HRCT1, Negatively Regulated by MiR-124-3p, Promotes Tumor Metastasis and the Growth of Gastric Cancer by Activating the ERBB2-MAPK Pathway

Overview

Journal Gastric Cancer

Specialties Gastroenterology
Oncology

Date 2023 Jan 5

PMID 36602696

Authors

Feng Hou

Duan-Bo Shi

Xiang-Yu Guo

Rui-Nan Zhao

Hui Zhang

Ran-Ran Ma

Jun-Yi He

Peng Gao

Affiliations

Soon will be listed here.

Abstract

Background: Gastric cancer is the fourth leading cause of cancer-related deaths worldwide. And patient outcomes are poor due to tumor relapse and metastasis. To develop new therapeutic strategies, it is of great importance to explore the mechanism underlying the progression of gastric cancer.

Methods: Primary gastric cancer samples with lymph node metastases (LNM) and without LNM were subjected to mRNA microarray assay. The differentially expressed genes were confirmed by RT-qPCR. HRCT1 protein expression was further detected using an immunohistochemistry (IHC) assay. In vitro and in vivo assays were performed to investigate the role of HRCT1 in tumor invasion, metastasis, and proliferation. The expressions of the downstream target genes of HRCT1 were detected by microarray, RT-qPCR and Western blot assays. Dual-luciferase reporter and Western blot assays were carried out to identify miRNAs target to HRCT1.

Results: HRCT1 was upregulated in gastric cancer, and high expression of HRCT1 was associated with poor overall survival (OS) and disease-free survival (DFS). Moreover, HRCT1protein expression was an independent predictor for poor OS and DFS. HRCT1 could promote gastric cancer cells' migration, invasion, and proliferation in vitro as well as tumor metastasis and growth in vivo. Notably, our data showed that HRCT1 promoted gastric cancer progression by activating the ERBB2-MAPK signaling pathway. At least partially, the expression of HRCT1 could be negatively regulated by miR-124-3p.

Conclusions: The upregulated expression of HRCT1 predicts poor survival for patients with gastric cancer. HRCT1 promotes tumor progression by activating the ERBB2-MAPK pathway. HRCT1, negatively regulated by miR-124-3p, may be a potential therapeutic target for patients with gastric cancer.

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References

Rawla P, Barsouk A . Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol. 2019; 14(1):26-38. PMC: 6444111. DOI: 10.5114/pg.2018.80001. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Balakrishnan M, George R, Sharma A, Graham D . Changing Trends in Stomach Cancer Throughout the World. Curr Gastroenterol Rep. 2017; 19(8):36. PMC: 6918953. DOI: 10.1007/s11894-017-0575-8. View

Xie L, Zhang Z, Tan Z, He R, Zeng X, Xie Y . MicroRNA-124 inhibits proliferation and induces apoptosis by directly repressing EZH2 in gastric cancer. Mol Cell Biochem. 2014; 392(1-2):153-9. DOI: 10.1007/s11010-014-2028-0. View

Wang J, Liu B, Zhou L, Huang Y . MicroRNA-124-3p suppresses cell migration and invasion by targeting ITGA3 signaling in bladder cancer. Cancer Biomark. 2019; 24(2):159-172. DOI: 10.3233/CBM-182000. View

Ye J, Liao Q, Zeng X, Liu C, Ding Y, Liu X . inhibited progression of nasopharyngeal carcinoma by interaction with PCDH8 and the inactivation of PI3K/AKT/mTOR pathway. J Cancer. 2021; 12(16):4933-4944. PMC: 8247379. DOI: 10.7150/jca.57152. View

Yan K, Hou L, Liu T, Jiao W, Ma Q, Fang Z . lncRNA OGFRP1 functions as a ceRNA to promote the progression of prostate cancer by regulating SARM1 level via miR-124-3p. Aging (Albany NY). 2020; 12(10):8880-8892. PMC: 7288971. DOI: 10.18632/aging.103007. View

Shi D, Wang Y, Xing A, Gao J, Zhang H, Guo X . C/EBPα-induced miR-100 expression suppresses tumor metastasis and growth by targeting ZBTB7A in gastric cancer. Cancer Lett. 2015; 369(2):376-85. DOI: 10.1016/j.canlet.2015.08.029. View

Bernards N, Creemers G, Nieuwenhuijzen G, Bosscha K, Pruijt J, Lemmens V . No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy. Ann Oncol. 2013; 24(12):3056-60. DOI: 10.1093/annonc/mdt401. View

10.

Joshi S, Badgwell B . Current treatment and recent progress in gastric cancer. CA Cancer J Clin. 2021; 71(3):264-279. PMC: 9927927. DOI: 10.3322/caac.21657. View

11.

Mezynski M, Farrelly A, Cremona M, Carr A, Morgan C, Workman J . Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer. J Transl Med. 2021; 19(1):184. PMC: 8088633. DOI: 10.1186/s12967-021-02842-1. View

12.

Liu Y, Chen L, Jiang D, Luan L, Huang J, Hou Y . HER2 promotes epithelial-mesenchymal transition through regulating osteopontin in gastric cancer. Pathol Res Pract. 2021; 227:153643. DOI: 10.1016/j.prp.2021.153643. View

13.

Yang Y, Ren F, Tian Z, Song W, Cheng B, Feng Z . Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway. Front Pharmacol. 2018; 9:1392. PMC: 6277458. DOI: 10.3389/fphar.2018.01392. View

14.

Zhu Y, Zhu X, Wei X, Tang C, Zhang W . HER2-targeted therapies in gastric cancer. Biochim Biophys Acta Rev Cancer. 2021; 1876(1):188549. DOI: 10.1016/j.bbcan.2021.188549. View

15.

Ilson D . Advances in the treatment of gastric cancer: 2020-2021. Curr Opin Gastroenterol. 2021; 37(6):615-618. PMC: 9585687. DOI: 10.1097/MOG.0000000000000776. View

16.

Wu S, Chen M, Huang J, Zhang F, Lv Z, Jia Y . ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly. Cancer Res. 2020; 81(4):986-1000. DOI: 10.1158/0008-5472.CAN-20-0049. View

17.

Du F, Sun L, Chu Y, Li T, Lei C, Wang X . DDIT4 promotes gastric cancer proliferation and tumorigenesis through the p53 and MAPK pathways. Cancer Commun (Lond). 2018; 38(1):45. PMC: 6034313. DOI: 10.1186/s40880-018-0315-y. View

18.

Xiang Z, Li J, Song S, Wang J, Cai W, Hu W . A positive feedback between IDO1 metabolite and COL12A1 via MAPK pathway to promote gastric cancer metastasis. J Exp Clin Cancer Res. 2019; 38(1):314. PMC: 6637527. DOI: 10.1186/s13046-019-1318-5. View

19.

Hou F, Shi D, Chen Y, Gao P . Human Epidermal Growth Factor Receptor-2 Promotes Invasion and Metastasis in Gastric Cancer by Activating Mitogen-activated Protein Kinase Signaling. Appl Immunohistochem Mol Morphol. 2018; 27(7):529-534. DOI: 10.1097/PAI.0000000000000672. View

20.

Zhong X, Coukos G, Zhang L . miRNAs in human cancer. Methods Mol Biol. 2011; 822:295-306. PMC: 4076826. DOI: 10.1007/978-1-61779-427-8_21. View