|
1
|
Zhao K, Li X, Feng Y, Wang J, Yao W. The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside. Biomark Res 2024; 12:30. [PMID: 38433242 PMCID: PMC10910842 DOI: 10.1186/s40364-024-00559-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 01/03/2024] [Indexed: 03/05/2024] Open
Abstract
As a major component of the digestive system malignancies, tumors originating from the hepatic and biliary ducts seriously endanger public health. The kinesins (KIFs) are molecular motors that enable the microtubule-dependent intracellular trafficking necessary for mitosis and meiosis. Normally, the stability of KIFs is essential to maintain cell proliferation and genetic homeostasis. However, aberrant KIFs activity may destroy this dynamic stability, leading to uncontrolled cell division and tumor initiation. In this work, we have made an integral summarization of the specific roles of KIFs in hepatocellular and biliary duct carcinogenesis, referring to aberrant signal transduction and the potential for prognostic evaluation. Additionally, current clinical applications of KIFs-targeted inhibitors have also been discussed, including their efficacy advantages, relationship with drug sensitivity or resistance, the feasibility of combination chemotherapy or other targeted agents, as well as the corresponding clinical trials. In conclusion, the abnormally activated KIFs participate in the regulation of tumor progression via a diverse range of mechanisms and are closely associated with tumor prognosis. Meanwhile, KIFs-aimed inhibitors also carry out a promising tumor-targeted therapeutic strategy that deserves to be further investigated in hepatobiliary carcinoma (HBC).
Collapse
Affiliation(s)
- Kai Zhao
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Xiangyu Li
- Department of Thoracic Surgery Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Yunxiang Feng
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Jianming Wang
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
- Affiliated Tianyou Hospital, Wuhan University of Science & Technology, 430064, Wuhan, China.
| | - Wei Yao
- Department of Oncology Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
| |
Collapse
|
|
2
|
Che L, Wu JS, Du ZB, He YQ, Yang L, Lin JX, Lei Z, Chen XX, Guo DB, Li WG, Lin YC, Lin ZN. Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14030821. [PMID: 35159089 PMCID: PMC8834292 DOI: 10.3390/cancers14030821] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/27/2022] [Accepted: 02/03/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary New therapeutic strategies are urgently needed to improve the anti-cancer effect for hepatocellular carcinoma (HCC). Overexpression of cyclooxygenase-2 (COX-2) is found in several types of cancers and correlates with a poor prognosis. However, it remains unclear how the mitochondrial translocation of COX-2 is involved in mitochondrial dynamics and sensitizes HCC cells to multipattern anti-tumor therapy. We explored the impact of targeting mitochondrial COX-2 (mito-COX-2) intervention toward mitochondrial dynamics on platinum-based chemotherapeutics in HCC cells and xenograft nude mouse models. Our study indicates that the mito-COX-2 represents a candidate predictive biomarker and potential target to regulate anti-cancer sensitization of HCC, and possibly for other types of COX-2-high-expression cancers. Abstract Mitochondria are highly dynamic organelles and undergo constant fission and fusion, which are both essential for the maintenance of cell physiological functions. Dysregulation of dynamin-related protein 1 (Drp1)-dependent mitochondrial dynamics is associated with tumorigenesis and the chemotherapeutic response in hepatocellular carcinoma (HCC). The enzyme cyclooxygenase-2 (COX-2) is overexpressed in most cancer types and correlates with a poor prognosis. However, the roles played by the translocation of mitochondrial COX-2 (mito-COX-2) and the interaction between mito-COX-2 and Drp1 in chemotherapeutic responses remain to be elucidated in the context of HCC. Bioinformatics analysis, paired HCC patient specimens, xenograft nude mice, immunofluorescence, transmission electron microscopy, molecular docking, CRISPR/Cas9 gene editing, proximity ligation assay, cytoplasmic and mitochondrial fractions, mitochondrial immunoprecipitation assay, and flow cytometry analysis were performed to evaluate the underlying mechanism of how mito-COX-2 and p-Drp1Ser616 interaction regulates the chemotherapeutic response via mitochondrial dynamics in vitro and in vivo. We found that COX-2 and Drp1 were frequently upregulated and confer a poor prognosis in HCC. We also found that the proportion of mito-COX-2 and p-Drp1Ser616 was increased in HCC cell lines. In vitro, we demonstrated that the enhanced mitochondrial translocation of COX-2 promotes its interaction with p-Drp1Ser616 via PTEN-induced putative kinase 1 (PINK1)-mediated Drp1 phosphorylation activation. This increase was associated with higher colony formation, cell proliferation, and mitochondrial fission. These findings were confirmed by knocking down COX-2 in HCC cells using CRISPR/Cas9 technology. Furthermore, inhibition of Drp1 using pharmacologic inhibitors (Mdivi-1) or RNA interference (siDNM1L) decreased mito-COX-2/p-Drp1Ser616 interaction-mediated mitochondrial fission, and increased apoptosis in HCC cells treated with platinum drugs. Moreover, inhibiting mito-COX-2 acetylation with the natural phytochemical resveratrol resulted in reducing cell proliferation and mitochondrial fission, occurring through upregulation of mitochondrial deacetylase sirtuin 3 (SIRT3), which, in turn, increased the chemosensitivity of HCC to platinum drugs in vitro and in vivo. Our results suggest that targeting interventions to PINK1-mediated mito-COX-2/p-Drp1Ser616-dependent mitochondrial dynamics increases the chemosensitivity of HCC and might help us to understand how to use the SIRT3-modulated mito-COX-2/p-Drp1Ser616 signaling axis to develop an effective clinical intervention in hepatocarcinogenesis.
Collapse
Affiliation(s)
- Lin Che
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
| | - Jia-Shen Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
| | - Ze-Bang Du
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
| | - Yu-Qiao He
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
| | - Lei Yang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
| | - Jin-Xian Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
| | - Zhao Lei
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
| | - Xiao-Xuan Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
| | - Dong-Bei Guo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
| | - Wen-Gang Li
- Department of Hepatobiliary Surgery and Pancreatic & Organ Transplantation Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China;
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Yu-Chun Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
- Correspondence: (Y.-C.L.); (Z.-N.L.); Tel.: +86-592-2880615 (Y.-C.L.); Fax: +86-592-2881578 (Y.-C.L.)
| | - Zhong-Ning Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (L.C.); (J.-S.W.); (Z.-B.D.); (Y.-Q.H.); (L.Y.); (J.-X.L.); (Z.L.); (X.-X.C.); (D.-B.G.)
- Correspondence: (Y.-C.L.); (Z.-N.L.); Tel.: +86-592-2880615 (Y.-C.L.); Fax: +86-592-2881578 (Y.-C.L.)
| |
Collapse
|
|
3
|
Srivani Nagam L, Vadde R, Jinka R. Polymorphisms in hepatocellular carcinoma. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA 2022:125-133. [DOI: 10.1016/b978-0-323-98806-3.00013-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
4
|
Zhong X, Luo M, Wu Y, Zhou X, Yu X, Liu L, Chen S. Genetic variants in STAT4 and their interactions with environmental factors for the incidence of hepatocellular carcinoma. Cancer Biomark 2021; 32:3-9. [PMID: 33896832 DOI: 10.3233/cbm-203162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND A recent genome-wide association study (GWAS) has posed STAT4 as a promising susceptibility gene for hepatocellular carcinoma (HCC). However, the most significant variant in this GWAS, rs7574865, yielded inconsistent results. OBJECTIVE This study, in a Southern Chinese population, was aimed to clarify the roles in HCC incidence of the rs7574865 and other two potentially functional variants, rs897200 and rs1031507 in STAT4. METHODS This study enrolled 631 new HCC cases and 631 cancer-free controls. The genetic association was estimated using the multivariate logistic regression model. The pairwise gene-environment interactions were assessed using the multiplicative term in regression model and the "Delta" method for the additive scale. RESULTS In the multivariate analysis, the rs7574865 TT genotype conferred a decreased risk of HCC compared to the GG genotype (adjusted OR = 0.62, 95%CI = 0.38∼0.99). The significant association of rs7574865 was also observed under the additive genetic model, with an adjusted OR of 0.81 (95%CI = 0.65∼0.99). Nevertheless, other two variants alone showed no significant association, as well as the haplotypes and genetic risk scores. Further analysis indicated a potential interaction between the rs897200 and alcohol drinking (P= 0.048 and 0.072 for additive and multiplicative interactions, respectively). Drinkers with the rs897200 CT+CC genotypes presented an increased disease-risk, as compared with non-drinkers carrying the TT genotype (adjusted OR = 1.68, 95%CI = 1.11∼2.54). CONCLUSIONS The variant in STAT4, rs7574865, serves as a potential marker for predicting incidence of HCC. The rs897200 variant possibly interplays with alcohol drinking to alter HCC risk in the Southern Chinese, but warrants further investigation.
Collapse
Affiliation(s)
- Xuan Zhong
- Department of Tumor, Injury and Nutrition, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, Guangdong, China.,Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Meihua Luo
- Shunde Hospital of Southern Medical University, Foshan, Guangdong, China
| | - Yanmei Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Xinfeng Zhou
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Xinfa Yu
- Shunde Hospital of Southern Medical University, Foshan, Guangdong, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Sidong Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
5
|
Wu Y, Lin Z, Luo M, Yu X, Chen S, Liu L. Effects of genetic polymorphisms in INTS10 and their interaction with environmental factors on progression from persistent HBV infection to hepatocellular carcinoma. Mol Carcinog 2021; 60:620-626. [PMID: 34133796 DOI: 10.1002/mc.23328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/23/2021] [Accepted: 06/04/2021] [Indexed: 12/28/2022]
Abstract
Genome-wide association study recently identified a novel antiviral gene INTS10 (index rs7000921) in suppression of hepatitis B virus (HBV) replication. However, data were lacking on single nucleotide polymorphisms (SNPs) of INTS10 in the context of hepatocellular carcinoma (HCC) induced by HBV infection. Herein, we conducted a case-control study, including 737 HBV-related HCC cases and 750 persistently HBV-infected controls, to investigate the effect of INTS10 SNPs and their gene-environment interactions on HBV-related HCC. In multivariate analysis, the CT genotype of rs7000921 conferred a decreased risk of HBV-related HCC compared to the TT genotype (adjusted odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64-0.98, p for permutation test = .038). Among the 12 tagSNPs, the rs4268139 yielded a borderline significant association with disease risk under the additive model (adjusted OR = 0.80, 95% CI = 0.63-1.00, p for permutation test = .061). Random forest model further suggested the rs7000921 and rs7822495 as the two-top ranked important SNPs, and thus a weighted genetic risk score (wGRS) was generated from these two SNPs plus rs4268139. The highest tertile of wGRS was associated with an increased risk, with an adjusted OR of 1.36 (95% CI = 1.05-1.75, p for permutation test = .016) compared to the lowest wGRS. Furthermore, an additive interaction was seen between wGRS and drinking (attributable proportion due to interaction [AP] = 0.21, 95% CI = 0.02-0.43, p = .016). The additive interaction between wGRS and smoking approached near significance (AP = 0.15, 95% CI = 0.00-0.32, p = .045). INTS10 polymorphisms may contribute to the progression from HBV infection to HCC. More importantly, INTS10 polymorphisms interact with drinking and smoking to affect the progression.
Collapse
Affiliation(s)
- Yanmei Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Zibo Lin
- Department of Prevention and Health Care, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Meihua Luo
- Shunde Hospital of Southern Medical University, Foshan, Guangdong, China
| | - Xinfa Yu
- Shunde Hospital of Southern Medical University, Foshan, Guangdong, China
| | - Sidong Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
6
|
Chen FT, Zhong FK. Kinesin Family Member 18A (KIF18A) Contributes to the Proliferation, Migration, and Invasion of Lung Adenocarcinoma Cells In Vitro and In Vivo. DISEASE MARKERS 2019; 2019:6383685. [PMID: 31772692 PMCID: PMC6854991 DOI: 10.1155/2019/6383685] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 04/13/2019] [Accepted: 09/16/2019] [Indexed: 12/25/2022]
Abstract
OBJECTIVE To determine the expression levels of KIF18A in lung adenocarcinoma and its relationship with the clinicopathologic features of patients undergoing radical colectomy and explore the potential role in the progression of lung adenocarcinoma. METHODS Immunohistochemical assays were performed to explore the expression levels of KIF18A in 82 samples of lung adenocarcinoma and corresponding normal tissues. According to the levels of KIF18A expression in lung adenocarcinoma tissue samples, patients were classified into the KIF18A high expression group and low expression group. Clinical data related to the perioperative clinical features (age, gender, smoking, tumor size, differentiation, clinical stage, and lymph node metastasis), the potential correlation between KIF18A expression levels, and clinical features were analyzed, and the effects of KIF18A on lung adenocarcinoma cell proliferation, migration, and invasion were measured by colony formation assay, MTT assay, wound healing assay, and transwell assays. The possible effects of KIF18A on tumor growth and metastasis were measured in mice through tumor growth and tumor metastasis assays in vivo. RESULTS KIF18A in lung adenocarcinoma tissues. Further, KIF18A was significantly associated to clinical characteristic features including the tumor size (P = 0.033) and clinical stage (P = 0.041) of patients with lung adenocarcinoma. Our data also investigated that KIF18A depletion dramatically impairs the proliferation, migration, and invasion capacity of lung adenocarcinoma cells in vitro and inhibits tumor growth and metastasis in mice. CONCLUSIONS Our study reveals the involvement of KIF18A in the progression and metastasis of lung adenocarcinoma and provides a novel therapeutic target for the treatment of lung adenocarcinoma.
Collapse
Affiliation(s)
- Fu-Tao Chen
- Department of Respiratory Medicine, The Second People's Hospital of Lianyungang, No. 161, Xingfu Road, Haizhou District, Lianyungang City, 222023 Jiangsu Province, China
| | - Fu-Kuan Zhong
- Department of Respiratory Medicine, The Second People's Hospital of Lianyungang, No. 161, Xingfu Road, Haizhou District, Lianyungang City, 222023 Jiangsu Province, China
| |
Collapse
|
|
7
|
Ji X, Zhang J, Liu L, Lin Z, Pi L, Lin Z, Tian N, Lin X, Chen S, Yu X, Gao Y. Association of tagSNPs at lncRNA MALAT-1 with HCC Susceptibility in a Southern Chinese Population. Sci Rep 2019; 9:10895. [PMID: 31350456 PMCID: PMC6659651 DOI: 10.1038/s41598-019-47165-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 07/10/2019] [Indexed: 12/20/2022] Open
Abstract
As a long non-coding RNA (lncRNA) and a transcriptional regulator, Metastasis associated lung adenocarcioma transcript-1 (MALAT-1) has been reported to be associated with proliferation and metastasis of hepatocellular carcinoma (HCC). However, the effects of MALAT-1 single nucleotide polymorphisms (SNPs) on HCC remains poorly understood. This study, including 624 HCC cases and 618 controls, aimed to explore the potential associations between three common tagSNPs at MALAT-1 and HCC risk in a Southern Chinese population. No significant associations were observed between the three tagSNPs and HCC risk under any genetic models after adjusting for potential confounders. Additionally, there were no any significant associations in the stratified analysis, combined effect analysis, and multifactor dimensionality reduction (MDR) analysis. Unification analysis of mediation and interaction on HCC risk further showed that four decomposition of total effects ((controlled direct effect (CDE), the reference interaction effect (INTref), the mediated interaction effect (INTmed), or the pure indirect effect (PIE)) were also not significant. Neither was the association between the MALAT-1 SNPs and progression factors of HCC, including TNM staging, metastasis, and cancer embolus; Overall, this study suggested that tagSNPs rs11227209, rs619586, and rs3200401 at MALAT-1 were not significantly associated with HCC susceptibility. Nevertheless, large population-based studies are warranted to further explore the role of MALAT-1 SNPs in HCC incidence and development.
Collapse
Affiliation(s)
- Xiaohui Ji
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Junguo Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Ziqiang Lin
- Department of Psychiatry, New York University Langone School of Medicine, One Park Ave, New York, NY, 10016, USA
| | - Lucheng Pi
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Zhifeng Lin
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Nana Tian
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Xinqi Lin
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Sidong Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Xinfa Yu
- Shunde Hospital of Southern Medical University, Foshan, Guangzhou, China.
| | - Yanhui Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China.
| |
Collapse
|
|
8
|
Luo YY, Zhang HP, Huang AL, Hu JL. Association between KIF1B rs17401966 genetic polymorphism and hepatocellular carcinoma susceptibility: an updated meta-analysis. BMC MEDICAL GENETICS 2019; 20:59. [PMID: 30947687 PMCID: PMC6449895 DOI: 10.1186/s12881-019-0778-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 03/03/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several studies have focused on the association between KIF1B rs17401966 polymorphism and susceptibility to hepatitis B virus-related (HBV-related) hepatocellular carcinoma (HCC), but the conclusions have been inconsistent. We have conducted this updated meta-analysis to explore the association between KIF1B rs17401966 polymorphism and HCC susceptibility. METHODS Eligible studies were identified through systematic searches in PubMed, OVID, ISI Web of Science, Chinese National Knowledge Infrastructure, and Wanfang databases. The quality of evidence was systematically assessed by use of the Newcastle-Ottawa Scale for case control studies in meta-analyses. RESULTS Ten studies containing 18 independent case-control studies were included. The results revealed a significant association between KIF1B rs17401966 polymorphism and susceptibility to HCC under a random-effect allelic model (OR = 0.85, 95% CI 0.76-0.94, P = 0.003); HBV-positive subgroup (OR = 0.82, 95% CI 0.72-0.95, P = 0.007); and Chinese-subgroup (OR = 0.82, 95% CI 0.72-0.93, P = 0.002). CONCLUSIONS G-allele appears to be a protective allele of KIF1B for HCC, especially in HBV-positive and Chinese populations. More well-designed studies with larger sample size and various ethnic groups and risk factors are needed to establish that KIF1B rs17401966 polymorphism is significantly associated with risk of HCC.
Collapse
Affiliation(s)
- Ying-Ying Luo
- Intensive Care Unit, The Third People's Hospital of Chengdu, The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, Sichuan, China.,Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong-Peng Zhang
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ai-Long Huang
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Jie-Li Hu
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| |
Collapse
|
|
9
|
Zhang YF, Zeng XL, Lu HW, Ji H, Lu L, Liu PD, Hong RF, Li YM. Association between KIF1B (rs17401966) polymorphism and hepatocellular carcinoma susceptibility: a meta-analysis. Onco Targets Ther 2018; 11:3225-3235. [PMID: 29881295 PMCID: PMC5985779 DOI: 10.2147/ott.s162205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Introduction The results of the earlier published studies on the association between KIF1B (rs17401966) polymorphism and hepatocellular carcinoma (HCC) risk are inconclusive. Hence, we performed this meta-analysis to evaluate the relationship between KIF1B (rs17401966) polymorphism and HCC risk. Methods Databases including PubMed, Web of Science and the Cochrane Library and bibliographies of relevant papers were screened to identify relevant studies published up to March 25, 2018. Pooled ORs and 95% CIs were calculated to evaluate the association. The subgroup analysis was conducted based on ethnicity, age, region and environment. A total of 19 studies from 11 eligible articles published from 2010 to 2016, with 8,741 cases and 10,812 controls, were included. Results The pooled results indicated that the association between KIF1B (rs17401966) polymorphism and the decreased HCC risk was significant. Subgroup analysis stratified by ethnicity showed the same association in Chinese, but not in non-Chinese population. When stratified by age, both old and young patients showed a decrease in HCC risk. When stratified by region, we detected the same association in Chinese in southern China. Similarly when stratified by environment, we observed the same association in Chinese in inland areas; however, no statistically significant association was observed in those in coastal areas. Conclusion This meta-analysis suggested that KIF1B (rs17401966) polymorphism could decrease HCC risk in Chinese and in overall population, but not in non-Chinese. This association remained significant in Chinese in southern China and inland areas, but not in those in northern and central China and coastal areas. Further large-scale multicenter studies are warranted to confirm these findings.
Collapse
Affiliation(s)
- Ya-Fei Zhang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xian-Ling Zeng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hong-Wei Lu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hong Ji
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Le Lu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Peng-di Liu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ruo-Feng Hong
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi-Ming Li
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| |
Collapse
|
|
10
|
The association of lncRNA-HULC polymorphisms with hepatocellular cancer risk and prognosis. Gene 2018; 670:148-154. [PMID: 29803923 DOI: 10.1016/j.gene.2018.05.096] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/10/2018] [Accepted: 05/23/2018] [Indexed: 02/09/2023]
Abstract
BACKGROUND Genetic polymorphisms in lncRNA HULC may affect the susceptibility and clinical outcome of cancer. We aimed to investigate the association of HULC tagSNPs with the risk and prognosis of hepatocellular cancer, as well as the influence of the SNPs on lncRNA expression level. METHODS A total of 1338 samples were recruited in the risk study. Among them, 351 HCC patients were involved in the prognosis study. SNP genotyping was performed using KASP method and lncRNA expression was detected by Real-time PCR. RESULTS We found a promoter SNP, rs1041279, was associated with a 1.41-fold increased HCC risk (P = 0.032). In the stratified analysis, rs1041279 had greater ORs for the increased HCC risk in the male subgroup (P = 0.014, OR = 1.54). Furthermore, multi-logistic regression analysis revealed a two-way interaction effect of smoking-rs2038540 SNP on HCC risk (OR = 4.20). And MDR analysis consistently demonstrated a SNP-environmental interaction among smoking-drinking-rs2038540 SNP as the best model for predicting HCC risk (P = 0.0107). In our study, no significant association was found between HULC SNPs and the overall survival (P > 0.05), and no significant effect was observed of rs1041279 SNP on lncRNA-HULC expression (P > 0.05). CONCLUSION lncRNA-HULC rs1041279 SNP and the interaction of rs2038540 SNP with environmental factors could enhance HCC risk.
Collapse
|
|
11
|
Liu L, Tian N, Zhou C, Lin X, Lv W, Lin Z, Lin Z, Qi Y, Yang Y, Chen S, Yu X, Gao Y. A potentially functional variant of ARID1B interacts with physical activity in association with risk of hepatocellular carcinoma. Oncotarget 2018; 8:31057-31064. [PMID: 28415691 PMCID: PMC5458188 DOI: 10.18632/oncotarget.16074] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 02/27/2017] [Indexed: 01/01/2023] Open
Abstract
The tumor suppressor role of AT-rich interactive domain containing protein 1B (ARID1B) has drawn much attention in area of cancer etiology. However, it had remained unknown whether or not genetic variants of ARID1B involved in development of hepatocellular carcinoma (HCC). In this study, three putatively functional variants in ARID1B (rs73013281C>T, rs167007A>G, and rs9397984C>T) were selected using bioinformatics tools, and a case-control study of 611 cases and 614 controls was conducted to investigate genetic associations with HCC risk in a Southern Chinese population. Two-dimensional gene-environment interactions were also explored using both multiplicative and additive scales. A dominant effect of the rs73013281 was found for HCC risk, with an adjusted odds ratio (OR) of 1.70 [95% confidence interval (CI) = 1.03-2.80] for the CT/TT genotypes compared to the CC genotype. In stratified analysis, the detrimental effect of the T allele on elevated HCC risk was attenuated by physical activity, with an adjusted OR of 2.75 (95% CI = 1.39-5.41) among inactive individuals against that of 0.89 (95% CI = 0.42-1.91) in those who exercised regularly. Expectably, the rs73013281 showed both multiplicative and additive interactions with physical activity (P = 0.037 and 0.006, respectively). In conclusion, these results highlighted the significant genetic contribution of the ARID1B variant, rs73013281, to susceptibility for HCC, especially in interaction with physical activity.
Collapse
Affiliation(s)
- Li Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Nana Tian
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Chengyu Zhou
- Department of Oncology, Shunde First People's Hospital, Foshan, China
| | - Xinqi Lin
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Weibiao Lv
- Department of Clinical Laboratory, Shunde First People's Hospital, Foshan, China
| | - Zhifeng Lin
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zibo Lin
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yongfen Qi
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yi Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Sidong Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xinfa Yu
- Department of Oncology, Shunde First People's Hospital, Foshan, China
| | - Yanhui Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China
| |
Collapse
|
|
12
|
Tao R, Wang ZF, Qiu W, He YF, Yan WQ, Sun WY, Li HJ. Role of S100A3 in human hepatocellular carcinoma and the anticancer effect of sodium cantharidinate. Exp Ther Med 2017; 13:2812-2818. [PMID: 28588665 PMCID: PMC5450779 DOI: 10.3892/etm.2017.4294] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 11/15/2016] [Indexed: 12/11/2022] Open
Abstract
The fifth most common cancer worldwide is hepatocellular carcinoma (HCC), which has an annual mortality rate of ~800,000. Although surgical procedures for HCC, such as hepatic resection and liver transplantation, have progressed and the outcomes of patients have improved, HCC is still characterized by frequent recurrence, even after liver transplantation. In the present study the expression of the protein coding gene, S100 calcium binding protein A3 (S100A3), was observed in 62 HCC tissues and tumor-surrounding tissues. The present study indicated that S100A3 activation was involved in tumorigenesis and tumor aggressiveness. The protein and mRNA expression levels of S100A3 in the human HCC cell line (HepG2) were investigated using western blotting and reverse transcription-quantitative polymerase chain reaction analysis, respectively. The function of sodium cantharidinate in inducing HCC cell apoptosis was also investigated. Sodium cantharidinate inhibited the protein and gene expression of S100A3 in HepG2 cells in vitro. These data suggested that S100A3 has an important role in human HCC. The present study indicates that the functional properties of sodium cantharidinate are promising for the development of a novel drug that may control the expression of S100A3 and improve the treatment of human HCC in the near future.
Collapse
Affiliation(s)
- Ran Tao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
- Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Zhong-Feng Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wei Qiu
- Department of Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yu-Fang He
- Institute of Phytochemistry, Jilin Academy of Chinese Medicine Sciences, Changchun, Jilin 130012, P.R. China
| | - Wei-Qun Yan
- Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wen-Yi Sun
- Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hai-Jun Li
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| |
Collapse
|
|
13
|
Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: An update. World J Gastroenterol 2016; 22:9069-9095. [PMID: 27895396 PMCID: PMC5107590 DOI: 10.3748/wjg.v22.i41.9069] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/20/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.
Collapse
MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genomic Instability
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Molecular Diagnostic Techniques
- Molecular Targeted Therapy
- Mutation
- Patient Selection
- Phenotype
- Polymorphism, Single Nucleotide
- Precision Medicine
- Predictive Value of Tests
- Signal Transduction
Collapse
|