MiR-4435 is an UQCRB-related circulating miRNA in human colorectal cancer

• Published in: Scientific reports 2020-02, Vol.10 (1), p.2833-2833, Article 2833
• Main Authors: Hong, Ji Won, Kim, Jung Min, Kim, Jeong Eun, Cho, Hee, Kim, Dasol, Kim, Wankyu, Oh, Jong-Won, Kwon, Ho Jeong
• Format: Article
• Language: English
• Subjects: 38/109; 38/39; 38/91; 631/67/1504/1885/1393; 692/53/2421; Adult; Aged; Aged, 80 and over; Biomarkers; Biomarkers, Tumor - blood; Carrier Proteins - genetics; Cell culture; Cell Movement - genetics; Cell Proliferation - genetics; Circulating MicroRNA - blood; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - blood; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Cytochrome c; Electron transport; Exosomes; Exosomes - metabolism; Exosomes - pathology; Female; Gene Expression Regulation, Neoplastic - genetics; HEK293 Cells; Humanities and Social Sciences; Humans; Male; MicroRNAs - blood; MicroRNAs - genetics; Middle Aged; miRNA; Mitochondria; mRNA; multidisciplinary; Mutants; Reductase; Science; Science (multidisciplinary); Tissue inhibitor of metalloproteinase 3; Tissue Inhibitor of Metalloproteinase-3 - genetics; Tumor cell lines; Tumor suppressor genes; Ubiquinol
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-59610-2

Ubiquinol-cytochrome c reductase (UQCRB), a subunit of the mitochondrial complex III, is highly expressed in tissues from colorectal cancer patients. Since UQCRB is highly expressed in colorectal cancer, we investigated miRNAs from mutant UQCRB-expressing cell lines to identify new miRNA biomarkers. After sequencing miRNAs in the mutant UQCRB-expressing cell lines, miR-4435 was selected as a potential biomarker candidate from the six up-regulated miRNAs. The expression level of miR-4435 in the mutant UQCRB-expressing cell lines and colon cancer was increased. Notably, the expression level of miR-4435 was increased in exosomes isolated from cell culture medium, suggesting that miR-4435 is closely related to colon cancer and that large amounts of miR-4435 may be secreted outside of the cells through exosomes. Additionally, exosomes extracted from the serum samples of colorectal cancer patients showed increased miR-4435 levels depending on the cancer progression stage. Moreover, analyses of a miRNA database and mRNA-sequencing data of the mutant UQCRB-expressing cell lines revealed that TIMP3 , a tumor suppressor, could be a target of miR-4435. Additionally, the expression of miR-4435 was suppressed by UQCRB inhibitor treatment whereas TIMP3 was up-regulated. Upregulation of TIMP3 decreased proliferation of the mutant UQCRB-expressing cell lines and a colorectal cancer cell line. TIMP3 was also upregulated in response to miR-4435 inhibitor and UQCRB inhibitor treatments. Furthermore, these findings suggest that miR-4435 is related to an oncogenic function in UQCRB related disease, CRC, and that effects migration and invasion on mutant UQCRB-expressing cell lines and colorectal cancer cell. In conclusion, our results identified miR-4435 as a potential circulating miRNA biomarker of colorectal cancer associated with UQCRB.