Menu

PDF
Cite
Share

facebook

twitter

google

linkedin

Volume 41 Issue 3

Mar. 2025

Turn off MathJax

Article Contents

Abstract

References

Article Navigation > Journal of Clinical Hepatology > 2025 > 41(3): 485-492

Effect of Go-Ichi-Ni-San complex subunit 1 on disease progression and chemotherapy resistance in hepatocellular carcinoma

DOI: 10.12449/JCH250314

1.
Department of Clinical Laboratory，Clinical Laboratory Center，Tumor Hospital Affiliated to Xinjiang Medical University，Urumqi 830000，China
2.
Department of Clinical Laboratory，The Fifth Affiliated Hospital of Xinjiang Medical University，Urumqi 830000，China
3.
Experimental Diagnostic Center，Beijing Tiantan Hospital，Capital Medical University，Beijing 100070，China
4.
Department of Clinical Laboratory，Xinjiang Uygur Autonomous Region People’s Hospital，Urumqi 830000，China

Research funding:

Natural Science Foundation of Xinjiang Uygur Autonomous Region (2022D01C245);

Xinjiang Uygur Autonomous Region Industy-University Cooperation and Collaborative Education Project (MRHT1000023042108)

More Information

Corresponding author: MA Xiumin， maxiumin1210@sohu.com （ORCID： 0000-0001-8011-7513）
Received Date: 2024-07-20
Accepted Date: 2024-10-08
Published Date: 2025-03-25

Abstract

Objective To investigate the role and mechanism of Go-Ichi-Ni-San complex subunit 1 （GINS1） in the progression of hepatocellular carcinoma （HCC） and the development of chemotherapy resistance. Methods The tumor database GEPIA2 was used to analyze the differential expression of GINS1 between HCC patients and healthy individuals， and pathological tissue samples were collected from 40 HCC patients who were admitted to The Affiliated Tumor Hospital of Xinjiang Medical University and the First Affiliated Hospital of Xinjiang Medical University from May 2017 to January 2021. Immunohistochemical staining was used to measure the difference in the expression of GINS1 between HCC tissue and corresponding adjacent tissue， and the correlation between the expression level of GINS1 and the clinical TNM stage of HCC was analyzed. Western blot was also used to measure the difference in the expression of GINS1 between HCC Huh7/Hep3B/Li-7/MHCC97H cell lines and normal human QSG7701 hepatocytes. The method of lentivirus transfection was used to establish the MHCC97H cell line with stable GINS1 knockdown and its negative control cell line. CCK-8 assay and colony formation assay were used to measure cell proliferative capacity； scratch assay was used to measure cell migration ability； Transwell assay was used to measure cell invasion ability； cells were treated with oxaliplatin to measure their sensitivity to chemotherapy drugs. Nude mice were used to establish a tumor-bearing model and observe the effect of GINS1 knockdown on the growth of HCC in vivo. Western Blot was used to measure the expression levels of the proteins associated with the Notch pathway and the JAK/STAT pathway. The cells were treated with the Notch receptor agonist Jagged-1 to analyze the association between GINS1 and the Notch/JAK/STAT pathway. The independent-samples t test was used for comparison of continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. Results The expression of GINS1 was upregulated in HCC patients， HCC tissue， and HCC cell lines （all P<0.05）， and the expression level of GINS1 was positively correlated with the clinical TNM stage of HCC （r=0.822， P=0.011）. Compared with the negative control cells， the GINS1-knockdown MHCC97H cells showed significant reductions in proliferation， migration， and invasion activities （all P<0.01） and a significantly enhanced sensitivity to oxaliplatin （P<0.01）. Compared with the nude mice in the control group， GINS1 knockdown caused significant inhibition of tumor weight and volume in vivo in nude mice （all P<0.001）. Compared with the negative control cells， the GINS1-knockdown MHCC97H cells showed significant reductions in the expression levels of Notch1， Notch3， p-JAK2， and p-STAT3 （all P<0.05）， while there were no significant differences in the overall expression levels of JAK2 and STAT3 （P>0.05）. After Jagged-1 treatment， the GINS1-knockdown MHCC97H cells showed significant increases in proliferation， migration， and invasion activities and a significant reduction in sensitivity to oxaliplatin， as well as significant increases in the levels of p-JAK2 and p-STAT3 （all P<0.05）. Conclusion GINS1 is upregulated in HCC and can promote HCC progression and chemotherapy resistance through the Notch/JAK2/STAT3 pathway.
- Go-Ichi-Ni-San （GINS） Complex,
- Carcinoma， Hepatocellular,
- Drug Resistance， Neoplasm,
- Signal Transduction

References

[1]	WANG Y, DENG BC. Hepatocellular carcinoma: Molecular mechanism, targeted therapy, and biomarkers[J]. Cancer Metastasis Rev, 2023, 42( 3): 629- 652. DOI: 10.1007/s10555-023-10084-4.
[2]	National Health Commission of the People’s Republic of China. Standard for diagnosis and treatment of primary liver cancer(2024 edition)[J]. J Clin Hepatol, 2024, 40( 5): 893- 918. DOI: 10.12449/JCH240508. 中华人民共和国国家卫生健康委员会. 原发性肝癌诊疗指南(2024年版)[J]. 临床肝胆病杂志, 2024, 40( 5): 893- 918. DOI: 10.12449/JCH240508.
[3]	WANG WY, WEI C. Advances in the early diagnosis of hepatocellular carcinoma[J]. Genes Dis, 2020, 7( 3): 308- 319. DOI: 10.1016/j.gendis.2020.01.014.
[4]	YE Y, SONG YN, HE SF, et al. GINS2 promotes cell proliferation and inhibits cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2[J]. Cancer Gene Ther, 2019, 26( 3-4): 103- 113. DOI: 10.1038/s41417-018-0045-y.
[5]	SEKEDAT MD, FENYÖ D, ROGERS RS, et al. GINS motion reveals replication fork progression is remarkably uniform throughout the yeast genome[J]. Mol Syst Biol, 2010, 6: 353. DOI: 10.1038/msb.2010.8.
[6]	OGINO H, ISHINO S, MAYANAGI K, et al. The GINS complex from the thermophilic archaeon, Thermoplasma acidophilum may function as a homotetramer in DNA replication[J]. Extremophiles, 2011, 15( 4): 529- 539. DOI: 10.1007/s00792-011-0383-2.
[7]	YANG H, LIU XC, ZHU XL, et al. GINS1 promotes the proliferation and migration of glioma cells through USP15-mediated deubiquitination of TOP2A[J]. iScience, 2022, 25( 9): 104952. DOI: 10.1016/j.isci.2022.104952.
[8]	BAXLEY RM, LEUNG W, SCHMIT MM, et al. Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening[J]. Nat Commun, 2021, 12( 1): 1626. DOI: 10.1038/s41467-021-21878-x.
[9]	XU XL, CHEN E, MO LH, et al. BRCA1 represses DNA replication initiation through antagonizing estrogen signaling and maintains genome stability in parallel with WEE1-MCM2 signaling during pregnancy[J]. Hum Mol Genet, 2019, 28( 5): 842- 857. DOI: 10.1093/hmg/ddy398.
[10]	AHMAD M, HAMEED Y, KHAN M, et al. Up-regulation of GINS1 highlighted a good diagnostic and prognostic potential of survival in three different subtypes of human cancer[J]. Braz J Biol, 2021, 84: e250575. DOI: 10.1590/1519-6984.250575.
[11]	FU QQ, ZHENG H, WANG X, et al. GINS1 promotes the initiation and progression of bladder cancer by activating the AKT/mTOR/c-Myc signaling pathway[J]. Exp Cell Res, 2024, 440( 1): 114125. DOI: 10.1016/j.yexcr.2024.114125.
[12]	WANG KC, WANG MD, YANG T. Key points in AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma(2023)[J]. J Clin Hepatol, 2023, 39( 9): 2081- 2086. DOI: 10.3969/j.issn.1001-5256.2023.09.008. 王科淳, 王明达, 杨田.《2023年美国肝病学会实践指导: 肝细胞癌的预防、诊断和治疗》意见要点[J]. 临床肝胆病杂志, 2023, 39( 9): 2081- 2086. DOI: 10.3969/j.issn.1001-5256.2023.09.008.
[13]	LI Z, ZHU JY. Interpretation of guidelines for the diagnosis and treatment of primary liver cancer(2024 edition)[J]. J Clin Hepatol, 2024, 40( 7): 1324- 1327. DOI: 10.12449/JCH240707. 李照, 朱继业.《原发性肝癌诊疗指南(2024年版)》解读[J]. 临床肝胆病杂志, 2024, 40( 7): 1324- 1327. DOI: 10.12449/JCH240707.
[14]	UENO M, ITOH M, KONG LY, et al. PSF1 is essential for early embryogenesis in mice[J]. Mol Cell Biol, 2005, 25( 23): 10528- 10532. DOI: 10.1128/MCB.25.23.10528-10532.2005.
[15]	NAGAHAMA Y, UENO M, MIYAMOTO S, et al. PSF1, a DNA replication factor expressed widely in stem and progenitor cells, drives tumorigenic and metastatic properties[J]. Cancer Res, 2010, 70( 3): 1215- 1224. DOI: 10.1158/0008-5472.CAN-09-3662.
[16]	MAI WH, CHEN CX, LIU QY, et al. Regulation of Notch signaling pathway in immune responses during infection[J]. Chin J Immunol, 2024, 40( 4): 872- 879. 麦文豪, 陈楚溪, 刘巧媛, 等. Notch信号通路在感染过程中对免疫应答的调控作用[J]. 中国免疫学杂志, 2024, 40( 4): 872- 879.
[17]	ZHOU BH, LIN WL, LONG YL, et al. Notch signaling pathway: Architecture, disease, and therapeutics[J]. Signal Transduct Target Ther, 2022, 7( 1): 95. DOI: 10.1038/s41392-022-00934-y.
[18]	ZHANG XY, SU TH, WU YF, et al. N6-methyladenosine reader YTHDF1 promotes stemness and therapeutic resistance in hepatocellular carcinoma by enhancing NOTCH1 expression[J]. Cancer Res, 2024, 84( 6): 827- 840. DOI: 10.1158/0008-5472.CAN-23-1916.
[19]	WU WR, SHI XD, ZHANG FP, et al. Activation of the Notch1-c-myc-VCAM1 signalling axis initiates liver progenitor cell-driven hepatocarcinogenesis and pulmonary metastasis[J]. Oncogene, 2022, 41( 16): 2340- 2356. DOI: 10.1038/s41388-022-02246-5.
[20]	GRAMANTIERI L, GIOVANNINI C, LANZI A, et al. Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma[J]. Liver Int, 2007, 27( 7): 997- 1007. DOI: 10.1111/j.1478-3231.2007.01544.x.
[21]	HU L, XUE F, SHAO MH, et al. Aberrant expression of Notch3 predicts poor survival for hepatocellular carcinomas[J]. Biosci Trends, 2013, 7( 3): 152- 156.
[22]	GIOVANNINI C, BAGLIONI M, BARON TOALDO M, et al. Notch3 inhibition enhances sorafenib cytotoxic efficacy by promoting GSK3b phosphorylation and p21 down-regulation in hepatocellular carcinoma[J]. Oncotarget, 2013, 4( 10): 1618- 1631. DOI: 10.18632/oncotarget.1221.
[23]	GIOVANNINI C, SALZANO AM, BAGLIONI M, et al. Brivanib in combination with Notch3 silencing shows potent activity in tumour models[J]. Br J Cancer, 2019, 120( 6): 601- 611. DOI: 10.1038/s41416-018-0375-4.
[24]	ZHU WH, LIANG Q, YANG X, et al. Combination of sorafenib and Valproic acid synergistically induces cell apoptosis and inhibits hepatocellular carcinoma growth via down-regulating Notch3 and pAkt[J]. Am J Cancer Res, 2017, 7( 12): 2503- 2514.
[25]	XIN P, XU XY, DENG CJ, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases[J]. Int Immunopharmacol, 2020, 80: 106210. DOI: 10.1016/j.intimp.2020.106210.
[26]	YI L, LI WD, WANG Y, et al. Effects of aloperine on proliferation, apoptosis and immune escape of colorectal cancer cells by regulating IL-6/JAK1/STAT3 signaling pathway[J]. Chin J Immunol, 2024, 40( 7): 1436- 1440. 伊亮, 李伟东, 王有, 等. 苦豆碱调节IL-6/JAK1/STAT3信号通路对结直肠癌细胞增殖、凋亡和免疫逃逸的影响[J]. 中国免疫学杂志, 2024, 40( 7): 1436- 1440.
[27]	CARAGLIA M, VITALE G, MARRA M, et al. Alpha-interferon and its effects on signalling pathways within cells[J]. Curr Protein Pept Sci, 2004, 5( 6): 475- 485. DOI: 10.2174/1389203043379378.
[28]	ZHAO ZW, SONG JJ, TANG BF, et al. CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway[J]. J Exp Clin Cancer Res, 2020, 39( 1): 259. DOI: 10.1186/s13046-020-01769-7.

Relative Articles

Relative Articles

[1]	Zhi LIU, Xiaohong DU, Wengang CHAI. Efficacy of des-γ-carboxy-prothrombin in the diagnosis of hepatocellular carcinoma and its association with the clinical features of hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(10): 2014-2018. doi: 10.12449/JCH241014
[2]	Jun LIU, Ling WANG, Yuhuan JIANG, Jingzhi WANG, Huiming LI. Establishment of a risk model based on immunogenic cell death-related genes and its value in predicting the prognosis and tumor microenvironment characteristics of hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(12): 2473-2483. doi: 10.12449/JCH241218
[3]	Jiannan QIU, Peng WANG, Yin CAO, Zhongxia WANG, Junhua WU, Chunping JIANG. Effect of kinesin family member 15 on the proliferation of hepatocellular carcinoma cells and its mechanism of action[J]. Journal of Clinical Hepatology, 2024, 40(2): 327-334. doi: 10.12449/JCH240217
[4]	Tianqi ZHANG, Yuzhe CAO, Mengxuan ZUO, Yangkui GU. Research advances in second-line therapies for hepatocellular carcinoma after resistance to targeted therapy combined with immunotherapy[J]. Journal of Clinical Hepatology, 2024, 40(2): 386-390. doi: 10.12449/JCH240227
[5]	Xiaohua ZHANG, Ying FENG, Xianbo WANG. Role of the Hedgehog signaling pathway in hepatocellular carcinoma and its tumor microenvironment[J]. Journal of Clinical Hepatology, 2024, 40(4): 822-827. doi: 10.12449/JCH240429
[6]	Runbing ZHANG, Tingting SHI, Yang WU, Jiucong ZHANG, Xiaofeng ZHENG. The mechanism of autophagy inducing drug resistance of hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(11): 2315-2319. doi: 10.12449/JCH241128
[7]	Xiaomeng YAO, Keke SUN, Yunkai LIN, Hui WANG, Liwei DONG, Lei CHEN, Heping HU. Molecular mechanism of lenvatinib resistance in hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(12): 2524-2530. doi: 10.12449/JCH241225
[8]	Lingling ZHU, Yani ZHANG, Tingting SHI, Yang WU, Chun GAO, Xiaohui YU, Yujing HE, Jiucong ZHANG. The role of tumor necrosis factor-α in the development and progression of hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2024, 40(11): 2320-2325. doi: 10.12449/JCH241129
[9]	Hongxia LI, Yimeng SUN, Hongtao ZHANG, Shuwang HAN, Delin ZHANG, Haitao SHANG, Wu GUO, Junjian LIU, Zhonglian LI. Role of HBV DNA polymerase in mediating the immune escape of tumor cells in HBV-related hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2023, 39(12): 2858-2866. doi: 10.3969/j.issn.1001-5256.2023.12.017
[10]	Xing YANG, Shudi LI, Jiangkai LIU, Zhen WANG, Suling LI. Current research status of traditional Chinese medicine in the prevention and treatment of hepatocellular carcinoma by regulating the JAK/STAT signaling pathway[J]. Journal of Clinical Hepatology, 2023, 39(11): 2718-2729. doi: 10.3969/j.issn.1001-5256.2023.11.030
[11]	Rui SONG, Jing LI, Hongju YANG, Minyue LI, Jing YOU. Role of signal transducer and activator of transcription 1 in regulation of Treg/Th17 balance in hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2022, 38(11): 2627-2631. doi: 10.3969/j.issn.1001-5256.2022.11.038
[12]	Deng YangYang, Ge ShanFei, Yu YanQing, Xiong Ying. Cell signaling pathways associated with liver fibrosis and potential therapeutic strategies[J]. Journal of Clinical Hepatology, 2020, 36(5): 1141-1145. doi: 10.3969/j.issn.1001-5256.2020.05.043
[13]	Zhao DongKang, Luo WeiWei, Yu ShuiPing. Role of the Wnt signaling pathway in the development and progression of liver fibrosis[J]. Journal of Clinical Hepatology, 2018, 34(11): 2415-2419. doi: 10.3969/j.issn.1001-5256.2018.11.033
[14]	Zhang Xu, Liu Ping, Mu YongPing. Relationship between the Notch signaling pathway and the development and progression of liver fibrosis[J]. Journal of Clinical Hepatology, 2018, 34(1): 181-183. doi: 10.3969/j.issn.1001-5256.2018.01.039
[15]	Peng Qin, Zhao ShenJun, Li Wu. Research advances in signaling pathways involved in the development of hepatic fibrosis[J]. Journal of Clinical Hepatology, 2017, 33(5): 954-958. doi: 10.3969/j.issn.1001-5256.2017.05.035
[16]	Zhong XiaoMao, Han BaoSheng. Research advances in signaling pathways involved in liver regeneration mediated by oval cells[J]. Journal of Clinical Hepatology, 2016, 32(12): 2399-2402. doi: 10.3969/j.issn.1001-5256.2016.12.037
[17]	Zhou XueLing, Yu ShuiPing. Role of Wnt signaling pathway in progression of liver cirrhosis[J]. Journal of Clinical Hepatology, 2015, 31(9): 1540-1542. doi: 10.3969/j.issn.1001-5256.2015.09.045
[18]	Liu Jia, Zhu QinMei, Hu HongYi, Wang Su. Research advances in Hedgehog signaling pathway in hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2015, 31(2): 300-304. doi: 10.3969/j.issn.1001-5256.2015.02.041
[19]	Pan Jin, Ju Jian. Current perspectives on the JAK/STAT signaling pathway and its activating factors in liver fibrosis[J]. Journal of Clinical Hepatology, 2013, 29(5): 393-396.
[20]	Xie XueHai, Hao Kun, Yang YinMo. Hedgehog signaling pathway and pancreatic cancer[J]. Journal of Clinical Hepatology, 2010, 26(5): 468-471+478.

Cited By

Proportional views

Proportional views

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Figures(5) / Tables(2)

Get Citation

PDF

XML

Article Metrics

Article views (45) PDF downloads(6)

Proportional views

Related

The first journal specializing in hepatobiliary and pancreatic diseases in China

Supervisor：Ministry of Education of the People's Republic of China

Sponsor：Jilin University

Academic Support: Chinese Society of Hepatology，Chinese Medical Association

Address: 461 Xinjiang Road, Changchun

Submit：0431-88782044

Peer review：0431-88783542

Email：lcgdb@vip.163.com

YesterdayIP[1878]YesterdayPV[3517]TodayIP[637]TodayPV[958]Online[29]

Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd

/

DownLoad: Full-Size Img PowerPoint