Regulation of antitumor miR‐144‐5p targets oncogenes: Direct regulation of syndecan‐3 and its clinical significance

• Published in: Cancer science 2018-09, Vol.109 (9), p.2919-2936
• Main Authors: Yamada, Yasutaka, Arai, Takayuki, Kojima, Satoko, Sugawara, Sho, Kato, Mayuko, Okato, Atsushi, Yamazaki, Kazuto, Naya, Yukio, Ichikawa, Tomohiko, Seki, Naohiko
• Format: Article
• Language: English
• Subjects: Aged; Angiogenesis; antitumor; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell Proliferation - genetics; Clinical significance; Female; Gene expression; Gene regulation; Genomes; Heparan sulfate; Humans; Interleukin 1; Invasiveness; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Male; Medical prognosis; Metastasis; microRNA; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; miR‐144‐5p; Neoplasm Invasiveness - genetics; Oncogenes; Oncogenes - genetics; Original; Pathogenesis; Prognosis; Prostate cancer; Renal cell carcinoma; RNA Interference; RNA, Small Interfering - genetics; SDC3; SH2D1A protein; Studies; Syndecan; Syndecan-3 - genetics; Syndecan-3 - metabolism
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13722

In the human genome, miR‐451a, miR‐144‐5p (passenger strand), and miR‐144‐3p (guide strand) reside in clustered microRNA (miRNA) sequences located within the 17q11.2 region. Low expression of these miRNAs is significantly associated with poor prognosis of patients with renal cell carcinoma (RCC) (miR‐451a: P = .00305; miR‐144‐5p: P = .00128; miR‐144‐3p: P = 9.45 × 10−5). We previously reported that miR‐451a acted as an antitumor miRNA in RCC cells. Involvement of the passenger strand of the miR‐144 duplex in the pathogenesis of RCC is not well understood. Functional assays showed that miR‐144‐5p and miR‐144‐3p significantly reduced cancer cell migration and invasive abilities, suggesting these miRNAs acted as antitumor miRNAs in RCC cells. Analyses of miR‐144‐5p targets identified a total of 65 putative oncogenic targets in RCC cells. Among them, high expression levels of 9 genes (FAM64A, F2, TRIP13, ANKRD36, CENPF, NCAPG, CLEC2D, SDC3, and SEMA4B) were significantly associated with poor prognosis (P < .001). Among these targets, expression of SDC3 was directly controlled by miR‐144‐5p, and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC3 regulation. Data showed that expression of 10 of the downstream genes (IL18RAP, SDC3, SH2D1A, GZMH, KIF21B, TMC8, GAB3, HLA‐DPB2, PLEK, and C1QB) significantly predicted poor prognosis of the patients (P = .0064). These data indicated that the antitumor miR‐144‐5p/oncogenic SDC3 axis was deeply involved in RCC pathogenesis. Clustered miRNAs (miR‐451a, miR‐144‐5p, and miR‐144‐3p) acted as antitumor miRNAs, and their targets were intimately involved in RCC pathogenesis. Our study showed that expression of miR‐144‐5p and miR‐144‐3p was downregulated, and these microRNAs (miRNAs) acted as antitumor miRNAs in renal cell carcinoma. SDC3 was directly controlled by miR‐144‐5p, and its expression enhanced cancer cell aggressiveness. Clustered miRNAs (miR‐451a, miR‐144‐5p, and miR‐144‐3p) acted as antitumor miRNAs, and their targets were intimately involved in renal cell carcinoma pathogenesis.