Tumor-suppressive microRNAs regulate ECM pathways in prostate cancer

• Project/Area Number: 15K20070
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Chiba University
• Principal Investigator: Nishikawa Rika 千葉大学, 大学院医学研究院, 特任研究員 (60746783)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: マイクロRNA / 前立腺癌 / miR-29a/b/c / 細胞外マトリックス / 転移促進遺伝子 / 癌抑制遺伝子 / focal adhesion

Outline of Final Research Achievements

Based on the miRNA expression signature of prostate cancer (PCa) showed that members of the microRNA-29 family (miR-29a/b/c) were reduced in PCa tissues, suggesting that they functioned as antitumor miRNAs. Ectopic expression of all member of miR-29 inhibited cancer cell migration and invasion. Genome-wide gene expression analysis and luciferase reporter assay demonstrated that lysyl oxidase like 2（LOXL2）was directly regulated by antitumor miR-29a/b/c in PCa cells. Overexpressed LOXL2 was detected in PCa clinical specimens, and silencing of LOXL2 inhibited cancer cell migration and invasion in PCa cells. Basically, the function of the LOXL2 is covalent crosslinking of collagen and/or elastin in the ECM. Recent studies showed that aberrant expression of ECM proteins has been contributed to cancer cell metastasis. The identification of novel molecular pathways and targets regulated by the miR-29-LOXL2 axis may lead to a better understanding of PCa development and metastasis.

Research Products

• [Journal Article] Regulation of metastasis-promoting LOXL2 gene expression by antitumor microRNAs in prostate cancer. (2017)
  • Author(s): Kato M, Kurozumi A, Goto Y, Matsushita R, Okato A, Nishikawa R, Fukumoto I, Koshizuka K, Ichikawa T, Seki N.
  • Journal Title: J Hum Genet Volume: 62 Issue: 1 Pages: 123-132
  • DOI: 10.1038/jhg.2016.68
  • NAID: 40021036352
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulation of the collagen cross-linking enzymes LOXL2 and PLOD2 by tumor-suppressive microRNA-26a/b in renal cell carcinoma. (2016)
  • Author(s): Kurozumi A, Kato M, Goto Y, Matsushita R, Nishikawa R, Okato A, Fukumoto I, Ichikawa T, Seki N.
  • Journal Title: Int J Oncol Volume: in press Issue: 5 Pages: 1837-46
  • DOI: 10.3892/ijo.2016.3440
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tumor-suppressive microRNA-29 family inhibits cancer cell migration and invasion directly targeting LOXL2 in lung squamous cell carcinoma. (2016)
  • Author(s): Mizuno K, Seki N, Mataki H, Matsushita R, Kamikawaji K, Kumamoto T, Takagi K, Goto Y, Nishikawa R, Kato M, Enokida H, Nakagawa M, Inoue H.
  • Journal Title: Int J Oncol Volume: 48 Issue: 2 Pages: 450-450
  • DOI: 10.3892/ijo.2015.3289
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-suppressive microRNA-223 inhibits cancer cell migration and invasion by targeting ITGA3/ITGB1 signaling in prostate cancer. (2016)
  • Author(s): Kurozumi A, Goto Y, Matsushita R, Fukumoto I, Kato M, Nishikawa R, Sakamoto S, Enokida H, Nakagawa M, Ichikawa T, Seki N.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 1 Pages: 84-94
  • DOI: 10.1111/cas.12842
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Tumour-suppressive microRNA-29s directly regulate LOXL2 expression and inhibit cancer cell migration and invasion in renal cell carcinoma. (2015)
  • Author(s): Nishikawa R, Chiyomaru T, Enokida H, Inoguchi S, Ishihara T, Matsushita R, Goto Y, Fukumoto I, Nakagawa M, Seki N.
  • Journal Title: FEBS Letters Volume: 589 Issue: 16 Pages: 2136-2145
  • DOI: 10.1016/j.febslet.2015.06.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-205 inhibits cancer cell migration and invasion via modulation of centromere protein F regulating pathways in prostate cancer. (2015)
  • Author(s): Nishikawa R, Goto Y, Kurozumi A, Matsushita R, Enokida H, Kojima S, Naya Y, Nakagawa M, Ichikawa T, Seki N
  • Journal Title: Int J Urol Volume: 22 Issue: 9 Pages: 867-877
  • DOI: 10.1111/iju.12829
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MicroRNA-26a/b directly regulate La-related protein 1 and inhibit cancer cell invasion in prostate cancer. (2015)
  • Author(s): Kato M, Goto Y, Matsushita R, Kurozumi A, Fukumoto I, Nishikawa R, Sakamoto S, Enokida H, Nakagawa M, Ichikawa T, Seki N.
  • Journal Title: International Journal of Oncology Volume: 47 Issue: 2 Pages: 710-718
  • DOI: 10.3892/ijo.2015.3043
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Regulation of metastatic-promoting LOXL2 gene expression by tumor-suppressor miRNAs in prostate cancer. (2016)
  • Author(s): 加藤繭子、黒住顕、五島悠介、松下良介、岡東篤、西川里佳、福本一郎、塚越慶一、市川智彦、関直彦
  • Organizer: 第75回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] microRNA-223 inhibits cancer cell migration and invasion by targeting ITGA3/ITGB1 signaling in prostate cancer. (2016)
  • Author(s): 黒住顕、五島悠介、松下良介、福本一郎、加藤繭子、西川里佳、坂本信一、榎田英樹、中川昌之、市川智彦、関直彦
  • Organizer: 第75回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly regulate metastasis-promoting LOXL2 in prostate cancer (2016)
  • Author(s): Mayuko Kato, Akira Kurozumi, Yusuke Goto, Ryosuke Matsushita, Ichiro Fukumoto, Atsushi Okato, Rika Nishikawa, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: Ernest N. Morial Convention Center, New Orleans（米国）
  • Year and Date: 2016-04-16
  • Int'l Joint Research