IN VIVO TARGETING OF ADAM9 GENE EXPRESSION USING SHRNA SUPPRESSES PROSTATE CANCER GROWTH BY REGULATING REG4 DEPENDENT CELL CYCLE PROGRESSION

You have accessJournal of UrologyProstate Cancer: Basic Research (II)1 Apr 2013322 IN VIVO TARGETING OF ADAM9 GENE EXPRESSION USING SHRNA SUPPRESSES PROSTATE CANCER GROWTH BY REGULATING REG4 DEPENDENT CELL CYCLE PROGRESSION Chia-Ling Hsieh, Che-Ming Liu, Yun-Chi He, and Shian-Ying Sung Chia-Ling HsiehChia-Ling Hsieh Taichung, Taiwan More articles by this author , Che-Ming LiuChe-Ming Liu Taichung, Taiwan More articles by this author , Yun-Chi HeYun-Chi He Taichung, Taiwan More articles by this author , and Shian-Ying SungShian-Ying Sung Taichung, Taiwan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1707AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM) 9 has been found to be upregulated during cancer progression and hormone therapies through reactive oxygen species as a mediator. Here, we present in vitro and in vivo evidences that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shADAM9) inhibited human prostate cancer cell proliferation in a in vitro and blocked tumor growth in the in vivo of prostate cancer bone metastasis. METHODS To analyze prostate cancer progression after knockdown ADAM9 expression, xenograft mouse model of cell proliferation by intra-tibia injection was conducted. Therapeutic studies by intra-tumoral injection of shADAM9 after tumor reach to the 200 mm3 was conducted. Intersection cDNA microarray of two different shADAM9 knockdown PC3 cells were evaluated the correlated gene expression, followed by confirmed their roles in cell cycle regulation and stress responses. RESULTS We demonstrated a significant decreases of cell proliferation after knockdown of ADAM9 expression in the in vivo animal studies. In addition, Tartrate-resistant acid phosphatase staining of bone lesion showed the inhibition of osteoclastogenesis can be detected in the tumor loci that were knockdown of ADAM9 expression. This inhibition of cell proliferation also can be detected when we applied shADAM9 as therapeutic agent that showed block tumor growth. IHC analyses of tumors confirmed knockdown of ADAM9 resulted in the inhibition of tumor proliferation rather than apoptosis. This is due to the induction of G0/G1 arrest after knockdown of ADAM9 expression. Intersection cDNA microarray analyses confirmed the reduction of REG4 expression, that was associated with up-regulation of cell cycle negative regulators, P21Cip1/WAF1 and P27Kip1 under stress condition. This stress induces ADAM9 downstream REG4 and cell cycle activities was controlled by endogenous superoxide level that is mimicking to the ROS elevation induction by drug therapies of cancer cells. Hence, our studies revealed the possibility to target ADAM9 as combination agent to decrease therapeutic resistance. CONCLUSIONS These results indicated ADAM9 involved in the regulation of cancer cells proliferation by indirection inhibition of P21Cip1/WAF1 and P27Kip1 expression. As a result, inhibition of ADAM9 expression could be useful to decrease cancer proliferation and enhance therapeutic effects of late stage prostate cancer patients. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e130-e131 Peer Review Report Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Chia-Ling Hsieh Taichung, Taiwan More articles by this author Che-Ming Liu Taichung, Taiwan More articles by this author Yun-Chi He Taichung, Taiwan More articles by this author Shian-Ying Sung Taichung, Taiwan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...