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Regulation of aberrantly expressed SERPINH1 by antitumor miR-148a-5p inhibits cancer cell aggressiveness in gastric cancer

Journal of Human Genetics volume 65, pages 647–656 (2020)Cite this article

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Abstract

RNA-sequencing-based microRNA (miRNA) expression signatures have revealed that miR-148a-5p (the passenger strand of the miR-148a-duplex) is downregulated in various kinds of cancer tissues. Analysis of The Cancer Genome Atlas (TCGA) database showed that low expression of miR-148a-5p was predictive of a lower survival rate (p = 0.041) in patients with gastric cancer (GC). Downregulation of miR-148a-5p was confirmed in GC clinical specimens, and its ectopic expression attenuated GC cell proliferation. Our search for miRNA target genes identified a total of 18 oncogenic targets of miR-148a-5p in GC cells. Among these targets, high expression levels of six genes (THBS2, P4HA3, SERPINH1, CDH11, BCAT1, and KCNG3) were closely associated with a poor prognosis (10-year survival rates) in GC patients (p < 0.05) according to TCGA database analyses. Furthermore, we focused on SERPINH1 as a chaperone protein involved in collagen folding in humans. Aberrant expression of SERPINH1 (mRNA and protein levels) was confirmed in GC clinical specimens. Knockdown assays of SERPINH1 using siRNAs resulted in inhibition of the aggressive phenotype of GC cells. Exploring the molecular networks controlled by miRNAs (including miRNA passenger strands) will broaden our understanding of the molecular pathogenesis of GC.

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Acknowledgements

This study was supported by KAKENHI grants (grant nos. 17H04285, 18K08626, 18K09338, 18K16322, 19K09200, 19K09077).

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  1. These authors contributed equally: Kosuke Kawagoe, Masumi Wada

Authors and Affiliations

  1. Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

    Kosuke Kawagoe, Masumi Wada, Tetsuya Idichi, Daisuke Matsushita, Takaaki Arigami, Hiroshi Kurahara, Kosei Maemura & Shoji Natsugoe

  2. Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan

    Reona Okada, Yasutaka Yamada, Keishi Okubo & Naohiko Seki

  3. Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba, Japan

    Shogo Moriya

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Kawagoe, K., Wada, M., Idichi, T. et al. Regulation of aberrantly expressed SERPINH1 by antitumor miR-148a-5p inhibits cancer cell aggressiveness in gastric cancer. J Hum Genet 65, 647–656 (2020). https://doi.org/10.1038/s10038-020-0746-6

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