Basic Study
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World J Gastrointest Oncol. Feb 15, 2023; 15(2): 286-302
Published online Feb 15, 2023. doi: 10.4251/wjgo.v15.i2.286
Cancerous inhibitor of protein phosphatase 2A enhances chemoresistance of gastric cancer cells to oxaliplatin
Yong-Xun Zhao, Li-Bin Ma, Ze Yang, Fang Wang, Hui-Ying Wang, Jia-Yao Dang
Yong-Xun Zhao, Li-Bin Ma, Ze Yang, The Seventh Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
Fang Wang, Department of Pathology, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
Hui-Ying Wang, Jia-Yao Dang, The First Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
Author contributions: Zhao YX, Yang Z, Dang JY, and Wang F performed the experiments and image acquisition; Zhao YX, Ze Yang, Ma LB, and Wang HY designed the study and wrote the manuscript; Zhao YX, Yang Z, and Ma LB edited the manuscript.
Supported by This work was supported by the Natural Science Foundation of Gansu Province, China, No. 17JR5RA272 and No. 22JR5RA923; and the Research Fund Project of The First Hospital of Lanzhou University, No. ldyyyn2021-120, No. ldyyyn2020-98 and No. ldyyyn2021-30.
Institutional review board statement: The study was reviewed and approved by the Lanzhou University No.1 Hospital Institutional Review Board (Approval No. LDYYLL-2022-376).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: The datasets used and/or analyzed during this study are available from the corresponding author upon reasonable request.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yong-Xun Zhao, PhD, Surgeon, The Seventh Department of General Surgery, The First Hospital of Lanzhou University, No. 1 Donggang West Road, Lanzhou 730000, Gansu Province, China. yongxunzh@163.com
Received: September 8, 2022
Peer-review started: September 8, 2022
First decision: November 12, 2022
Revised: November 23, 2022
Accepted: January 5, 2023
Article in press: January 5, 2023
Published online: February 15, 2023
Processing time: 159 Days and 10.9 Hours
Abstract
BACKGROUND

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a newly discovered oncogene. It is an active cell proliferation regulatory factor that inhibits tumor apoptosis in gastric cancer (GC) cells. CIP2A is functionally related to chemoresistance in various types of tumors according to recent studies. The underlying mechanism, however, is unknown. Further, the primary treatment regimen for GC is oxaliplatin-based chemotherapy. Nonetheless, it often fails due to chemoresistance of GC cells to oxaliplatin.

AIM

The goal of this study was to examine CIP2A expression and its association with oxaliplatin resistance in human GC cells.

METHODS

Immunohistochemistry was used to examine CIP2A expression in GC tissues and adjacent normal tissues. CIP2A expression in GC cell lines was reduced using small interfering RNA. After confirming the silencing efficiency, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium and flow cytometry assays were used to evaluate cell proliferation and apoptosis caused by oxaliplatin treatment. Further, the key genes and protein changes were verified using real-time quantitative reverse transcription PCR and Western blotting, respectively, before and after intervention. For bioinformatics analysis, we used the R software and Bioconductor project. For statistical analysis, we used GraphPad Prism 6.0 and the Statistical Package for the Social Sciences software version 20.0 (IBM, Armonk, United States).

RESULTS

A high level of CIP2A expression was associated with tumor size, T stage, lymph node metastasis, Tumor Node Metastasis stage, and a poor prognosis. Further, CIP2A expression was higher in GC cells than in normal human gastric epithelial cells. Using small interfering RNA against CIP2A, we discovered that CIP2A knockdown inhibited cell proliferation and significantly increased GC cell sensitivity to oxaliplatin. Moreover, CIP2A knockdown enhanced oxaliplatin-induced apoptosis in GC cells. Hence, high CIP2A levels in GC may be a factor in chemoresistance to oxaliplatin. In human GC cells, CIP2A regulated protein kinase B phosphorylation, and chemical inhibition of the protein kinase B signaling pathway was significantly associated with increased sensitivity to oxaliplatin. Therefore, the protein kinase B signaling pathway was correlated with CIP2A-enhanced chemoresistance of human GC cells to oxaliplatin.

CONCLUSION

CIP2A expression could be a novel therapeutic strategy for chemoresistance in GC.

Keywords: Cancerous inhibitor of protein phosphatase 2A; Gastric cancer; Oxaliplatin; Chemoresistance; Akt

Core Tip: Gastric cancer (GC) is primarily treated with oxaliplatin-based chemotherapy. Patients who receive chemotherapy often develop resistance. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel oncogene. Recent studies suggested that CIP2A is linked to chemoresistance in various cancers. The purpose of this study was to look into the relationship between CIP2A expression and oxaliplatin resistance in GC. The findings revealed that GC tissues have higher CIP2A expression than matched adjacent normal gastric tissues, and CIP2A expression plays an important role in the chemoresistance of GC, suggesting a new treatment strategy for GC.