|
1
|
Duan H, Ding X, Luo H. KISS-1, Mediated by Promoter Methylation, Suppresses Esophageal Squamous Cell Carcinoma Metastasis via MMP2/9/MAPK Axis. Dig Dis Sci 2022; 67:4780-4796. [PMID: 34993679 DOI: 10.1007/s10620-021-07335-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS KISS-1 is an established tumor suppressor that inhibits metastases in various malignancies. However, little is known regarding its role in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to identify the possible mechanisms of KISS-1 in ESCC metastasis. METHODS The expression levels of KISS-1 mRNA and protein in ESCC samples and cell lines were analyzed by qRT-PCR, IHC, and western blotting. Bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP) were used to analyze the methylation pattern of KISS-1 promoter in ESCC cells with or without 5-Aza-dC treatment. The role of KISS-1 in the progression and metastasis of ESCC was analyzed through in vitro functional assays. RESULTS KISS-1 mRNA and protein were markedly downregulated in ESCC tissues and cell lines compared to the respective controls. Hypermethylation of KISS-1 promoter correlated to its lower expression levels in ESCC, and KISS-1 demethylation inhibited tumor progression. Ectopic KISS-1 overexpression inhibited tumor cell metastasis in vitro. In addition, KISS-1 overexpression downregulated the matrix metalloproteinase 2 and 9 (MMP2 and 9) and inhibited epithelial-mesenchymal transition (EMT). Finally, KISS-1 downregulated phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2) and phosphorylated p38 mitogen-activated protein kinase (MAPK) without affecting their total expression levels in the ESCC cells. MAPK/ERK and p38 MAPK agonists reversed the suppressive effects of KISS-1. CONCLUSIONS The hypermethylation of KISS-1 promoter partly contributed to its downregulation in ESCC. KISS-1 inhibits the metastasis of ESCC cells by targeting the MMP2/9/ERK/p38 MAPK axis.
Collapse
Affiliation(s)
- Houyu Duan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Xiang Ding
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Hesheng Luo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China.
| |
Collapse
|
|
2
|
Zhu N, Zhao M, Song Y, Ding L, Ni Y. The KiSS-1/GPR54 system: Essential roles in physiological homeostasis and cancer biology. Genes Dis 2020; 9:28-40. [PMID: 35005105 PMCID: PMC8720660 DOI: 10.1016/j.gendis.2020.07.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 07/13/2020] [Accepted: 07/15/2020] [Indexed: 12/29/2022] Open
Abstract
KiSS-1, first identified as an anti-metastasis gene in melanoma, encodes C-terminally amidated peptide products, including kisspeptin-145, kisspeptin-54, kisspeptin-14, kisspeptin-13 and kisspeptin-10. These products are endogenous ligands coupled to G protein-coupled receptor 54 (GPR54)/hOT7T175/AXOR12. To date, the regulatory activities of the KiSS-1/GPR54 system, such as puberty initiation, antitumor metastasis, fertility in adulthood, hypothalamic-pituitary-gonadal axis (HPG axis) feedback, and trophoblast invasion, have been investigated intensively. Accumulating evidence has demonstrated that KiSS-1 played a key role in reproduction and served as a promising biomarker relative to the diagnosis, identification of therapeutic targets and prognosis in various carcinomas, while few studies have systematically summarized its subjective factors and concluded the functions of KiSS-1/GPR54 signaling in physiology homeostasis and cancer biology. In this review, we retrospectively summarized the regulators of the KiSS-1/GPR54 system in different animal models and reviewed its functions according to physiological homeostasis regulations and above all, cancer biology, which provided us with a profound understanding of applying the KiSS-1/GPR54 system into medical applications.
Collapse
Affiliation(s)
- Nisha Zhu
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, Jiangsu 210008, PR China
| | - Mengxiang Zhao
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, Jiangsu 210008, PR China
| | - Yuxian Song
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, Jiangsu 210008, PR China
| | - Liang Ding
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, Jiangsu 210008, PR China
| | - Yanhong Ni
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, Jiangsu 210008, PR China
| |
Collapse
|
|
3
|
Reduced Kiss‑1 expression is associated with clinical aggressive feature of gastric cancer patients and promotes migration and invasion in gastric cancer cells. Oncol Rep 2020; 44:1149-1157. [PMID: 32705229 PMCID: PMC7388581 DOI: 10.3892/or.2020.7676] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) causes high morbidity and mortality in patients largely due to its invasion and metastasis. Kiss‑1 has been shown to be a metastasis suppressor in various malignancies. However, its clinical significance and biological functions in GC have not been thoroughly investigated. The present study investigated the association between Kiss‑1 expression and its methylation status and clinicopathological features in GC. Kiss‑1 expression was reduced in GC and its low expression was associated with poor histological grade, lymph node metastasis and TNM III+IV stage. Kiss‑1 overexpression in AGS GC cells significantly inhibited cell proliferation, migration and invasion in vitro. Kiss‑1 knockdown promoted the proliferation, migration and invasion of HGC‑27 cells. In summary, the data demonstrated that a low expression of Kiss‑1 played a suppressive role for the proliferation, migration and invasion of GC cells. Its expression and methylation levels were associated with the clinical progression of GC. Thus, Kiss‑1 is a potential diagnostic and prognostic marker as well as a new target for the treatment of GC.
Collapse
|
|
4
|
MicroRNA 345 (miR345) regulates KISS1-E-cadherin functional interaction in breast cancer brain metastases. Cancer Lett 2020; 481:24-31. [PMID: 32246957 DOI: 10.1016/j.canlet.2020.03.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 12/12/2022]
Abstract
Brain metastases manifest the advanced stage of breast cancer disease with poor prognosis for patient survival. Recent reports demonstrate that some therapeutic agents can activate the expression of several breast cancer-associated genes, whose products are involved in the onset and development of brain metastases. In this study, we discovered a functional link between KISS1 and E-cadherin that could be observed in both primary brain metastatic lesions and paired cell lines, such as parental CN34TGL and MDA-MB-231 and their respective brain metastatic subclones CN34Brm2Ctgl and MDA-MB-231Br. Remarkably, expression of KISS1 and E-cadherin genes consistently showed an inverse correlation in all of the above cell/tissue types. While E-cadherin expression was strongly upregulated in metastatic clones isolated from blood and brain, the levels of this protein in parental MDA-MB-231 cell line was low. Furthermore, E-cadherin upregulation can be artificially induced in MDA-MB-231Br and CN34Brm2Ctgl cell populations by knocking down KISS1 expression directly or through overexpressing the miR345 mimic. In the aggregate, our data suggest that the tumor microenvironment, which controls breast cancer spreading via miR345-regulated KISS1 expression, might modulate metastatic spreading by a mechanism(s) involving upregulation of E-cadherin production.
Collapse
|
|
5
|
Motti ML, Meccariello R. Minireview: The Epigenetic Modulation of KISS1 in Reproduction and Cancer. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16142607. [PMID: 31336647 PMCID: PMC6679060 DOI: 10.3390/ijerph16142607] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 07/04/2019] [Accepted: 07/17/2019] [Indexed: 01/07/2023]
Abstract
Epigenetics describes how both lifestyle and environment may affect human health through the modulation of genome functions and without any change to the DNA nucleotide sequence. The discovery of several epigenetic mechanisms and the possibility to deliver epigenetic marks in cells, gametes, and biological fluids has opened up new perspectives in the prevention, diagnosis, and treatment of human diseases. In this respect, the depth of knowledge of epigenetic mechanisms is fundamental to preserving health status and to developing targeted interventions. In this minireview, we summarize the epigenetic modulation of the KISS1 gene in order to provide an example of epigenetic regulation in health and disease.
Collapse
Affiliation(s)
- Maria Letizia Motti
- Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, via Medina 40, 80133 Napoli, Italy
| | - Rosaria Meccariello
- Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, via Medina 40, 80133 Napoli, Italy.
| |
Collapse
|
|
6
|
Sun H, Huang H, Li D, Zhang L, Zhang Y, Xu J, Liu Y, Liu Y, Zhao Y. PBX3 hypermethylation in peripheral blood leukocytes predicts better prognosis in colorectal cancer: A propensity score analysis. Cancer Med 2019; 8:4001-4011. [PMID: 31140752 PMCID: PMC6639175 DOI: 10.1002/cam4.2321] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/15/2019] [Accepted: 05/16/2019] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE The significance of gene methylation in peripheral blood leukocytes (PBLs) for assessing cancer prognosis is poorly understood. Our purpose is to assess the association between PBX3 methylation in PBLs and colorectal cancer (CRC) prognosis. METHODS A total of 369 CRC patients were followed up for up to 10 years in this cohort study. PBL PBX3 methylation levels were determined by methylation-sensitive high-resolution melting. Cox regression models and Log-rank tests were used to analyze the associations between PBX3 methylation status and CRC prognosis with a propensity score (PS) method to control confounding biases. RESULTS In this study, we found that CRC patients with PBL PBX3 hypermethylation status had a better overall survival (OS) (hazard ratio [HRPS-adjusted ], 0.72 [95% CI, 0.52-1.00]; P = 0.049). Subgroup analyses showed that the beneficial effect of PBX3 hypermethylation status on CRC 10-years OS remained significant among UICC stage III patients ([HRPS-adjusted ], 0.60 [95% CI, 0.38 to 0.95]; P = 0.029) and colon cancer patients ([HRPS-adjusted ], 0.49 [95% CI, 0.26 to 0.92]; P = 0.027). CONCLUSION PBL PBX3 hypermethylation is positively associated with better prognosis of CRC, especially for the UICC stage III CRC patients and colon cancer patients.
Collapse
Affiliation(s)
- Hongru Sun
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Hao Huang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Dapeng Li
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Lei Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Yuanyuan Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Jing Xu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Ying Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Yupeng Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| |
Collapse
|
|
7
|
Wang XQ, Fang PF, Zhang C, Xu YY, Song XB, Liang J, Xia QR. Low KISS1 expression predicts poor prognosis for patients with colorectal cancer: A meta-analysis. Clin Exp Pharmacol Physiol 2019; 46:625-634. [PMID: 30932210 DOI: 10.1111/1440-1681.13093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 03/22/2019] [Accepted: 03/26/2019] [Indexed: 12/24/2022]
Abstract
KISS1 and KISS1R, a novel pair of metastasis suppressors, are likely to be associated with the prognosis of colorectal cancer (CRC). Here, a meta-analysis was performed to study the role of KISS1 and KISS1R in CRC. Heterogeneity, stability and publication bias were all estimated. Six publications describing a total of 559 CRC patients were included in the present study. Low KISS1 expression predicted 70% higher risk of poor prognosis for general patients (HR, 1.71; 95% CI, 1.28-2.29) and 99% higher risk for East Asian patients (HR, 1.99; 95% CI, 1.46-2.72). Limited evidence indicated that decreased KISS1R expression might predict poor outcome (HR, 2.96; 95% CI, 1.51-5.82). Neither heterogeneity nor publication bias was identified. The current analyses suggest that low KISS1 expression predicts poor overall survival among East Asian patients with CRC. Evidence on other races and KISS1R are still insufficient, and additional studies are required to clarify the risk of CRC associated with KISS1R by race.
Collapse
Affiliation(s)
| | | | - Cheng Zhang
- Anhui Provincial Cancer Institute, Hefei, China.,The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ya-Yun Xu
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China.,Anhui Mental Health Center, Hefei, China
| | | | - Jun Liang
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China.,Anhui Mental Health Center, Hefei, China
| | - Qing-Rong Xia
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China.,Anhui Mental Health Center, Hefei, China
| |
Collapse
|
|
8
|
KiSS1 in regulation of metastasis and response to antitumor drugs. Drug Resist Updat 2019; 42:12-21. [DOI: 10.1016/j.drup.2019.02.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/03/2019] [Accepted: 02/06/2019] [Indexed: 12/15/2022]
|
|
9
|
Vedeld HM, Goel A, Lind GE. Epigenetic biomarkers in gastrointestinal cancers: The current state and clinical perspectives. Semin Cancer Biol 2018; 51:36-49. [PMID: 29253542 PMCID: PMC7286571 DOI: 10.1016/j.semcancer.2017.12.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 11/17/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023]
Abstract
Each year, almost 4.1 million people are diagnosed with gastrointestinal (GI) cancers. Due to late detection of this disease, the mortality is high, causing approximately 3 million cancer-related deaths annually, worldwide. Although the incidence and survival differs according to organ site, earlier detection and improved prognostication have the potential to reduce overall mortality burden from these cancers. Epigenetic changes, including aberrant promoter DNA methylation, are common events in both cancer initiation and progression. Furthermore, such changes may be identified non-invasively with the use of PCR based methods, in bodily fluids of cancer patients. These features make aberrant DNA methylation a promising substrate for the development of disease biomarkers for early detection, prognosis and for predicting response to therapy. In this article, we will provide an update and current clinical perspectives for DNA methylation alterations in patients with colorectal, gastric, pancreatic, liver and esophageal cancers, and discuss their potential role as cancer biomarkers.
Collapse
Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Ajay Goel
- Center for Gastrointestinal Research, and Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
| | - Guro E Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| |
Collapse
|
|
10
|
Prognostic DNA methylation markers for sporadic colorectal cancer: a systematic review. Clin Epigenetics 2018; 10:35. [PMID: 29564023 PMCID: PMC5851322 DOI: 10.1186/s13148-018-0461-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 02/21/2018] [Indexed: 02/06/2023] Open
Abstract
Background Biomarkers that can predict the prognosis of colorectal cancer (CRC) patients and that can stratify high-risk early stage patients from low-risk early stage patients are urgently needed for better management of CRC. During the last decades, a large variety of prognostic DNA methylation markers has been published in the literature. However, to date, none of these markers are used in clinical practice. Methods To obtain an overview of the number of published prognostic methylation markers for CRC, the number of markers that was validated independently, and the current level of evidence (LoE), we conducted a systematic review of PubMed, EMBASE, and MEDLINE. In addition, we scored studies based on the REMARK guidelines that were established in order to attain more transparency and complete reporting of prognostic biomarker studies. Eighty-three studies reporting on 123 methylation markers fulfilled the study entry criteria and were scored according to REMARK. Results Sixty-three studies investigated single methylation markers, whereas 20 studies reported combinations of methylation markers. We observed substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology. The median (range) REMARK score for the studies was 10.7 points (4.5 to 17.5) out of a maximum of 20 possible points. The median REMARK score was lower in studies, which reported a p value below 0.05 versus those, which did not (p = 0.005). A borderline statistically significant association was observed between the reported p value of the survival analysis and the size of the study population (p = 0.051). Only 23 out of 123 markers (17%) were investigated in two or more study series. For 12 markers, and two multimarker panels, consistent results were reported in two or more study series. For four markers, the current LoE is level II, for all other markers, the LoE is lower. Conclusion This systematic review reflects that adequate reporting according to REMARK and validation of prognostic methylation markers is absent in the majority of CRC methylation marker studies. However, this systematic review provides a comprehensive overview of published prognostic methylation markers for CRC and highlights the most promising markers that have been published in the last two decades. Electronic supplementary material The online version of this article (10.1186/s13148-018-0461-8) contains supplementary material, which is available to authorized users.
Collapse
|
|
11
|
Cao B, Zhou X, Yang W, Ma J, Zhou W, Fan D, Hong L. The role of cell-free DNA in predicting colorectal cancer prognosis. Expert Rev Gastroenterol Hepatol 2018; 12:39-48. [PMID: 28838275 DOI: 10.1080/17474124.2017.1372191] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Colorectal cancer is a cancer of the digestive system with poor prognosis. Cell-free DNA has received much attention with its unique predominance, especially in colorectal cancer. Areas covered: This study has summarized recent advancements and challenges regarding cell-free DNA in predicting CRC prognosis. Furthermore, the authors make predictions on the potential developments concerning cell-free DNA in future prognosis prediction techniques. Expert commentary: Cell-free DNA has the value of predicting CRC prognosis as an important biomarke. Further clinical trials should be performed to promote translating cell-free DNA into clinical applications.
Collapse
Affiliation(s)
- Bo Cao
- a The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Xin Zhou
- a The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Wanli Yang
- b State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Jiaojiao Ma
- b State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Wei Zhou
- b State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Daiming Fan
- b State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Liu Hong
- b State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| |
Collapse
|
|
12
|
Mousavi Ardehaie R, Hashemzadeh S, Behrouz Sharif S, Ghojazadeh M, Teimoori-Toolabi L, Sakhinia E. Aberrant methylated EDNRB can act as a potential diagnostic biomarker in sporadic colorectal cancer while KISS1 is controversial. Bioengineered 2017; 8:555-564. [PMID: 28140749 PMCID: PMC5639868 DOI: 10.1080/21655979.2017.1283458] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 01/08/2017] [Accepted: 01/12/2017] [Indexed: 12/26/2022] Open
Abstract
Cancers are among the most serious threats of human health worldwide. Survival and mortality rates of colorectal cancer (CRC) strongly depend on the early diagnosis. The aberrant methylation pattern of genes as a diagnostic biomarker can serve as a practical option for timely detection and contribute subsequently to the enhancement of survival rate in CRC patients, since methylation changes are not only frequent but also can occur in initial tumorogenesis stages. It has been indicated that EDNRB and KISS1 genes are hypermethylated through progression and development of CRC. In current study, after extraction of genomic DNA from 45 paired tumor and adjacent non-cancerous tissue samples and treatment with bisulfite conversion, the methylation status of EDNRB and KISS1 CpG rich regions were assessed quantitatively using MS-HRM assay to determine practicability of these aberrant methylations for diagnosis of sporadic CRC and its discrimination from corresponding normal tissues. The results showed that the methylation distribution differences, comparing tumor tissues with their adjacent non-cancerous tissues, were statistically significant in all selected locations within EDNRB gene promoter (P < 0.001); they had also some correlations with tumor stage and grade. Nonetheless, methylation distribution in KISS1 gene CpG rich region revealed no statistically significant differences between CRC and adjacent non-cancerous tissues (P = 0.060). Overall, it can be concluded that aberrant methylated EDNRB can be a promising potential diagnostic biomarker for CRC, while KISS1 is controversial and needs to be more investigated.
Collapse
Affiliation(s)
- Reza Mousavi Ardehaie
- Department of Biochemistry and Clinical Laboratory, Division of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Molecular Medicine Department, Pasteur Institute of Iran, Tehran, Iran
| | - Shahriar Hashemzadeh
- Department of General & Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, Iran
- Tuberculosis and lung research center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahin Behrouz Sharif
- Department of Biochemistry and Clinical Laboratory, Division of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Molecular Medicine Department, Pasteur Institute of Iran, Tehran, Iran
| | - Morteza Ghojazadeh
- Liver and Gastrointestinal Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ebrahim Sakhinia
- Department of Biochemistry and Clinical Laboratory, Division of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
13
|
Kandimalla R, Linnekamp JF, van Hooff S, Castells A, Llor X, Andreu M, Jover R, Goel A, Medema JP. Methylation of WNT target genes AXIN2 and DKK1 as robust biomarkers for recurrence prediction in stage II colon cancer. Oncogenesis 2017; 6:e308. [PMID: 28368388 PMCID: PMC5520503 DOI: 10.1038/oncsis.2017.9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 02/05/2017] [Accepted: 02/07/2017] [Indexed: 12/18/2022] Open
Abstract
Stage II colon cancer (CC) still remains a clinical challenge with patient stratification for adjuvant therapy (AT) largely relying on clinical parameters. Prognostic biomarkers are urgently needed for better stratification. Previously, we have shown that WNT target genes AXIN2, DKK1, APCDD1, ASCL2 and LGR5 are silenced by DNA methylation and could serve as prognostic markers in stage II CC patients using methylation-specific PCR. Here, we have extended our discovery cohort AMC90-AJCC-II (N=65) and methylation was analyzed by quantitative pyrosequencing. Subsequently, we validated the results in an independent EPICOLON1 CC cohort (N=79). Methylation of WNT target genes is negatively correlated to mRNA expression. A combination of AXIN2 and DKK1 methylation significantly predicted recurrences in univariate (area under the curve (AUC)=0.83, confidence interval (CI): 0.72–0.94, P<0.0001) analysis in stage II microsatellite stable (MSS) CC patients. This two marker combination showed an AUC of 0.80 (CI: 0.68–0.91, P<0.0001) in the EPICOLON1 validation cohort. Multivariate analysis in the Academic Medical Center (AMC) cohort revealed that both WNT target gene methylation and consensus molecular subtype 4 (CMS4) are significantly associated with poor recurrence-free survival (hazard ratio (HR)methylation: 3.84, 95% CI: 1.14–12.43; HRCMS4: 3.73, 95% CI: 1.22–11.48). CMS4 subtype tumors with WNT target methylation showed worse prognosis. Combining WNT target gene methylation and CMS4 subtype lead to an AUC of 0.89 (0.791–0.982, P<0.0001) for recurrence prediction. Notably, we observed that methylation of DKK1 is high in BRAF mutant and CIMP (CpG island methylator phenotype)-positive cancers, whereas AXIN2 methylation appears to be associated with CMS4. Methylation of AXIN2 and DKK1 were found to be robust markers for recurrence prediction in stage II MSS CC patients. Further validation of these findings in a randomized and prospective manner could pave a way to identify poor prognosis patients of stage II CC for AT.
Collapse
Affiliation(s)
- R Kandimalla
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.,Cancer Genomics Center, Amsterdam, The Netherlands.,Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Scott and White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - J F Linnekamp
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.,Cancer Genomics Center, Amsterdam, The Netherlands
| | - S van Hooff
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.,Cancer Genomics Center, Amsterdam, The Netherlands
| | - A Castells
- Institut de Malaties Digestives i Metabòliques, CIBERehd, Hospital Clínic, Barcelona, Spain
| | - X Llor
- University of Yale, New Haven, CT, USA
| | - M Andreu
- Gastroenterology Department, Hospital del Mar, Barcelona, Spain
| | - R Jover
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - A Goel
- Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Scott and White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - J P Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.,Cancer Genomics Center, Amsterdam, The Netherlands
| |
Collapse
|
|
14
|
Singh R, Bhatt MLB, Singh SP, Kumar V, Goel MM, Mishra DP, Kumar R. Evaluation of KiSS1 as a Prognostic Biomarker in North Indian Breast Cancer Cases. Asian Pac J Cancer Prev 2017; 17:1789-95. [PMID: 27221854 DOI: 10.7314/apjcp.2016.17.4.1789] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Breast cancer is the commonest female cancer worldwide and its propensity to metastasize negatively impacts on therapeutic outcome. Several clinicopathological parameters with prognostic/predictive significance have been associated with metastatic suppressor expression levels. The role of metastatic suppressor gene (MSG) KiSS1 in breast cancer remains unclear. Our goal was to investigate the possible clinical significance of KiSS1 breast cancer. MATERIALS AND METHODS The study was conducted on 87 histologically proven cases of breast cancer and background normal tiisue. Quantitative reverse transcriptase polymerase chain reaction (qRT PCR) and immunohistochemistry (IHC) were used to investigate KiSS1 at gene and protein levels, respectively, for correlation with several patient characteristics including age, family history, hormonal receptor status, stage, tumor size, nodal involvement and metastatic manifestation and finally with median overall survival (OS). RESULTS Our study revealed (i) KiSS1 levels were generally elevated in breast cancer vs normal tissue (< 0.05). (ii) however, a statistically significant lower expression of KiSS1 was observed in metastatic vs non metastatic cases (P = 0.04). (iii) KiSS1 levels strongly correlated with T,N,M category, histological grade and advanced stage (<0.001) but not other studied parameters. (iv) Lastly, a significant correlation between expression of KiSS1 and median OS was found (P = 0.04). CONCLUSIONS Conclusively, less elevated KiSS1 expression is a negative prognostic factor for OS, advancing tumor stage, axillary lymph node status, metastatic propensity and advancing grade of the breast cancer patient. Patients with negative KiSS1 expression may require a more intensive therapeutic strategy.
Collapse
Affiliation(s)
- Richa Singh
- Department of Radiotherapy, King George's Medical University, India E-mail :
| | | | | | | | | | | | | |
Collapse
|
|
15
|
|
|
16
|
Lam K, Pan K, Linnekamp JF, Medema JP, Kandimalla R. DNA methylation based biomarkers in colorectal cancer: A systematic review. Biochim Biophys Acta Rev Cancer 2016; 1866:106-20. [PMID: 27385266 DOI: 10.1016/j.bbcan.2016.07.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/30/2016] [Accepted: 07/01/2016] [Indexed: 12/11/2022]
Abstract
Since genetic and epigenetic alterations influence the development of colorectal cancer (CRC), huge potential lies in the use of DNA methylation as biomarkers to improve the current diagnosis, screening, prognosis and treatment prediction. Here we performed a systematic review on DNA methylation-based biomarkers published in CRC, and discussed the current state of findings and future challenges. Based on the findings, we then provide a perspective on future studies. Genome-wide studies on DNA methylation revealed novel biomarkers as well as distinct subgroups that exist in CRC. For diagnostic purposes, the most independently validated genes to study further are VIM, SEPT9, ITGA4, OSM4, GATA4 and NDRG4. These hypermethylated biomarkers can even be combined with LINE1 hypomethylation and the performance of markers should be examined in comparison to FIT further to find sensitive combinations. In terms of prognostic markers, myopodin, KISS1, TMEFF2, HLTF, hMLH1, APAF1, BCL2 and p53 are independently validated. Most prognostic markers published lack both a multivariate analysis in comparison to clinical risk factors and the appropriate patient group who will benefit by adjuvant chemotherapy. Methylation of IGFBP3, mir148a and PTEN are found to be predictive markers for 5-FU and EGFR therapy respectively. For therapy prediction, more studies should focus on finding markers for chemotherapeutic drugs as majority of the patients would benefit. Translation of these biomarkers into clinical utility would require large-scale prospective cohorts and randomized clinical trials in future. Based on these findings and consideration we propose an avenue to introduce methylation markers into clinical practice in near future. For future studies, multi-omics profiling on matched tissue and non-invasive cohorts along with matched cohorts of adenoma to carcinoma is indispensable to concurrently stratify CRC and find novel, robust biomarkers. Moreover, future studies should examine the timing and heterogeneity of methylation as well as the difference in methylation levels between epithelial and stromal tissues.
Collapse
Affiliation(s)
- Kevin Lam
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Kathy Pan
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Janneke Fiona Linnekamp
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Raju Kandimalla
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
| |
Collapse
|
|
17
|
Zhang B, Li A, Zuo F, Yu R, Zeng Z, Ma H, Chen S. Recombinant Lactococcus lactis NZ9000 secretes a bioactive kisspeptin that inhibits proliferation and migration of human colon carcinoma HT-29 cells. Microb Cell Fact 2016; 15:102. [PMID: 27287327 PMCID: PMC4901401 DOI: 10.1186/s12934-016-0506-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 06/01/2016] [Indexed: 01/14/2023] Open
Abstract
Background Proteinaceous bioactive substances and pharmaceuticals are most conveniently administered orally. However, the facing problems are the side effects of proteolytic degradation and denaturation in the gastrointestinal tract. In recent years, lactic acid bacteria (LAB) have been verified to be a promising delivery vector for susceptible functional proteins and drugs. KiSS-1 peptide, a cancer suppressor, plays a critical role in inhibiting cancer metastasis and its activity has been confirmed by direct administration. However, whether this peptide can be functionally expressed in LAB and exert activity on cancer cells, thus providing a potential alternative administration manner in the future, has not been demonstrated. Results A recombinant Lactococcus lactis strain NZ9000-401-kiss1 harboring a plasmid containing the gene of the tumor metastasis-inhibiting peptide KiSS1 was constructed. After optimization of the nisin induction conditions, the recombinant strain efficiently secreted KiSS1 with a maximum detectable amount of 27.9 μg/ml in Dulbecco’s Modified Eagle medium. The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide and would healing assays, respectively, indicated that the secreted KiSS1 peptide remarkably inhibited HT-29 cell proliferation and migration. Furthermore, the expressed KiSS1 was shown to induce HT-29 cell morphological changes, apoptosis and reduce the expression of matrix metalloproteinase 9 (MMP-9) at both mRNA and protein levels. Conclusions A recombinant L. lactis NZ9000-401-kiss1 successfully expressing the human kiss1 was constructed. The secreted KiSS1 peptide inhibited human HT-29 cells’ proliferation and migration probably by invoking, or mediating the cell-apoptosis pathway and by down regulating MMP-9 expression, respectively. Our results suggest that L. lactis is an ideal cell factory for secretory expression of tumor metastasis-inhibiting peptide KiSS1, and the KiSS1-producing L. lactis strain may serve as a new tool for cancer therapy in the future.
Collapse
Affiliation(s)
- Bo Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing, 100083, People's Republic of China.,Key Laboratory of Functional Dairy, Department of Food Science and Engineering, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, People's Republic of China
| | - Angdi Li
- Key Laboratory of Functional Dairy, Department of Food Science and Engineering, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, People's Republic of China
| | - Fanglei Zuo
- Key Laboratory of Functional Dairy, Department of Food Science and Engineering, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, People's Republic of China
| | - Rui Yu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing, 100083, People's Republic of China.,Key Laboratory of Functional Dairy, Department of Food Science and Engineering, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, People's Republic of China
| | - Zhu Zeng
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing, 100083, People's Republic of China.,Key Laboratory of Functional Dairy, Department of Food Science and Engineering, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, People's Republic of China
| | - Huiqin Ma
- College of Horticulture, China Agricultural University, Beijing, 100193, People's Republic of China
| | - Shangwu Chen
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing, 100083, People's Republic of China. .,Key Laboratory of Functional Dairy, Department of Food Science and Engineering, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, People's Republic of China.
| |
Collapse
|
|
18
|
Verma M. The Role of Epigenomics in the Study of Cancer Biomarkers and in the Development of Diagnostic Tools. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 867:59-80. [PMID: 26530360 DOI: 10.1007/978-94-017-7215-0_5] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epigenetics plays a key role in cancer development. Genetics alone cannot explain sporadic cancer and cancer development in individuals with no family history or a weak family history of cancer. Epigenetics provides a mechanism to explain the development of cancer in such situations. Alterations in epigenetic profiling may provide important insights into the etiology and natural history of cancer. Because several epigenetic changes occur before histopathological changes, they can serve as biomarkers for cancer diagnosis and risk assessment. Many cancers may remain asymptomatic until relatively late stages; in managing the disease, efforts should be focused on early detection, accurate prediction of disease progression, and frequent monitoring. This chapter describes epigenetic biomarkers as they are expressed during cancer development and their potential use in cancer diagnosis and prognosis. Based on epigenomic information, biomarkers have been identified that may serve as diagnostic tools; some such biomarkers also may be useful in identifying individuals who will respond to therapy and survive longer. The importance of analytical and clinical validation of biomarkers is discussed, along with challenges and opportunities in this field.
Collapse
Affiliation(s)
- Mukesh Verma
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute (NCI), National Institutes of Health (NIH), Suite# 4E102. 9609 Medical Center Drive, MSC 9763, Bethesda, MD, 20892-9726, USA.
| |
Collapse
|
|
19
|
Shin WJ, Cho YA, Kang KR, Kim JH, Hong SD, Lee JI, Hong SP, Yoon HJ. KiSS-1 expression in oral squamous cell carcinoma and its prognostic significance. APMIS 2016; 124:291-8. [DOI: 10.1111/apm.12507] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 12/06/2015] [Indexed: 02/01/2023]
Affiliation(s)
- Wui-Jung Shin
- Department of Oral Pathology; School of Dentistry; Seoul National University; Seoul Korea
| | - Young-Ah Cho
- Department of Oral and Maxillofacial Pathology; School of Dentistry; Kyung Hee University; Seoul Korea
| | - Kyung-Rim Kang
- Department of Oral Pathology; School of Dentistry; Seoul National University; Seoul Korea
| | - Ji-Hoon Kim
- Department of Oral Pathology; School of Dentistry; Seoul National University; Seoul Korea
- Dental Research Institute; School of Dentistry; Seoul National University; Seoul Korea
| | - Seong-Doo Hong
- Department of Oral Pathology; School of Dentistry; Seoul National University; Seoul Korea
- Dental Research Institute; School of Dentistry; Seoul National University; Seoul Korea
| | - Jae-Il Lee
- Department of Oral Pathology; School of Dentistry; Seoul National University; Seoul Korea
- Dental Research Institute; School of Dentistry; Seoul National University; Seoul Korea
| | - Sam-Pyo Hong
- Department of Oral Pathology; School of Dentistry; Seoul National University; Seoul Korea
- Dental Research Institute; School of Dentistry; Seoul National University; Seoul Korea
| | - Hye-Jung Yoon
- Department of Oral Pathology; School of Dentistry; Seoul National University; Seoul Korea
- Dental Research Institute; School of Dentistry; Seoul National University; Seoul Korea
| |
Collapse
|
|
20
|
Zhu C, Takasu C, Morine Y, Bando Y, Ikemoto T, Saito Y, Yamada S, Imura S, Arakawa Y, Shimada M. KISS1 Associates with Better Outcome via Inhibiting Matrix Metalloproteinase-9 in Colorectal Liver Metastasis. Ann Surg Oncol 2015; 22 Suppl 3:S1516-23. [PMID: 26471489 DOI: 10.1245/s10434-015-4891-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Indexed: 01/06/2023]
Abstract
BACKGROUND Cancer metastasis is a major contributor to patient death because of its systemic nature and resistance to therapeutic agents. KISS1, originally identified to be a metastasis suppressor, couples to its receptor KISS1R and plays a pivotal role in suppressing cancer metastasis. In this study, we investigated KISS1 and KISS1R expression in colorectal liver metastasis (CRLM), and analyzed their correlation with patients' clinicopathological variables, including prognosis. METHODS Overall, 55 patients with CRLM who underwent hepatectomy between 2003 and 2013 were enrolled in this study. Immunohistochemistry was performed to evaluate the protein expression of KISS1, KISS1R, and matrix metalloproteinase-9 (MMP-9). Clinicopathological variables, including prognosis, were compared between low- and high-expressing groups of KISS1 or KISS1R. We analyzed the correlation of KISS1 or KISS1R protein expression with MMP-9. RESULTS Expression of both KISS1 and KISS1R was significantly correlated with overall survival (p = 0.0283 and p = 0.0275, respectively). The 5-year overall survival rate of the KISS1 and KISS1R low groups was 44.3 and 39.3 %, and 73.7 and 67.9 % in the high groups, respectively. Multivariate analysis revealed that KISS1 low expression was an independent prognostic factor (p = 0.037, hazard ratio 0.20). Moreover, KISS1 low-expression patients had more frequent distant metastasis (p < 0.05). Furthermore, KISS1 low-expressing tumor tissues expressed more MMP-9 protein (p = 0.034), which was mainly expressed in neutrophils at the metastatic tumor edge. CONCLUSION KISS1 could be a promising prognostic and therapeutic marker in CRLM. KISS1 low expression may induce high MMP-9 expression in neutrophils.
Collapse
Affiliation(s)
- Chengzhan Zhu
- Department of Surgery, The University of Tokushima, Tokushima, Japan.,Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima, Japan
| | - Chie Takasu
- Department of Surgery, The University of Tokushima, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, The University of Tokushima, Tokushima, Japan
| | - Yoshimi Bando
- Department of Molecular and Environmental Pathology, The University of Tokushima, Tokushima, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, The University of Tokushima, Tokushima, Japan
| | - Yu Saito
- Department of Surgery, The University of Tokushima, Tokushima, Japan.,Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima, Japan
| | - Shinichiro Yamada
- Department of Surgery, The University of Tokushima, Tokushima, Japan.,Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima, Japan
| | - Satoru Imura
- Department of Surgery, The University of Tokushima, Tokushima, Japan
| | - Yusuke Arakawa
- Department of Surgery, The University of Tokushima, Tokushima, Japan
| | - Mitsuo Shimada
- Department of Surgery, The University of Tokushima, Tokushima, Japan.
| |
Collapse
|
|
21
|
Okugawa Y, Grady WM, Goel A. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Gastroenterology 2015; 149:1204-1225.e12. [PMID: 26216839 PMCID: PMC4589488 DOI: 10.1053/j.gastro.2015.07.011] [Citation(s) in RCA: 536] [Impact Index Per Article: 53.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 07/13/2015] [Accepted: 07/20/2015] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer "epigenome" has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, are presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.
Collapse
Affiliation(s)
- Yoshinaga Okugawa
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington.
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
| |
Collapse
|
|
22
|
Kostakis ID, Agrogiannis G, Vaiopoulos AG, Mylona E, Patsouris E, Kouraklis G, Koutsilieris M. A clinicopathological analysis of KISS1 and KISS1R expression in colorectal cancer. APMIS 2015; 123:629-37. [PMID: 26010933 DOI: 10.1111/apm.12397] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Accepted: 03/11/2015] [Indexed: 02/01/2023]
Abstract
Kisspeptins, the products of the KISS1 gene have tumor suppressing and antimetastatic properties. We aimed to study KISS1 and KISS1R expression in colorectal cancer. We analyzed KISS1 and KISS1R expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 111 patients with colorectal adenocarcinoma. KISS1 expression was much higher in the normal than in the malignant colonic mucosa. Regarding malignant tissues, KISS1 levels were higher in larger tumors, in stage III and IV cancers, in cancers with lymph node metastasis and in tumors located in the distal part of the large intestine. Patients with greater KISS1 levels had worse prognosis. No KISS1R expression was detected in normal or malignant tissues or in liver metastases. KISS1 expression is reduced during the malignant transformation of the colonic mucosa. However, larger and advanced colorectal cancers express more KISS1, without reaching the former normal levels, and increased KISS1 levels are associated with worse prognosis. Finally, neither the normal nor the malignant colonic epithelial cells produce KISS1R.
Collapse
Affiliation(s)
- Ioannis D Kostakis
- Second Department of Propedeutic Surgery, "Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.,Department of Experimental Physiology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - George Agrogiannis
- First Department of Pathology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Aristeidis G Vaiopoulos
- Second Department of Propedeutic Surgery, "Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.,Department of Experimental Physiology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Eleni Mylona
- First Department of Pathology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Efstratios Patsouris
- First Department of Pathology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Gregory Kouraklis
- Second Department of Propedeutic Surgery, "Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Michael Koutsilieris
- Department of Experimental Physiology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| |
Collapse
|
|
23
|
Prabhu VV, Sakthivel KM, Guruvayoorappan C. Kisspeptins (KiSS-1): essential players in suppressing tumor metastasis. Asian Pac J Cancer Prev 2015; 14:6215-20. [PMID: 24377507 DOI: 10.7314/apjcp.2013.14.11.6215] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Kisspeptins (KPs) encoded by the KiSS-1 gene are C-terminally amidated peptide products, including KP- 10, KP-13, KP-14 and KP-54, which are endogenous agonists for the G-protein coupled receptor-54 (GPR54). Functional analyses have demonstrated fundamental roles of KiSS-1 in whole body homeostasis including sexual differentiation of brain, action on sex steroids and metabolic regulation of fertility essential for human puberty and maintenance of adult reproduction. In addition, intensive recent investigations have provided substantial evidence suggesting roles of Kisspeptin signalling via its receptor GPR54 in the suppression of metastasis with a variety of cancers. The present review highlights the latest studies regarding the role of Kisspeptins and the KiSS-1 gene in tumor progression and also suggests targeting the KiSS-1/GPR54 system may represent a novel therapeutic approach for cancers. Further investigations are essential to elucidate the complex pathways regulated by the Kisspeptins and how these pathways might be involved in the suppression of metastasis across a range of cancers.
Collapse
|
|
24
|
Zhang Y, Huang Z, Zhu Z, Zheng X, Liu J, Han Z, Ma X, Zhang Y. Upregulated UHRF1 promotes bladder cancer cell invasion by epigenetic silencing of KiSS1. PLoS One 2014; 9:e104252. [PMID: 25272010 PMCID: PMC4182677 DOI: 10.1371/journal.pone.0104252] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 07/07/2014] [Indexed: 01/07/2023] Open
Abstract
Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), as an epigenetic regulator, plays important roles in the tumorigenesis and cancer progression. KiSS1 functions as a metastasis suppressor in various cancers, and epigenetic silencing of KiSS1 increases the metastatic potential of cancer cells. We therefore investigated whether UHRF1 promotes bladder cancer cell invasion by inhibiting KiSS1. The expression levels of UHRF1 and KiSS1 were examined by quantitative real-time PCR assay in vitro and in vivo. The role of UHRF1 in regulating bladder cancer metastasis was evaluated in bladder cancer cell. We found that UHRF1 levels are upregulated in most clinical specimens of bladder cancer when compared with paired normal tissues, and UHRF1 expression levels are significantly increased in primary tumors that subsequently metastasized compared with non-metastatic tumors. Forced expression of UHRF1 promotes bladder cancer cell invasion, whereas UHRF1 knockdown decreases cell invasion. Overexpression of UHRF1 increases the methylation of CpG nucleotides and reduces the expression of KiSS1. UHRF1 and KiSS1 expression level is negatively correlated in vivo and in vitro. Knockdown of KiSS1 promotes bladder cancer cell invasion. Importantly, forced expression of KiSS1 partly abrogates UHRF1-induced cell invasion. These data demonstrated that upregulated UHRF1 increases bladder cancer cell invasion by epigenetic silencing of KiSS1.
Collapse
Affiliation(s)
- Yu Zhang
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Department of Urology, Beijing You An Hospital, Capital Medical University, Beijing, China
- * E-mail: (YZ); (YhZ)
| | - Zhen Huang
- Department of Urology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Zhiqiang Zhu
- Department of Urology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Xin Zheng
- Department of Urology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Jianwei Liu
- Department of Urology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Zhiyou Han
- Department of Urology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Xuetao Ma
- Department of Urology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yuhai Zhang
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- * E-mail: (YZ); (YhZ)
| |
Collapse
|
|
25
|
Ji K, Ye L, Ruge F, Hargest R, Mason MD, Jiang WG. Implication of metastasis suppressor gene, Kiss-1 and its receptor Kiss-1R in colorectal cancer. BMC Cancer 2014; 14:723. [PMID: 25260785 PMCID: PMC4190326 DOI: 10.1186/1471-2407-14-723] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 09/19/2014] [Indexed: 12/27/2022] Open
Abstract
Background Kiss-1 and Kiss-1R have been suggested as a novel pair of metastasis suppressors for several human solid tumours, however, their role in colorectal cancer remains largely unknown. Therefore, the aim of this study was to investigate the role and signal transduction of Kiss-1 and Kiss-1R in colorectal cancer. Methods Ribozyme transgenes were used to knockdown high expression of Kiss-1 and Kiss-1R in HT115 and HRT18 cells. The stabilized transfected cells were then used to deduce the influence of Kiss-1 and Kiss-1R on the function of colorectal cancer cells by in vitro assays and ECIS assay. The effect of Kiss-1 on MMPs related to tumour metastasis was also deleted by zymography. The mRNA and protein expression of Kiss-1 and Kiss-1R, and their correlation to the clinical outcome in human colorectal cancer were investigated using real-time PCR and IHC respectively. Results Knocking down Kiss-1 resulted in increased invasion and migration of colorectal cancer cells. Kisspeptin-10 decreased cellular migration of colorectal cancer cells and required ERK signaling as shown during the ECIS based analyses. Reduction of MMP-9 was caused by Kisspeptin-10 and ERK inhibitor, shown by zymography. In human colorectal cancer tissues, the mRNA expression level of Kiss-1 had a negative correlation with Dukes staging, TNM staging, tumour size and lymph node involvement. Reduction of Kiss-1R was also linked to poor prognosis for the patients. Conclusions The present study has presented evidence that Kiss-1 may be a putative metastasis suppressor molecule in human colorectal cancer.
Collapse
Affiliation(s)
| | | | | | | | | | - Wen G Jiang
- Cardiff University-Peking University Joint Oncology Institute, Metastasis & Angiogenesis Research Group, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
| |
Collapse
|
|
26
|
Chen SQ, Chen ZH, Lin SY, Dai QB, Fu LX, Chen RQ. KISS1 methylation and expression as predictors of disease progression in colorectal cancer patients. World J Gastroenterol 2014; 20:10071-10081. [PMID: 25110434 PMCID: PMC4123336 DOI: 10.3748/wjg.v20.i29.10071] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/07/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the effect of aberrant methylation of the KISS1 promoter on the development of colorectal cancer (CRC) and to investigate reversing aberrant methylation of the KISS1 promoter as a potential therapeutic target.
METHODS: KISS1 promoter methylation, mRNA expression and protein expression were detected by methylation-specific polymerase chain reaction (PCR), real-time quantitative PCR and Western blotting, respectively, in 126 CRC tissues and 142 normal colorectal tissues. Human CRC cells with KISS1 promoter hypermethylation and poor KISS1 expression were treated in vitro with 5-aza-2’-deoxycytidine (5-Aza-CdR). After treatment, KISS1 promoter methylation, KISS1 mRNA and protein expression and cell migration and invasion were evaluated.
RESULTS: Hypermethylation of KISS1 occurred frequently in CRC samples (83.1%, 105/126), but was infrequent in normal colorectal tissues (6.34%, 9/142). Moreover, KISS1 methylation was associated with tumor differentiation, the depth of invasion, lymph node metastasis and distant metastasis (P < 0.001). KISS1 methylation was also associated with low KISS1 expression (P < 0.001). Furthermore, we observed re-expression of the KISS1 gene and decreased cell migration after 5-Aza-CdR treatment in a CRC cell line.
CONCLUSION: These data suggest that KISS1 is down-regulated in cancer tissues via promoter hypermethylation and therefore may represent a candidate target for treating metastatic CRC.
Collapse
|
|
27
|
Identification and comparison of aberrant key regulatory networks in breast, colon, liver, lung, and stomach cancers through methylome database analysis. PLoS One 2014; 9:e97818. [PMID: 24842468 PMCID: PMC4026530 DOI: 10.1371/journal.pone.0097818] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 04/24/2014] [Indexed: 12/29/2022] Open
Abstract
Aberrant methylation of specific CpG sites at the promoter is widely responsible for genesis and development of various cancer types. Even though the microarray-based methylome analyzing techniques have contributed to the elucidation of the methylation change at the genome-wide level, the identification of key methylation markers or top regulatory networks appearing common in highly incident cancers through comparison analysis is still limited. In this study, we in silico performed the genome-wide methylation analysis on each 10 sets of normal and cancer pairs of five tissues: breast, colon, liver, lung, and stomach. The methylation array covers 27,578 CpG sites, corresponding to 14,495 genes, and significantly hypermethylated or hypomethylated genes in the cancer were collected (FDR adjusted p-value <0.05; methylation difference >0.3). Analysis of the dataset confirmed the methylation of previously known methylation markers and further identified novel methylation markers, such as GPX2, CLDN15, and KL. Cluster analysis using the methylome dataset resulted in a diagram with a bipartite mode distinguishing cancer cells from normal cells regardless of tissue types. The analysis further revealed that breast cancer was closest with lung cancer, whereas it was farthest from colon cancer. Pathway analysis identified that either the “cancer” related network or the “cancer” related bio-function appeared as the highest confidence in all the five cancers, whereas each cancer type represents its tissue-specific gene sets. Our results contribute toward understanding the essential abnormal epigenetic pathways involved in carcinogenesis. Further, the novel methylation markers could be applied to establish markers for cancer prognosis.
Collapse
|
|
28
|
Zhang Y, Tang YJ, Li ZH, Pan F, Huang K, Xu GH. KiSS1 inhibits growth and invasion of osteosarcoma cells through inhibition of the MAPK pathway. Eur J Histochem 2013; 57:e30. [PMID: 24441183 PMCID: PMC3896032 DOI: 10.4081/ejh.2013.e30] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 09/16/2013] [Accepted: 09/17/2013] [Indexed: 01/05/2023] Open
Abstract
As a metastasis suppressor, KiSS1 has been implicated in numerous human cancers. However, recent studies have demonstrated that KiSS1 promotes tumor growth and metastasis in breast cancer, and it is unclear about the expression and function of KiSS1 in human osteosarcoma (OS). The aim of the present study was to investigate the role and molecular mechanisms of KiSS1 in human OS. The expression of KiSS1 was assessed by immunohistochemical assay using a tissue microarray procedure in forty cases of OS tissues. A gain-of-function approach was used to observe the effects of lentiviral vector-mediated overexpression of KiSS1 (Lv-KiSS1) on the biological behaviors including proliferative activities and invasive potential of OS MG-63 cells, indicated by MTT and Transwell assays, respectively. The results showed that the expression of KiSS1 protein in OS tissues was significantly lowered compared to that in adjacent non-cancerous tissues (ANCT) (42.5% vs 70.0%, P=0.023), and had negative correlation with distant metastases of the tumor (P=0.019). Overexpression of KiSS1 inhibited proliferation and invasion of OS cells with the decreased expression of p38 MAPK and matrix metalloproteinase-9 (MMP-9). Taken together, our findings indicate that the decreased expression of KiSS1 is correlated with distant metastasis of OS, and KiSS1 may function as a tumor suppressor in OS cells through inhibition of the MAPK pathway, suggesting that KiSS1 may serve as a potential therapeutic target for the treatment of cancer.
Collapse
Affiliation(s)
- Y Zhang
- Zhabei District Central Hospital.
| | | | | | | | | | | |
Collapse
|
|
29
|
Cvetković D, Babwah AV, Bhattacharya M. Kisspeptin/KISS1R System in Breast Cancer. J Cancer 2013; 4:653-61. [PMID: 24155777 PMCID: PMC3805993 DOI: 10.7150/jca.7626] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 09/22/2013] [Indexed: 01/18/2023] Open
Abstract
Kisspeptins (KP), peptide products of the kisspeptin-1 (KISS1) gene are the endogenous ligands for a G protein-coupled receptor (GPCR) - KP receptor (KISS1R). KISS1R couples to the Gαq/11 signaling pathway. KISS1 is a metastasis suppressor gene and the KP/KISS1R signaling has anti-metastatic and tumor-suppressant effects in numerous human cancers. On the other hand, recent studies indicate that KP/KISS1R pathway plays detrimental roles in breast cancer. In this review, we summarize recent developments in the understanding of the mechanisms regulating KP/KISS1R signaling in breast cancer metastasis.
Collapse
Affiliation(s)
- Donna Cvetković
- 1. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, N6A 5C1
| | | | | |
Collapse
|
|
30
|
Kostakis ID, Agrogiannis G, Vaiopoulos AG, Mylona E, Patsouris E, Kouraklis G, Koutsilieris M. KISS1 expression in colorectal cancer. APMIS 2013; 121:1004-10. [PMID: 24033850 DOI: 10.1111/apm.12161] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 07/12/2013] [Indexed: 12/20/2022]
Abstract
Kisspeptins, the products of the KISS1 gene, are involved in cancer invasion, migration, metastasis and angiogenesis, while they induce apoptosis in various cancers. Herein, we studied KISS1 expression in colorectal cancer. We analyzed KISS1 expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 60 patients with colorectal adenocarcinoma. The results correlated with various clinicopathological parameters. The expression of KISS1 was much higher in normal than in malignant colonic mucosa. However, among malignant tissues, KISS1 expression was higher in larger tumors (>4 cm) than in smaller ones (≤4 cm) and in stages III and IV than in stages I and II. In addition, it was higher in patients with lymph node metastases. Moreover, KISS1 levels in the normal mucosa and their difference from those in the malignant mucosa were higher in the right part of the large intestine than in the left one. KISS1 expression is reduced during the malignant transformation of the colonic mucosa and there is a difference in the expression pattern between the right and the left part of the large intestine. However, larger and advanced colorectal tumors express higher KISS1 levels than smaller and localized ones.
Collapse
Affiliation(s)
- Ioannis D Kostakis
- Second Department of Propedeutic Surgery, "Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School, Athens; Department of Experimental Physiology, National and Kapodistrian University of Athens, Medical School, Athens
| | | | | | | | | | | | | |
Collapse
|
|
31
|
SONG GUOQING, ZHAO YI. Different therapeutic effects of distinct KISS1 fragments on breast cancer in vitro and in vivo. Int J Oncol 2013; 43:1219-27. [DOI: 10.3892/ijo.2013.2029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Accepted: 07/07/2013] [Indexed: 11/06/2022] Open
|
|
32
|
Sun YB, Xu S. Expression of KISS1 and KISS1R (GPR54) may be used as favorable prognostic markers for patients with non-small cell lung cancer. Int J Oncol 2013; 43:521-30. [PMID: 23716269 DOI: 10.3892/ijo.2013.1967] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 04/29/2013] [Indexed: 11/06/2022] Open
Abstract
Lung cancer is the most commonly diagnosed cancer worldwide. Loss of KISS1 expression has been associated with progression and poor prognosis of various cancers, however, the precise role of KISS1 expression in non-small cell lung cancer (NSCLC) is not well defined. KISS1 receptor (KISS1R, also named GPR54) coupled to KISS1, has been shown to play a pivotal role in suppressing cancer metastasis. In this study, 56 NSCLC specimens were divided into stage IIIB (locally advanced) and stage IV (metastatic). The mRNA and protein levels of KISS1 and KISS1R in cancer tissues were found to be lower compared to that in normal tissues using RT-PCR and western blot analysis, respectively. In addition, the expression of both KISS1 and KISS1R in stage IV NSCLC was lower compared to that in stage IIIB stage NSCLC. The cumulative survival rate of the patients with KISS1 or KISS1R expression was significantly higher compared to that without expression. KISS1 or KISS1R expression in NSCLC can be used to indicate favorable prognosis for disease outcome. Metastin, the product of the KISS1 gene, was lower in the serum of patients with stage IV NSCLC compared to that in stage IIIB NSCLC.
Collapse
Affiliation(s)
- Yan-Bin Sun
- Department of Thoracic Surgery, The First Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, PR China
| | | |
Collapse
|
|
33
|
Semaan SJ, Kauffman AS. Emerging concepts on the epigenetic and transcriptional regulation of the Kiss1 gene. Int J Dev Neurosci 2013; 31:452-62. [PMID: 23510953 DOI: 10.1016/j.ijdevneu.2013.03.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 03/09/2013] [Accepted: 03/10/2013] [Indexed: 12/23/2022] Open
Abstract
Kisspeptin and its receptor have been implicated as critical regulators of reproductive physiology, with humans and mice without functioning kisspeptin systems displaying severe pubertal and reproductive defects. Alterations in the expression of Kiss1 (the gene encoding kisspeptin) over development, along with differences in Kiss1 expression between the sexes in adulthood, may be critical for the maturation and functioning of the neuroendocrine reproductive system and could possibly contribute to pubertal progression, sex differences in luteinizing hormone secretion, and other facets of reproductive physiology. It is therefore essential to understand how Kiss1 gene expression develops and what possible regulatory mechanisms govern the modulation of its expression. A number of recent studies, primarily in rodent or cell line models, have focused on the contributions of epigenetic mechanisms to the regulation of Kiss1 gene expression; thus far, mechanisms such as DNA methylation, histone acetylation, and histone methylation have been investigated. This review discusses the most recent findings on the epigenetic control of Kiss1 expression in adulthood, the evidence for epigenetic factors affecting Kiss1 expression during puberty and development, and findings regarding the contribution of epigenetics to the sexually dimorphic expression of Kiss1 in the hypothalamus.
Collapse
Affiliation(s)
- Sheila J Semaan
- University of California San Diego, Department of Reproductive Medicine, La Jolla, CA 92093, USA
| | | |
Collapse
|