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A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway.

ABSTRACT: Genomic instability plays a key role in the initiation and progression of colorectal cancer (CRC). Although cancer driver genes in CRC have been well characterized, identifying novel genes associated with carcinogenesis and treatment remains challenging because of tumor heterogeneity. Here, we analyzed the genomic alterations of 45 samples from CRC patients in northern China by whole-exome sequencing. In addition to the identification of six well-known CRC driver genes (APC, TP53, KRAS, FBXW7, PIK3CA, and PABPC), two tumor-related genes (MTCH2 and HSPA6) were detected, along with RRP7A and GXYLT1, which have not been previously linked to cancer. GXYLT1 was mutated in 40% (18/45) of the samples in our cohort. Functionally, GXYLT1 promoted migration and invasion in vitro and metastasis in vivo, while the GXYLT1^S212* mutant induced significantly greater effect. Furthermore, both GXYLT1 and GXYLT1^S212* interacted with ERK2. GXYLT1 induced metastasis via a mechanism involving the Notch and MAPK pathways, whereas the GXYLT1^S212* mutant mainly promoted metastasis by activating the MAPK pathway. We propose that GXYLT1 acts as a novel metastasis-associated driver gene and GXYLT1^S212* might serve as a potential indicator for therapies targeting the MAPK pathway in CRC.

SUBMITTER: Peng L

PROVIDER: S-EPMC9033806 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway.

Peng Lin L Zhao Min M Liu Tianqi T Chen Jiangbo J Gao Pin P Chen Lei L Xing Pu P Wang Zaozao Z Di Jiabo J Xu Qiang Q Qu Hong H Jiang Beihai B Su Xiangqian X

Cell death & disease 20220422 4

Genomic instability plays a key role in the initiation and progression of colorectal cancer (CRC). Although cancer driver genes in CRC have been well characterized, identifying novel genes associated with carcinogenesis and treatment remains challenging because of tumor heterogeneity. Here, we analyzed the genomic alterations of 45 samples from CRC patients in northern China by whole-exome sequencing. In addition to the identification of six well-known CRC driver genes (APC, TP53, KRAS, FBXW7, P ...[more]

PMID: 35459861

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Project description:To explore the relationship between miR-373 and the occurrence and development of colorectal cancer. Additionally, it aims to predict the potential cellular signaling pathways and regulatory mechanisms in which miR-373 may be involved and provides a theoretical basis and experimental evidence for the clinical application of miR-373 as a potential biomarker, molecular target, and prognostic indicator in colorectal cancer. Real-time quantitative PCR is used to analyze the expression of miR-373 in human colorectal cancer cell lines and normal human colonic epithelial cells. Further validation of the differential expression of miR-373 in colorectal cancer cell lines is being performed. Biological functions such as cell proliferation, invasion and apoptosis are being detected by MTT, CCK-8, transwell, cell cycle analysis, and flow cytometry experiments to verify the changes in the biological behavior of colon cancer cells after overexpression and interference of miR-373 in SW-480 cells and to explore the effects of miR-373 on cell proliferation, invasion, and apoptosis in colon cancer cells. Proteomic analysis is being conducted on proteins extracted from miR-373 overexpressing SW480 cells, and mass spectrometry is used for protein identification. GO, KEGG, and enrichment analysis are being employed to analyze the significantly differentially expressed proteins. The expression levels of pathway-related proteins are being verified using Western blot. Overexpression of miR-373 increased the invasive and metastatic ability of SW-480 cells; knockdown of miR-373 decreased the invasive and metastatic ability of SW-480 cells. However, there was no statistically significant effect on cell proliferation and apoptosis in SW-480 cells. Proteomic analysis identified 78 differentially expressed proteins based on fold change (FC) > 1.2 and P < 0.05. Annotation of differentially changed proteins revealed that the MAPK signaling pathway, PI3K-Akt signaling pathway, and FAK signaling pathway may play crucial roles in the migration and invasion of colorectal cancer. Western blot analysis showed that overexpression of miR-373 significantly increased the levels of p-ERK1/2 in SW480 cells. miR-373 may activate the ERK/MAPK signaling pathway to promote the invasion and migration of colorectal cancer cells.

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A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway.

Publications

A stop-gain mutation in GXYLT1 promotes metastasis of colorectal cancer via the MAPK pathway.

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