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Hu Y, Cui M. Meta-analysis of the diagnostic value of SOX1 methylation in different types of cervical cancer. World J Surg Oncol 2025; 23:147. [PMID: 40259371 PMCID: PMC12013204 DOI: 10.1186/s12957-025-03790-6] [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: 11/04/2024] [Accepted: 03/29/2025] [Indexed: 04/23/2025] Open
Abstract
OBJECTIVE This meta-analysis evaluates the diagnostic value of SOX1 methylation across different cervical cancer types, including squamous cell carcinoma and adenocarcinoma, to assess its efficacy as a biomarker. METHODS We reviewed studies published up to March 2024, employing a PICOS-based search strategy in databases like PubMed and Web of Science. We included clinical studies providing diagnostic performance indicators while excluding non-clinical and small-sample studies. Meta-Disc1.4 and Stata15.1 were used for statistical analyses focusing on SOX1 methylation's sensitivity, specificity, and diagnostic odds ratio. RESULTS Twelve articles encompassing 18 studies with 3,213 subjects were analyzed. The overall DOR for SOX1 methylation in cervical cancer diagnosis was 68.95 (95%CI: 27.63-172.07), with a Summary Receiver Operating Characteristic AUC of 0.92, indicating high diagnostic accuracy. Specifically, the DOR for adenocarcinoma was 87.57 (95%CI: 7.05-1087.44) with an AUC of 0.89, and for squamous cell carcinoma, it was 245.87 (95% CI: 26.49-2282.40) with an AUC of 0.93, reflecting significant diagnostic potential for both cancer types. No substantial publication bias was detected (P > 0.10). CONCLUSION SOX1 gene methylation demonstrates significant diagnostic value for both adenocarcinoma and squamous cell carcinoma of the cervix, particularly effective in large sample sizes and cervical exfoliated cell samples for early detection and screening, supporting its utility as a reliable biomarker.
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Affiliation(s)
- Yanling Hu
- Department of Gynecology, Taiyuan Centre Hospital/The Ninth Clinical Medical College of Shanxi Medical University, Fendong Street, Xiaodian District, Taiyuan, 030032, Shanxi, China
| | - Min Cui
- Department of Gynecology, Taiyuan Centre Hospital/The Ninth Clinical Medical College of Shanxi Medical University, Fendong Street, Xiaodian District, Taiyuan, 030032, Shanxi, China.
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2
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Jasim SA, Farhan SH, Ahmad I, Hjazi A, Kumar A, Jawad MA, Pramanik A, Altalbawy MAF, Alsaadi SB, Abosaoda MK. A cutting-edge investigation of the multifaceted role of SOX family genes in cancer pathogenesis through the modulation of various signaling pathways. Funct Integr Genomics 2025; 25:6. [PMID: 39753912 DOI: 10.1007/s10142-024-01517-6] [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] [Received: 09/03/2024] [Revised: 11/20/2024] [Accepted: 12/27/2024] [Indexed: 01/14/2025]
Abstract
This detailed study examines the complex role of the SOX family in various tumorigenic contexts, offering insights into how these transcription factors function in cancer. As the study progresses, it explores the specific contributions of each SOX family member. The significant roles of the SOX family in the oncogenic environment are well-recognized, highlighting a range of regulatory mechanisms that influence tumor progression. In brain, lung, and colorectal cancers, SOX types like SOX2, SOX3, and SOX4 promote the migration, proliferation, and angiogenesis of cancer cells. Conversely, in pancreatic, gastric, and breast cancers, SOX types, including SOX1, SOX9, and SOX17 inhibit various cancer cell activities such as proliferation and invasion. This thorough investigation enhances our understanding of the SOX family's complex role in cancer, establishing a foundation for future research and potential therapeutic strategies targeting these versatile transcription factors.
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Affiliation(s)
- Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-maarif, Anbar, Iraq.
| | | | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Ashwani Kumar
- Department of Life Sciences, School of Sciences, Jain (Deemed-to-be) University, Bengaluru, Karnataka, 560069, India
- Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | | | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - M A Farag Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Salim B Alsaadi
- Department of Pharmaceutics, Al-Hadi University College, Baghdad, 10011, Iraq
| | - Munther Kadhim Abosaoda
- College of Pharmacy, The Islamic University, Najaf, Iraq
- College of Pharmacy, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Pharmacy, The Islamic University of Babylon, Al Diwaniyah, Iraq
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3
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Melnikov N, Pittala S, Shteinfer-Kuzmine A, Shoshan-Barmatz V. Mitochondrial VDAC1 Silencing in Urethane-Induced Lung Cancer Inhibits Tumor Growth and Alters Cancer Oncogenic Properties. Cancers (Basel) 2024; 16:2970. [PMID: 39272828 PMCID: PMC11393979 DOI: 10.3390/cancers16172970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 09/15/2024] Open
Abstract
Alterations in cellular metabolism are vital for cancer cell growth and motility. Here, we focused on metabolic reprogramming and changes in tumor hallmarks in lung cancer by silencing the expression of the mitochondrial gatekeeper VDAC1. To better mimic the clinical situation of lung cancer, we induced lung cancer in A/J mice using the carcinogen urethane and examined the effectiveness of si-m/hVDAC1-B encapsulated in PLGA-PEI nanoparticles. si-m/hVDAC1-B, given intravenously, induced metabolism reprogramming and inhibited tumor growth as monitored using MRI. Mice treated with non-targeted (NT) PLGA-PEI-si-NT showed many large size tumors in the lungs, while in PLGA-PEI-si-m/hVDAC-B-treated mice, lung tumor number and area were markedly decreased. Immunofluorescence staining showed decreased expression of VDAC1 and metabolism-related proteins and altered expression of cancer stem cell markers. Morphological analysis showed two types of tumors differing in their morphology; cell size and organization within the tumor. Based on specific markers, the two tumor types were identified as small cell (SCLC) and non-small cell (NSCLC) lung cancer. These two types of tumors were found only in control tumors, suggesting that PLGA-PEI-si-m/hVDAC1-B also targeted SCLC. Indeed, using a xenograft mouse model of human-derived SCLC H69 cells, si-m/hVDAC1-B inhibited tumor growth and reduced the expression of VDAC1 and energy- and metabolism-related enzymes, and of cancer stem cells in the established xenograft. Additionally, intravenous treatment of urethane-induced lung cancer mice with the VDAC1-based peptide, Retro-Tf-D-LP4, showed inhibition of tumor growth, and decreased expression levels of metabolism- and cancer stem cells-related proteins. Thus, silencing VDAC1 targeting both NSCLC and SCLC points to si-VDAC1 as a possible therapeutic tool to treat these lung cancer types. This is important as target NSCLC tumors undergo transformation to SCLC.
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Affiliation(s)
- Nataly Melnikov
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Srinivas Pittala
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Anna Shteinfer-Kuzmine
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Varda Shoshan-Barmatz
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
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Advance of SOX Transcription Factors in Hepatocellular Carcinoma: From Role, Tumor Immune Relevance to Targeted Therapy. Cancers (Basel) 2022; 14:cancers14051165. [PMID: 35267473 PMCID: PMC8909699 DOI: 10.3390/cancers14051165] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/12/2022] [Accepted: 02/18/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the deadliest human health burdens worldwide. However, the molecular mechanism of HCC development is still not fully understood. Sex determining region Y-related high-mobility group box (SOX) transcription factors not only play pivotal roles in cell fate decisions during development but also participate in the initiation and progression of cancer. Given the significance of SOX factors in cancer and their ‘undruggable’ properties, we summarize the role and molecular mechanism of SOX family members in HCC and the regulatory effect of SOX factors in the tumor immune microenvironment (TIME) of various cancers. For the first time, we analyze the association between the levels of SOX factors and that of immune components in HCC, providing clues to the pivotal role of SOX factors in the TIME of HCC. We also discuss the opportunities and challenges of targeting SOX factors for cancer. Abstract Sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) factors belong to an evolutionarily conserved family of transcription factors that play essential roles in cell fate decisions involving numerous developmental processes. In recent years, the significance of SOX factors in the initiation and progression of cancers has been gradually revealed, and they act as potential therapeutic targets for cancer. However, the research involving SOX factors is still preliminary, given that their effects in some leading-edge fields such as tumor immune microenvironment (TIME) remain obscure. More importantly, as a class of ‘undruggable’ molecules, targeting SOX factors still face considerable challenges in achieving clinical translation. Here, we mainly focus on the roles and regulatory mechanisms of SOX family members in hepatocellular carcinoma (HCC), one of the fatal human health burdens worldwide. We then detail the role of SOX members in remodeling TIME and analyze the association between SOX members and immune components in HCC for the first time. In addition, we emphasize several alternative strategies involved in the translational advances of SOX members in cancer. Finally, we discuss the alternative strategies of targeting SOX family for cancer and propose the opportunities and challenges they face based on the current accumulated studies and our understanding.
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Singh A, Gupta S, Sachan M. Evaluation of the Diagnostic Potential of Candidate Hypermethylated Genes in Epithelial Ovarian Cancer in North Indian Population. Front Mol Biosci 2021; 8:719056. [PMID: 34778370 PMCID: PMC8581490 DOI: 10.3389/fmolb.2021.719056] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/12/2021] [Indexed: 01/22/2023] Open
Abstract
Most ovarian cancers, despite improvement in management of cancer, are still diagnosed at an advanced stage. Early detection plays an essential role in reducing ovarian cancer mortality and, therefore, is critically needed. Liquid biopsies-based approaches hold significant promise for cancer detection. The present study investigates a panel of epigenetic biomarkers for the detection of epithelial ovarian cancer. A qPCR assay has been developed based on the assessment of DNA methylation markers in circulating cell-free DNA as a minimally invasive tool. Herein, the promoter methylation of seven ovarian cancer-specific genes (RASSF1A, DAPK1, SOX1, HOXA9, HIC1, SPARC, and SFRP1) was analyzed quantitatively in 120 tissue samples by MethyLight assay. The best-performing genes were further evaluated for their methylation status in 70 matched serum cell-free DNA of cancerous and non-cancerous samples. Additionally, DNA methylation patterns of these best-performing genes were validated by clonal bisulfite sequencing. The ROC (Receiver-operator characteristic) curves were constructed to evaluate the diagnostic performances of both individual and combined gene panels. The seven candidate genes displayed a methylation frequency of 61.0-88.0% in tissue samples. The promoter methylation frequencies for all the seven candidate genes were significantly higher in cancer samples than in normal matched controls. In tissue samples, the multiplex MethyLight assay for HOXA9, HIC1, and SOX1 were the best performing gene panels in terms of sensitivity and specificity. The three best-performing genes exhibited individual frequencies of 53.0-71.0% in serum CFDNA, and the multiplex assay for these genes were identified to discriminate serum from cancer patients and healthy individuals (area under the curve: HOXA9+HIC1 = 0.95, HIC1+SOX1 = 0.93 and HOXA9+SOX1 = 0.85). The results of MethyLight showed high concordance with clonal bisulfite sequencing results. Individual genes and combined panel exhibited better discriminatory efficiencies to identify ovarian cancer at various stages of disease when analyzed in tissue and serum cell-free DNA. We report a qPCR-based non-invasive epigenetic biomarker assay with high sensitivity and specificity for OC screening. Our findings also reveal the potential utility of methylation-based detection of circulating cell-free tumor DNA in the clinical management of ovarian cancer.
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Affiliation(s)
- Alka Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
| | - Sameer Gupta
- Department of Surgical Oncology, King George Medical University, Lucknow, India
| | - Manisha Sachan
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
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Gong W, Martin TA, Sanders AJ, Jiang A, Sun P, Jiang WG. Location, function and role of stromal cell‑derived factors and possible implications in cancer (Review). Int J Mol Med 2021; 47:435-443. [PMID: 33416125 PMCID: PMC7797432 DOI: 10.3892/ijmm.2020.4811] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/29/2020] [Indexed: 01/07/2023] Open
Abstract
Despite improvements in therapy and management, cancer represents and remains a major cause of mortality and morbidity worldwide. Although genetics serve an important role in tumorigenesis and tumour progression, the tumour microenvironment (TME) in solid tumours is also important and has been indicated to contribute to these processes. Stromal cell‑derived factors (SDFs) represent an important family within the TME. The family includes SDF‑1, SDF‑2, SDF2‑like 1 (SDF2L1), SDF‑3, SDF‑4 and SDF‑5. SDF‑1 has been demonstrated to act as a positive regulator in a number of types of tumour, such as oesophago‑gastric, pancreatic, lung, breast, colorectal and ovarian cancer, while the biology and functions of other members of the SDF family, including SDF‑2, SDF2L1, SDF‑4 and SDF‑5, in cancer are different, complex and controversial, and remain mainly unknown. Full identification and understanding of the SDFs across multiple types of cancer is required to elucidate their function and establish potential key targets in cancer.
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Affiliation(s)
- Wenjing Gong
- Department of Oncology, Yantai Yuhuangding Hospital, Medical College, Qingdao University, Yantai, Shandong 264000, P.R. China,Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
| | - Tracey A. Martin
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
| | - Andrew J. Sanders
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
| | - Aihua Jiang
- Department of Anaesthesiology, Yantai Yuhuangding Hospital, Medical College, Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Ping Sun
- Department of Oncology, Yantai Yuhuangding Hospital, Medical College, Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Wen G. Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff CF14 4XN, UK,Correspondence to: Professor Wen G. Jiang, Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Henry Wellcome Building, Cardiff CF14 4XN, UK, E-mail:
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7
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Singh A, Gupta S, Badarukhiya JA, Sachan M. Detection of aberrant methylation of HOXA9 and HIC1 through multiplex MethyLight assay in serum DNA for the early detection of epithelial ovarian cancer. Int J Cancer 2020; 147:1740-1752. [PMID: 32191343 DOI: 10.1002/ijc.32984] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 02/22/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023]
Abstract
Accumulated evidence revealed that aberrant CpG island hypermethylation plays an important role in carcinogenesis which can serve as a promising target for molecular detection in body fluids. Despite a myriad of attempts to diagnose ovarian cancer (OC) at an early stage, this clinical aim remains a major challenge. To date, no single biomarker is able to accurately detect early OC in either tissue or body fluid. Aberrant DNA methylation patterns in circulating DNA provide highly specific cancer signals. In our study, we establish a novel panel of methylation-specific genes for the development of a TaqMan based qPCR assay to quantify methylation levels. We analyzed promoter methylation of homeobox A9 (HOXA9) and hypermethylated in cancer 1 (HIC1) quantitatively in 120 tissue samples and in 70 matched serum cell-free DNA (CFDNA) of cancerous and noncancerous samples by MethyLight assay. HOXA9 and HIC1 methylation occurred in 82.3 and 80.0% of OC tissue samples in singleplex assay, thereby confirming that methylation was highly cancer-specific. When either or both gene promoter showed methylation, the sensitivity was 88.2% with a specificity of 88.6% in tissue samples. The combined sensitivity for this novel marker panel in serum CFDNA was 88.9% (area under the curve [AUC] = 0.95). In contrast, no hypermethylation was observed in serum from matched cancer-free control women. Our results confirm the elevated performance of novel epigenetic marker panel (HOXA9 and HIC1) when analyzed in tissue and matched serum samples. Our findings reveal the potential of this biomarker panel as a suitable diagnostic serum biomarker for early screening of OC.
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Affiliation(s)
- Alka Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
| | - Sameer Gupta
- Department of Surgical Oncology, King George Medical University, Lucknow, India
| | | | - Manisha Sachan
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
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8
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A Novel Prognostic DNA Methylation Panel for Colorectal Cancer. Int J Mol Sci 2019; 20:ijms20194672. [PMID: 31547144 PMCID: PMC6801964 DOI: 10.3390/ijms20194672] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers and the second leading cause of cancer-related deaths. Discrepancies in clinical outcomes are observed even among patients with same-stage CRC due to molecular heterogeneity. Thus, biomarkers for predicting prognosis in CRC patients are urgently needed. We previously demonstrated that stage II CRC patients with NKX6.1 methylation had poor 5-year overall survival. However, the methylation frequency of NKX6.1 was only 23% in 151 pairs of CRC tissues. Thus, we aimed to develop a more robust prognostic panel for CRC using NKX6.1 in combination with three genes: LIM homeobox transcription factor 1α (LMX1A), sex-determining region Y-box 1 (SOX1), and zinc finger protein 177 (ZNF177). Through quantitative methylation analysis, we found that LMX1A, SOX1, and ZNF177 were hypermethylated in CRC tissues. LMX1A methylation was significantly associated with poor 5-year overall, and disease-free survivals in stage I and II CRC patients. Sensitivity and specificity analyses of the four-gene combination revealed the best sensitivity and optimal specificity. Moreover, patients with the four-gene methylation profile exhibited poorer disease-free survival than those without methylation. A significant effect of the four-gene methylation status on overall survival and disease-free survival was observed in early stage I and II CRC patients (p = 0.0016 and p = 0.0230, respectively). Taken together, these results demonstrate that the combination of the methylation statuses of NKX6.1, LMX1A, SOX1, and ZNF177 creates a novel prognostic panel that could be considered a molecular marker for outcomes in CRC patients.
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Abstract
The present study is to analyze the difference of gene methylation in early cervical adenocarcinoma and to find molecular markers for predicting the occurrence and development of cervical adenocarcinoma.A total of 15 cases of primary cervical adenocarcinoma and 10 cases of primary cervical squamous cell carcinoma at stages IB1 or IIA1 were included in the study. Infinium MethylationEPIC BeadChip (850K) was used to screen specifically expressed genes in cervical adenocarcinoma tissues. Bisulfite sequencing polymerase chain reaction (BSP) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to verify the methylation levels in cervical adenocarcinoma, cervical squamous cell carcinoma, and normal cervical tissues.Sex determining region Y-box 1 (SOX1) and cyclin D1 (CCND1) genes participated in multiple signaling pathways, being the central nodes of gene regulatory networks. SOX1 gene, but not CCND1 gene, was a specifically methylated gene in cervical adenocarcinoma according to BSP. According to qRT-PCR, methylation level of SOX1 in cervical adenocarcinoma tissues is significantly different from that in cervical squamous cell carcinoma tissues or normal cervical tissues, and the methylation level of CCND1 in cervical adenocarcinoma tissues or cervical squamous cell carcinoma tissues is significantly different from that in normal cervical tissues.The present study demonstrates that tumor-suppressor gene SOX1 is a methylation-specific expression gene of cervical adenocarcinoma and is expected to become a specific molecular marker for the diagnosis of cervical adenocarcinoma. However, CCND1 gene was not proven to be a specific methylation expression gene in cervical adenocarcinoma in the present study.
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10
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Chang SY, Kuo CC, Wu CC, Hsiao CW, Hu JM, Hsu CH, Chou YC, Shih YL, Lin YW. NKX6.1 hypermethylation predicts the outcome of stage II colorectal cancer patients undergoing chemotherapy. Genes Chromosomes Cancer 2018; 57:268-277. [PMID: 29363224 DOI: 10.1002/gcc.22529] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 01/19/2018] [Accepted: 01/19/2018] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a common malignancy worldwide. CRC patients in the same stage often present with dramatically different clinical scenarios. Thus, robust prognostic biomarkers are urgently needed to guide therapies and improve treatment outcomes. The NKX6.1 gene has been identified as a hypermethylation marker in cervical cancer, functioning as a metastasis suppressor by regulating epithelial-mesenchymal transition. Here, we investigated whether hypermethylation of NKX6.1 might be a prognostic biomarker for CRC. By analyzing the methylation and expression of NKX6.1 in CRC tissues and CRC cell lines. We quantitatively examined the NKX6.1 methylation levels in 151 pairs of CRC tissues by using methylation-specific polymerase chain reaction analysis and found that NKX6.1 was hypermethylated in 35 of 151 CRC tissues (23%). NKX6.1 gene expression was inversely correlated with the DNA methylation level in CRC cell lines in vitro. Then, we analyzed the association of NKX6.1 methylation with clinical characteristics of these CRC patients. Our data demonstrated that patients with NKX6.1 methylation presented poorer 5-year overall survival (P = 0.0167) and disease-free survival (P = 0.0083) than patients without NKX6.1 methylation after receiving adjuvant chemotherapy. Most importantly, these data revealed that stage II CRC patients with NKX6.1 methylation had poorer 5-year disease-free survival (P = 0.0322) than patients without NKX6.1 methylation after adjuvant chemotherapy. Our results demonstrate that methylation of NKX6.1 is a novel prognostic biomarker in CRC and that it may be used as a predictor of the response to chemotherapy.
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Affiliation(s)
- Sou-Yi Chang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Hematology & Oncology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Taipei, Taiwan, Republic of China
| | - Chih-Chi Kuo
- Teaching and Research Office, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Chang-Chieh Wu
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Cheng-Wen Hsiao
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Je-Ming Hu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Chih-Hsiung Hsu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.,School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Yu-Lueng Shih
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Ya-Wen Lin
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.,Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China
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Detection of promoter methylation status of suppressor of cytokine signaling 3 (SOCS3) in tissue and plasma from Chinese patients with different hepatic diseases. Clin Exp Med 2017; 18:79-87. [DOI: 10.1007/s10238-017-0473-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 09/07/2017] [Indexed: 12/19/2022]
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12
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Liu Y, Zhou Q, Zhou D, Huang C, Meng X, Li J. Secreted frizzled-related protein 2-mediated cancer events: Friend or foe? Pharmacol Rep 2017; 69:403-408. [PMID: 28273499 DOI: 10.1016/j.pharep.2017.01.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 12/22/2016] [Accepted: 01/09/2017] [Indexed: 01/04/2023]
Abstract
Secreted frizzled-related protein (SFRP)2, an identified member of the SFRPs family of molecules, is often methylated in human cancers and its down-regulation is closely related to Wnt signaling activity and tumor progression. Although the blocker of the Wnt signaling has not been fully used in clinical trial, interest has been further enhanced by the realization of SFRPs' potential as targets to modulate Wnt signaling and cancer cell growth. Emerging evidence showed that SFRP2 was an anti-oncogene, however, a steady flow of research has indicated that it may also have tumor promotion effects in some cancer types. Furthermore, SFRP2 methylation was shown to accelerate cancer cell invasion and growth in tumor progression. In this review, we define recent understanding of the diverse roles of SFRP2 in tumorigenesis, and it might promote the development of novel drugs for curing cancer by targeting SFRP2.
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Affiliation(s)
- Yanhui Liu
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Anhui Institute of Innovative Drugs, Hefei 230032, China
| | - Qun Zhou
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Anhui Institute of Innovative Drugs, Hefei 230032, China
| | - Dexi Zhou
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Anhui Institute of Innovative Drugs, Hefei 230032, China
| | - Cheng Huang
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Anhui Institute of Innovative Drugs, Hefei 230032, China
| | - Xiaoming Meng
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Anhui Institute of Innovative Drugs, Hefei 230032, China
| | - Jun Li
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; Anhui Institute of Innovative Drugs, Hefei 230032, China.
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Zhang H, Yu C, Chen M, Li Z, Tian S, Jiang J, Sun C. miR-522 contributes to cell proliferation of hepatocellular carcinoma by targeting DKK1 and SFRP2. Tumour Biol 2016; 37:11321-9. [PMID: 26960688 DOI: 10.1007/s13277-016-4995-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 02/25/2016] [Indexed: 01/23/2023] Open
Abstract
The morbidity and mortality of hepatocellular carcinoma (HCC) is very high, finding new therapeutic targets are critical for HCC treatment. miR-522 has been demonstrated to be upregulated in HCC tissues, but its role in HCC progression remains to be elucidated. In this report, we found miR-522 was upregulated in HCC cells and tissues, miR-522 overexpression promoted cell proliferation, colony formation, and cell cycle progression, whereas knockdown of miR-522 reduced these effects. We also analyzed the expression of several key cell cycle regulatory proteins and found overexpression of miR-522-inhibited cell cycle inhibitors p21 and p27 expression and enhanced cyclin D1 expression and the level of Rb phosphorylation, vice versa. These suggested miR-522-accelerated G1/S transition. DKK1 (dickkopf-1) and SFRP2 (secreted frizzled-related protein 2) were the targets of miR-522, their expression was inversely with miR-522 in HCC tissues. DKK1 and SFRP2 the antagonists of Wnt signaling, suggesting miR-522-promoted HCC progression through activating Wnt signaling. miR-522 might be a valuable target for HCC therapy.
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Affiliation(s)
- Hao Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, 28 Guiyi Street, Yunyan District, Guiyang, 550004, Guizhou, China
| | - Chao Yu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, 28 Guiyi Street, Yunyan District, Guiyang, 550004, Guizhou, China
| | - Meiyuan Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, 28 Guiyi Street, Yunyan District, Guiyang, 550004, Guizhou, China
| | - Zhu Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, 28 Guiyi Street, Yunyan District, Guiyang, 550004, Guizhou, China
| | - Se Tian
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, 28 Guiyi Street, Yunyan District, Guiyang, 550004, Guizhou, China
| | - Jianxin Jiang
- Department of Hepatic-Biliary-Pancreatic Surgery, Hubei Cancer Hospital, 116 Zhuodaoquan south road, Hongshan district, Wuhan, 430079, Hubei, People's Republic of China.
| | - Chengyi Sun
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, 28 Guiyi Street, Yunyan District, Guiyang, 550004, Guizhou, China.
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WU YOUTU, LIU CHUNHUI, YU SHENGYUAN, GAO HUA, LI ZHENYE, LI CHUZHONG, ZHANG YAZHUO. Assessment of sFRP4 as a bio-marker for predicting aggressiveness and recurrence of growth hormone-secreting pituitary adenomas. Oncol Rep 2016; 35:2991-9. [DOI: 10.3892/or.2016.4650] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Accepted: 01/06/2016] [Indexed: 11/05/2022] Open
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Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs. Cell Res 2016; 26:171-89. [PMID: 26809499 DOI: 10.1038/cr.2016.15] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 11/20/2015] [Accepted: 11/24/2015] [Indexed: 12/15/2022] Open
Abstract
SOX2 is a key regulator of multiple types of stem cells, especially embryonic stem cells (ESCs) and neural progenitor cells (NPCs). Understanding the mechanism underlying the function of SOX2 is of great importance for realizing the full potential of ESCs and NPCs. Here, through genome-wide comparative studies, we show that SOX2 executes its distinct functions in human ESCs (hESCs) and hESC-derived NPCs (hNPCs) through cell type- and stage-dependent transcription programs. Importantly, SOX2 suppresses non-neural lineages in hESCs and regulates neurogenesis from hNPCs by inhibiting canonical Wnt signaling. In hESCs, SOX2 achieves such inhibition by direct transcriptional regulation of important Wnt signaling modulators, WLS and SFRP2. Moreover, SOX2 ensures pluripotent epigenetic landscapes via interacting with histone variant H2A.Z and recruiting polycomb repressor complex 2 to poise developmental genes in hESCs. Together, our results advance our understanding of the mechanism by which cell type-specific transcription factors control lineage-specific gene expression programs and specify cell fate.
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Kaur M, Singh A, Singh K, Gupta S, Sachan M. Development of a multiplex MethyLight assay for the detection of DAPK1 and SOX1 methylation in epithelial ovarian cancer in a north Indian population. Genes Genet Syst 2016; 91:175-181. [DOI: 10.1266/ggs.15-00051] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Affiliation(s)
- Manpreet Kaur
- Department of Biotechnology, Motilal Nehru National Institute of Technology
| | - Alka Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology
| | - Kiran Singh
- Department of Molecular Human Genetics, Banaras Hindu University
| | - Sameer Gupta
- Department of Surgical Oncology, King George Medical University
| | - Manisha Sachan
- Department of Biotechnology, Motilal Nehru National Institute of Technology
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Abstract
Liver cancer (hepatocellular carcinoma or HCC) is a major cancer worldwide. Research in this field is needed to identify biomarkers that can be used for early detection of the disease as well as new approaches to its treatment. Epigenetic biomarkers provide an opportunity to understand liver cancer etiology and evaluate novel epigenetic inhibitors for treatment. Traditionally, liver cirrhosis, proteomic biomarkers, and the presence of hepatitis viruses have been used for the detection and diagnosis of liver cancer. Promising results from microRNA (miRNA) profiling and hypermethylation of selected genes have raised hopes of identifying new biomarkers. Some of these epigenetic biomarkers may be useful in risk assessment and for screening populations to identify who is likely to develop cancer. Challenges and opportunities in the field are discussed in this chapter.
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SOX 1, contrary to SOX 2, suppresses proliferation, migration, and invasion in human laryngeal squamous cell carcinoma by inhibiting the Wnt/β-catenin pathway. Tumour Biol 2015; 36:8625-35. [PMID: 26040764 DOI: 10.1007/s13277-015-3389-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 03/24/2015] [Indexed: 12/12/2022] Open
Abstract
Sex-determining region Y (SRY)-box protein 1 (SOX 1) has been reported to have the inhibiting effects on various cancer cells; however, the expression and effect of SOX 1 on laryngeal squamous cell carcinoma (LSCC) have not been determined. Therefore, the aim of this study was to assess the anti-proliferation and metastatic effects of SOX 1 and its related mechanisms on LSCC. According to our present study, first, we found that overexpression of SOX 1 could significantly inhibit proliferation and promote apoptosis in Tu212 cells. Additionally, overexpression of SOX 1 suppressed the migration and invasion potential of Tu212 cells via regulating Wnt/β-catenin pathway. Finally, we demonstrated for the first time that overexpression of SOX 1 could downregulate the expression of SOX 2, and co-expression of SOX 1 and SOX 2 could reverse the anti-tumor effect of SOX 1. In conclusion, our studies suggested that SOX 1 suppressed cell growth and invasion in Tu212 cells by inhibiting Wnt/β-catenin pathway, and the anti-tumor effect of SOX 1 could be weakened by SOX 2, which may be a potential molecular basis for clinical treatment of LSCC.
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Wu Y, Bai J, Li Z, Wang F, Cao L, Liu C, Yu S, Yu G, Zhang Y. Low expression of secreted frizzled-related protein 4 in aggressive pituitary adenoma. Pituitary 2015; 18:335-42. [PMID: 24917361 DOI: 10.1007/s11102-014-0579-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The secreted frizzled-related proteins (sFRPs) are reported to be antagonists of a number of tumors. This study was designed to investigate the relationship of sFRP4 with aggressiveness of pituitary adenomas. MATERIAL AND METHOD Specimens were classified into three groups: normal control (n = 10), non-aggressive group (n = 42) and aggressive group (n = 26) according to preoperative magnetic resonance imaging (MRI)/computed tomography. sFRP4 were investigated by PCR, Western blotting, and immunohistochemistry (IHC). The methylation status of the sFRP4 promoter region was observed by MassArray. Cell culture and 5-aza-2-deoxycytidine treatment was performed to observe the relationship of downregulation of sFRP4 with methylation of the sFRP4 gene. RESULTS PCR and Western blot results showed that sFRP4 expression was downregulated in aggressive pituitary adenomas, which was confirmed by IHC. Methylation of the sFRP4 promoter was increased in aggressive pituitary adenomas. And methylation of the sFRP4 promoter lead to downregulation of sFRP4 expression. CONCLUSIONS sFRP4 expression is inversely related to the aggressiveness of pituitary adenomas, and act as a tumor suppressor.
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Affiliation(s)
- Youtu Wu
- Beijing Neurosurgical Institute, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, People's Republic of China
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sFRP-4, a potential novel serum marker for chronic hepatitis B-related hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2015; 14:164-70. [PMID: 25865689 DOI: 10.1016/s1499-3872(15)60352-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The current methods used for diagnosing hepatocellular carcinoma (HCC) are unsatisfactory. Here, we assessed the serum levels of secreted frizzled related protein 4 (sFRP-4) for diagnosing HCC in patients infected with chronic hepatitis B (CHB). METHODS In 272 patients with CHB enrolled, 142 were patients with HCC. Thirty-three healthy subjects were recruited as healthy controls. The CHB patients were assigned to a test group or a validation group based on the time of enrollment. Human antibody arrays were used to screen 15 patients (8 CHB-related HCC patients, 7 CHB patients) for serum markers. Four markers and one candidate marker were assessed in the test group and validation group, respectively. RESULTS Human antibody assays indicated that the serum levels of sFRP-4 in HCC patients were significantly higher than those in CHB patients (P<0.05). Additionally, serum sFRP-4 levels were significantly higher in the HCC patients than those in the non-HCC patients in both test group (79.7 vs 41.3 ng/mL; P<0.001) and validation group (89.0 vs 39.0 ng/mL; P<0.001). Areas under the Receiver Operating Characteristic curves (AUCs) for alpha-fetoprotein (AFP) and sFRP-4 were similar in both test group and validation group. In the test group, the combination of sFRP-4 (a sensitivity of 94.4%, a specificity of 60.5% at 46.4 ng/mL) and AFP (a sensitivity of 75.0%, a specificity of 87.2% at 11.3 ng/mL) showed better performance for diagnosing HCC (a sensitivity of 79.2% and a specificity of 95.3%). The AUC for combined sFRP-4 and AFP increased to 0.941 (95% CI: 0.908-0.975), and similar results were seen in the validation group. CONCLUSION sFRP-4 is a candidate serum marker for diagnosing HCC in CHB patients, and the combination of sFRP-4 with AFP may improve the diagnostic accuracy of HCC.
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Huang C, Tian Y, Peng R, Zhang C, Wang D, Han S, Jiao C, Wang X, Zhang H, Wang Y, Li X. Association of downregulation of WWOX with poor prognosis in patients with intrahepatic cholangiocarcinoma after curative resection. J Gastroenterol Hepatol 2015; 30:421-433. [PMID: 25168293 DOI: 10.1111/jgh.12722] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM Downregulation of the WW domain containing oxidoreductase (WWOX) has been reported to be involved in tumorigenesis in several neoplasms. This study sought to investigate the expression and role of WWOX in intrahepatic cholangiocarcinoma (ICC). METHODS WWOX expression was measured by quantitative real-time polymerase chain reaction (PCR), immunoblot, immunofluorescence, and immunohistochemistry. The prognostic significance was assessed by Kaplan-Meier and Cox regression analyses. The role of WWOX in proliferation, anchorage-independent growth, gene expression regulation, and tumorigenesis was assessed by WWOX re-expression using lentivirus. Methylation-specific PCR was performed to evaluate the methylation status of the WWOX gene regulatory region. A DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (AZA), was used to activate the endogenous WWOX gene in ICC cells both in vitro and in vivo. RESULTS The expression of WWOX in ICC tissues was much lower than that in nontumorous samples and showed reverse correlation with proliferative status. Restoration of WWOX expression resulted in suppression of the growth of WWOX-deficient ICC cells through activation of the intrinsic apoptotic signaling pathway, but did not affect growth of WWOX-sufficient human intrahepatic biliary epithelial derived non-cancer cells. Multivariate analyses revealed that downregulation of WWOX was an unfavorable predictor for overall survival and cumulative recurrence rates. The WWOX gene regulatory region was frequently methylated in ICC tissues and cell lines, and intratumoral WWOX restoration, through AZA injection, suppressed tumor growth in nude mice. CONCLUSION Downregulation of WWOX may occur as a result of hypermethylation and implies a poor prognosis in ICC; WWOX re-expression may be a potential molecular therapeutic target for ICC.
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Affiliation(s)
- Changjun Huang
- Department of General Surgery, Luohe Central Hospital Affiliated to Luohe Medical College, Luohe, China; Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, China
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Li N, Li S. Epigenetic inactivation of SOX1 promotes cell migration in lung cancer. Tumour Biol 2015; 36:4603-10. [DOI: 10.1007/s13277-015-3107-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 01/14/2015] [Indexed: 11/28/2022] Open
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23
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Bi WR, Yang CQ, Xing HL. Transfection with recombinant adenovirus vector expressing secreted frizzled related protein inhibits liver fibrosis in mice. Shijie Huaren Xiaohua Zazhi 2014; 22:4379-4385. [DOI: 10.11569/wcjd.v22.i29.4379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To construct a recombinant adenovirus vector expressing secreted frizzled related protein (SFRP), and to assess the inhibitory effect of SFRP overexpression on experimental hepatic fibrosis (HF) in mice.
METHODS: Liposome-mediated transfection was used to introduce recombinant adenovirus pAd-Track-PPARγ2-CMV carrying the SFRP5 gene into liver cells from mice with CCl4 induced HF to obtain recombinant adenovirus infected HF cells. Western blot, immunofluorescence microscopy and confocal laser microscopy were used to analyze the inhibitory effect of SFRP overexpression on experimental HF.
RESULTS: Cells infected with the recombinant adenovirus vector had higher expression of SFRP5 protein. Double immunofluorescence showed SFRP5 over expression inhibited the expression of α-smooth muscle actin (α-SMA) and fibroblast-specific protein-1 (FSP-1) in liver cells. Pathological examination revealed that SFRP5 over expression significantly reduced the occurrence of epithelial-mesenchymal transition (EMT) in liver cells (SFRP group vs control group, P < 0.05).
CONCLUSION: We have successfully constructed a recombinant adenovirus containing the SFRP5 gene, and it can effectively increase the expression of SFRP5 gene in mouse HF cells, thereby inhibiting the occurrence of EMT and HF.
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Anestopoulos I, Voulgaridou GP, Georgakilas AG, Franco R, Pappa A, Panayiotidis MI. Epigenetic therapy as a novel approach in hepatocellular carcinoma. Pharmacol Ther 2014; 145:103-19. [PMID: 25205159 DOI: 10.1016/j.pharmthera.2014.09.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 09/02/2014] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver malignancy and one with high fatality. Its 5-year survival rate remains low and thus, there is a need for improvement of current treatment strategies as well as development of novel targeted methodologies in order to optimize existing therapeutic protocols. To this end, only recently, it was discovered that its pathophysiology also involves epigenetic alterations in DNA methylation, histone modifications and/or non-coding microRNA patterns. Unlike genetic events, epigenetic alterations are reversible and thus potentially considered to be an alternative option in cancer treatment protocols. In this review, we describe the general characteristics and resulted major alterations of the epigenetic machinery as well as current state of progress of epigenetic therapy (via different single or combinatorial experimental approaches) in HCC.
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Affiliation(s)
- Ioannis Anestopoulos
- Department of Molecular Biology & Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | | | - Alexandros G Georgakilas
- School of Applied Mathematical & Physical Sciences, National Technical University of Athens, Athens, Greece
| | - Rodrigo Franco
- Redox Biology Center, School of Veterinary Medicine & Biomedical Sciences, Redox Biology Center, University of Nebraska-Lincoln, USA
| | - Aglaia Pappa
- Department of Molecular Biology & Genetics, Democritus University of Thrace, Alexandroupolis, Greece
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Anwar SL, Lehmann U. DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma. World J Gastroenterol 2014; 20:7894-7913. [PMID: 24976726 PMCID: PMC4069317 DOI: 10.3748/wjg.v20.i24.7894] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 01/24/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Epigenetic alterations have been identified as a major characteristic in human cancers. Advances in the field of epigenetics have contributed significantly in refining our knowledge of molecular mechanisms underlying malignant transformation. DNA methylation and microRNA expression are epigenetic mechanisms that are widely altered in human cancers including hepatocellular carcinoma (HCC), the third leading cause of cancer related mortality worldwide. Both DNA methylation and microRNA expression patterns are regulated in developmental stage specific-, cell type specific- and tissue-specific manner. The aberrations are inferred in the maintenance of cancer stem cells and in clonal cell evolution during carcinogenesis. The availability of genome-wide technologies for DNA methylation and microRNA profiling has revolutionized the field of epigenetics and led to the discovery of a number of epigenetically silenced microRNAs in cancerous cells and primary tissues. Dysregulation of these microRNAs affects several key signalling pathways in hepatocarcinogenesis suggesting that modulation of DNA methylation and/or microRNA expression can serve as new therapeutic targets for HCC. Accumulative evidence shows that aberrant DNA methylation of certain microRNA genes is an event specifically found in HCC which correlates with unfavorable outcomes. Therefore, it can potentially serve as a biomarker for detection as well as for prognosis, monitoring and predicting therapeutic responses in HCC.
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Cisplatin-induced downregulation of SOX1 increases drug resistance by activating autophagy in non-small cell lung cancer cell. Biochem Biophys Res Commun 2013; 439:187-90. [PMID: 23994634 DOI: 10.1016/j.bbrc.2013.08.065] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 08/20/2013] [Indexed: 12/28/2022]
Abstract
SOX1 was aberrant methylated in hepatocellular cancer and non-small cell lung cancer (NSCLC). Long-term cisplatin exposure promotes methylation of SOX1 in ovarian cancer cell, suggesting that SOX1 may be involved in cisplatin resistance. Our aim was to test the hypothesis that cisplatin resistance is associated with alteration of SOX1 expression in NSCLC. Expression of levels of SOX1 was examined using RT-PCR in cisplatin resistance cells and parental cells. The level of SOX1 mRNA in cisplatin resistance cells was markedly reduced when compared to parental cells. Promoter methylation of SOX1 was induced in cisplatin resistance cells. We also found that SOX1 silencing enhanced the cisplatin-mediated autophagy in NSCLC. This study shows that inactivation of SOX1 by promoter hypermethylation, at least in part, is responsible for cisplatin resistance in human NSCLC.
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Bai AH, Cheng AS. Alliance of epigenetic forces for the activation of oncogenic Wnt/β-catenin signaling. J Gastroenterol Hepatol 2013; 28:383-5. [PMID: 23441716 DOI: 10.1111/jgh.12090] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/28/2012] [Indexed: 02/06/2023]
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