Inhibition of Musashi-1 enhances chemotherapeutic sensitivity in gastric cancer patient-derived xenografts

Author:

Liu Fan123,Yang Huan2,Zhang Xinyu2,Sun Xianglin2,Zhou Jiamin2,Li Yuan4,Liu Yifei4,Zhuang Zhixiang1,Wang Guohua2ORCID

Affiliation:

1. Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China

2. Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, Nantong 226019, China

3. Department of Oncology, Affiliated Hospital of Nantong University, Nantong 226001, China

4. Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226001, China

Abstract

Musashi-1 (MSI1), a neural RNA-binding protein, is considered a gastric and intestinal stem cell marker. Although the function of MSI1 in gastric cancer has attracted increasing interest, it is not known whether MSI1 can be used as a biomarker to monitor gastric cancer development and response to treatment. Here, the role of MSI1 in the chemotherapeutic sensitivity of gastric cancer was investigated. Patients with high MSI1 levels had poor outcomes, implicating the gene in the development and progression of the disease. We overexpressed and silenced MSI1 in the human gastric cancer cell lines MKN45 and HGC27, finding that knockdown reduced proliferation, invasion, and migration, while promoting apoptosis. A patient-derived xenograft gastric cancer model was constructed in which mice received chemical drugs, si-MSI1, or a drug-si-MSI1 combination. It was found that blocking MSI1 expression reduced gastric cancer drug tolerance. The combination treatment with si-MSI1 was superior to 5F-dUMP and cisplatin, either separately or in combination, indicating that including si-MSI1 was better than drug therapy alone. Transcriptome sequencing analysis showed that MSI1 altered cell cycle regulation and growth signal transduction, including that of blood vessel epicardial substance (BVES). These results suggest that MSI1 reduces the tolerance of gastric cancer to chemical drugs through modulation of MSI1/BVES signaling.

Funder

Jiangsu Provincial Key Research and Development Program

Nantong Science and Technology Bureau

Publisher

SAGE Publications

Subject

General Biochemistry, Genetics and Molecular Biology

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