Molecular Pathogenesis of Colorectal Cancer: Impact of Oncogenic Targets Regulated by Tumor Suppressive miR-139-3p

• Published in: International journal of molecular sciences Vol. 23; no. 19; p. 11616
• Main Authors: Yasudome, Ryutaro, Seki, Naohiko, Asai, Shunichi, Goto, Yusuke, Kita, Yoshiaki, Hozaka, Yuto, Wada, Masumi, Tanabe, Kan, Idichi, Tetsuya, Mori, Shinichiro, Ohtsuka, Takao
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.10.2022; MDPI
• Subjects: AKT protein; Argonaute 2 protein; Binding sites; Cancer; Cell cycle; Cell Line, Tumor; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA methylation; expression signature; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Hexokinase; Hexokinase - metabolism; Humans; Immunoprecipitation; Keratin; Keratins - metabolism; Kinases; KRT80; Medical prognosis; Medical research; microRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR-139-3p; miRNA; Mutation; Passengers; Pathogenesis; Phosphorylation; Protein kinase; Proto-Oncogene Proteins c-akt - metabolism; RNA, Small Interfering; RNA-induced silencing complex; RNA-Induced Silencing Complex - genetics; RNA-mediated interference; Serine - metabolism; siRNA; Strands; Threonine - metabolism; Transfection; tumor suppressor; Tumors; KRT80; expression signature; colorectal cancer; microRNA; tumor suppressor; AKT; miR-139-3p; HK2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231911616

We recently determined the RNA sequencing-based microRNA (miRNA) expression signature of colorectal cancer (CRC). Analysis of the signature showed that the expression of both strands of pre- ( , the guide strand, and , the passenger strand) was significantly reduced in CRC tissues. Transient transfection assays revealed that expression of blocked cancer cell malignant transformation (e.g., cell proliferation, migration, and invasion). Notably, expression of markedly blocked RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation in CRC cells. A combination of in silico database and gene expression analyses of -transfected cells revealed 29 putative targets regulated by in CRC cells. RNA immunoprecipitation analysis using an Argonaute2 (AGO2) antibody revealed that was efficiently incorporated into the RNA-induced silencing complex. Aberrant expression of Keratin 80 ( ) was detected in CRC clinical specimens by immunostaining. A knockdown assay using small interfering RNA (siRNA) targeting showed that reducing expression suppressed the malignant transformation (cancer cell migration and invasion) of CRC cells. Importantly, inhibiting expression reduced AKT phosphorylation in CRC cells. Moreover, hexokinase-2 (HK2) expression was reduced in cells transfected with the siRNAs or . The involvement of miRNA passenger strands (e.g., ) in CRC cells is a new concept in miRNA studies. Our tumor-suppressive miRNA-based approach helps elucidate the molecular pathogenesis of CRC.