cell lines. In Zn-deficient esophagus, the miR-31 promoter region and NF-κΒ binding site were activated. Zn replenishment restored the regulation of this genomic region and a normal esophageal phenotype. CONCLUSIONS The data define the in vivo signaling pathway underlying interaction of Zn deficiency and miR-31 overexpression in esophageal neoplasia and provide a mechanistic rationale for miR-31 as a therapeutic target for ESCC.
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Affiliation(s)
- Cristian Taccioli
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Michela Garofalo
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Hongping Chen
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Yubao Jiang
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Guidantonio Malagoli Tagliazucchi
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Gianpiero Di Leva
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Hansjuerg Alder
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Paolo Fadda
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Justin Middleton
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Karl J Smalley
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Tommaso Selmi
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Srivatsava Naidu
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - John L Farber
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Carlo M Croce
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN)
| | - Louise Y Fong
- Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN).
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