KRAS mutation leads to decreased expression of regulator of calcineurin 2, resulting in tumor proliferation in colorectal cancer
نویسندگان
چکیده
KRAS mutations occur in 30-40% of all cases of human colorectal cancer (CRC). However, to date, specific therapeutic agents against KRAS-mutated CRC have not been developed. We previously described the generation of mouse models of colon cancer with and without Kras mutations (CDX2P-G22Cre;Apc(flox/flox); LSL-Kras(G12D) and CDX2P-G22Cre;Apc(flox/flox) mice, respectively). Here, the two mouse models were compared to identify candidate genes, which may represent novel therapeutic targets or predictive biomarkers. Differentially expressed genes in tumors from the two mouse models were identified using microarray analysis, and their expression was compared by quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemical analyses in mouse tumors and surgical specimens of human CRC, with or without KRAS mutations, respectively. Furthermore, the functions of candidate genes were studied using human CRC cell lines. Microarray analysis of 34 000 transcripts resulted in the identification of 19 candidate genes. qRT-PCR analysis data showed that four of these candidate genes (Clps, Irx5, Bex1 and Rcan2) exhibited decreased expression in the Kras-mutated mouse model. The expression of the regulator of calcineurin 2 (RCAN2) was also observed to be lower in KRAS-mutated human CRC. Moreover, inhibitory function for cancer cell proliferation dependent on calcineurin was indicated with overexpression and short hairpin RNA knockdown of RCAN2 in human CRC cell lines. KRAS mutations in CRC lead to a decrease in RCAN2 expression, resulting in tumor proliferation due to derepression of calcineurin-nuclear factor of activated T cells (NFAT) signaling. Our findings suggest that calcineurin-NFAT signal may represent a novel molecular target for the treatment of KRAS-mutated CRC.
منابع مشابه
بررسی جهش در اگزون7 ژن اکسین2 در سرطان کولورکتال (مطالعات آزمایشگاهی و بیوانفورماتیکی)
Background & Aims: Colorectal cancer is the third most common cancer in Iran. Wnt pathway changes are commonly reported in this type of cancer. Some of the important activities of this pathway are the role of carcinogenicity, cellular proliferation, cell migration, and so on. Axin2 acts as a negative regulator in the Wnt / TCF signaling pathway and helps in the formation of the beta-catenin des...
متن کاملAltered expression of Lnc-OC1 and SIRT1 genes in colorectal cancer tissue
Backgrounds: SIRT1 plays an important role in many physiological processes, including metabolism, neuronal protection, senecence and inflammatory, by staging histones and multiple transcription factors. However, the complex mechanisms of SIRT1 signaling in tumors are not yet fully understood, as it acts as both an oncogen and a tumor suppressor. On the other hand, it has been shown that the Lnc...
متن کاملMutation Analysis of TP53 Tumor Suppressor Gene in Colorectal Cancer in Patients from Iran (Kerman Province)
Objective(s) P53 is an important tumor suppressor, which is mutated in later stages of many cancers and leads to resistance to chemotherapy. The aim of this study was to reveal mutations of TP53 in colorectal cancer in Kerman province. Materials and Methods A total of Forty-three colon cancer specimens as paraffin block or fresh tissues, which passed stage IIIA, were selected. Three exons 5,...
متن کاملارزیابی فراوانی جهشهای ژن KRAS در بیماران ایرانی مبتلا به سرطان کولورکتال
Background: Kirsten rat sarcoma (KRAS) gene is a target of genetic alterations which are diagnostic and prognostic biomarkers in patients with metastatic colorectal cancer who are treated with monoclonal anti-EGFR antibodies such as cetuximab and panitumumab. KRAS mutations are seen in 35-42% of patients with colorectal cancer. The high frequency of these mutations in colorectal cancer represen...
متن کاملCTGF and MLH1 Gene Expression Levels in Colorectal Cancer Tumor Tissues and Adjacent Normal Tissues in Patients in Golestan Province
Background and purpose: Colorectal cancer is the third most common type of cancer in terms of incidence and the second most common cause of cancer-related death worldwide. The aim of this study was to investigate the expression of CTGF and MLH1 gene in colorectal cancer tumor tissues and adjacent normal tissues in patients in Golestan province. Materials and methods: In this experimental study...
متن کامل