Dataset Information

Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer.

ABSTRACT: Somatic cell reprogramming using the microRNAs miR-200c, miR-302s, and miR-369s leads to increased expression of cyclin-dependent kinase inhibitors in human colorectal cancer (CRC) cells and suppressed tumor growth. Here, we investigated whether these microRNAs inhibit colorectal tumorigenesis in CPC;Apc mice, which are prone to colon and rectal polyps. Repeated administration of microRNAs inhibited polyp formation. Microarray analysis indicated that c-MAF, which reportedly shows oncogene-like behavior in multiple myeloma and T cell lymphoma, decreased in tumor samples but increased in microRNA-treated normal mucosa. Immunohistochemistry identified downregulation of c-MAF as an early tumorigenesis event in CRC, with low c-MAF expression associated with poor prognosis. Of note, c-MAF expression and p53 protein levels were inversely correlated in CRC samples. c-MAF knockout led to enhanced tumor formation in azoxymethane/dextran sodium sulfate-treated mice, with activation of cancer-promoting genes. c-MAF may play a tumor-suppressive role in CRC development.

SUBMITTER: Itakura H

PROVIDER: S-EPMC10119606 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer.

Itakura Hiroaki H Hata Tsuyoshi T Okuzaki Daisuke D Takeda Koki K Iso Kenji K Qian Yamin Y Morimoto Yoshihiro Y Adachi Tomohiro T Hirose Haruka H Yokoyama Yuhki Y Ogino Takayuki T Miyoshi Norikatsu N Takahashi Hidekazu H Uemura Mamoru M Mizushima Tsunekazu T Hinoi Takao T Mori Masaki M Doki Yuichiro Y Eguchi Hidetoshi H Yamamoto Hirofumi H

iScience 20230323 4

Somatic cell reprogramming using the microRNAs miR-200c, miR-302s, and miR-369s leads to increased expression of cyclin-dependent kinase inhibitors in human colorectal cancer (CRC) cells and suppressed tumor growth. Here, we investigated whether these microRNAs inhibit colorectal tumorigenesis in CPC;Apc mice, which are prone to colon and rectal polyps. Repeated administration of microRNAs inhibited polyp formation. Microarray analysis indicated that c-MAF, which reportedly shows oncogene ...[more]

PMID: 37091240

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Project description:Ataxia telangiectasia and Rad3‑related (ATR) is a kinase that repairs DNA damage. Although inhibitors that selectively target ATR have been developed, their effectiveness in colorectal cancer has not been widely reported. The present study hypothesized that anticancer agents that effectively act in the S phase before the G2/M checkpoint may be ideal agents for concomitant use with ATR inhibitors, which act at the G2/M checkpoint. Therefore, the present study examined the combined effects of AZD6738, an ATR inhibitor, and trifluridine (FTD), which acts in the S phase and has a high DNA uptake rate. In vitro cell viability assays, flow cytometry and western blotting were performed to evaluate cell viability, and changes in cell cycle localization and protein expression. The results revealed that in colorectal cancer cells, the combination of AZD6738 and FTD inhibited cell viability, cell cycle arrest at the G2/M checkpoint and Chk1 phosphorylation, and increased apoptotic protein expression levels more than that when treated with FTD alone. HT29, a BRAF‑mutant cell line known to be resistant to anticancer drugs, was used to induce tumors in vivo. Since FTD does not have sufficient efficacy when administered orally, it was mixed with tipiracil to prevent degradation; this mixture is known as TAS‑102. TAS‑102 alone exerted minimal tumor suppressive effects; however, when used in combination with AZD6738, tumor suppression was observed, suggesting that AZD6738 may increase the effectiveness of a weakly effective drug. Although ATR inhibitors are effective against p53 mutants, the present study demonstrated that these inhibitors were also effective against the p53 wild‑type HCT116 colorectal cancer cell line. In conclusion, combination therapy with AZD6738 and FTD enhanced the inhibition of tumor proliferation in vitro and in vivo. In the future, we aim to investigate the potentiating effect of AZD6738 on 5‑fluouracil‑resistant cell lines that are difficult to treat.

Dataset Information

Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer.

Publications

Tumor-suppressive role of the <i>musculoaponeurotic</i> <i>fibrosarcoma</i> gene in colorectal cancer.

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