Study of the molecular mechanism by which RECK suppresses drug resistance and cancer stemness by regulating Her2/Neu and Notch oncogenic pathways

• Main Authors: Kun-jing Hong, 洪琨景
• Other Authors: Wen-Chun Hung
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/fzjkyg

博士 === 國立中山大學 === 生物醫學研究所 === 104 === Reversion-inducing cysteine rich protein with Kazal motifs (RECK) is an endogenous metastatic suppressor gene, which can inhibit matrix metalloproteinase MMP-2, MMP-9 and MT1-MMP to reduce cancer metastasis. Clinical study showed that RECK is highly express in normal cells, but low in cancers. In general, RECK is a membrane-anchored tumor suppressor glycoprotein and correlate with the angiogenesis and metastasis in vitro and in vivo. Interesting, we found that RECK not only inhibits activity of matrix metalloproteinase, but also regulates some signaling pathways. In the first part of this study, we demonstrated that RECK inhibited Her2/Neu receptor dimerization and autophosphorylation which caused reduction of ERK and AKT kinase activity and down-regulation of Her2/Neu target genes. RECK expression is reduced in 58.8% of breast cancer tissues and is associated with lymph node invasion supporting its anti-metastatic role. In the second part, the data demonstrated that the phosphorylation of ATM and ATR pathways and γ-H2AX foci were detected in restoring the expression of RECK in breast cancer cells. RECK inhibited the Her2 signaling and attenuated the expression of the downstream molecules Jun activation domain-binding protein 1 (Jab1) and the DNA repair protein Rad51 to impede DNA repair and to increase drug sensitivity. In the third part, we selected the CD133-positive cancer stem-like cells from gastric cancer cells. Ectopic expression of RECK induced down-regulation of the expression stemness genes including Nanog, Oct4, Sox2 and the formation of cancer stem cell. In further study, RECK represses stemness gene expression and stem-like properties by inhibiting ADAM-mediated Notch1 shedding and activation. Taken together, we provide evidences that RECK regulates Her2/Neu and Notch oncogenic pathways to repress cancer cell drug resistant and tumorigenic of cancer stem cell.