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

 Ji Won Hong  ;  Jung Min Kim  ;  Jeong Eun Kim  ;  Hee Cho  ;  Dasol Kim  ;  Wankyu Kim  ;  Jong-Won Oh  ;  Ho Jeong Kwon 
 SCIENTIFIC REPORTS, Vol.10(1) : 2833, 2020-02 
Journal Title
Issue Date
Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor / blood ; Carrier Proteins / genetics* ; Cell Movement / genetics ; Cell Proliferation / genetics ; Circulating MicroRNA / blood ; Colorectal Neoplasms / blood ; Colorectal Neoplasms / genetics* ; Colorectal Neoplasms / pathology ; Exosomes / metabolism ; Exosomes / pathology ; Female ; Gene Expression Regulation, Neoplastic / genetics ; HEK293 Cells ; Humans ; Male ; MicroRNAs / blood ; MicroRNAs / genetics* ; Middle Aged ; RNA, Long Noncoding ; Tissue Inhibitor of Metalloproteinase-3 / genetics*
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.
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