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PO3-7-25

Matrix metalloproteinase 3 (MMP3) regulates expression of Hsp gene in high-metastatic cell line of colon cancer

[Speaker] Yuka Okusha:1
[Co-author] Takanori Eguchi:1,2, Chiharu Sogawa:1, Kuniaki Okamoto:1, Ken-Ichi Kozaki:1
1:Dept Dent Pharmacol, Okayama Univ Grad Sch Med Dent Pharm Sci, Japan, 2:Adv Res Ctr Oral Craniofacial Sci, Okayama Univ Grad Sch Med Dent Pharm Sci, Japan

The control of cancer metastasis is crucial in prognosis for cancer. Members of matrix metalloproteinase (MMP) family have been known to promote cancer cell transformation, migration, invasion, and metastasis through alteration of tumor microenvironment, intracellular signaling pathways and genome status. Recently, the non-proteolytic PEX domain of MMP3 has been shown to activate Heat shock protein (Hsp) genes. HSP family has been implicated in tumorigenesis in histological investigations of human breast cancer. Therefore, to elucidate the mechanism of cancer metastasis and investigate the relation between MMPs and HSPs, we provided comprehensive analysis of gene expression using microarray in high- and low-metastatic sublines (LuM1 and NM11, respectively) derived from a murine colon adenocarcinoma cell line, parental colon26. Among the 62,976 genes tested, we found 104 genes involved cancer cell invasion, EMT, and metastasis in LuM1 cells. Among the 104 metastasis-related genes expressed specifically, two members of Mmp gene family, Mmp3 and Mmp9, and Hsp gene family, Hspa2 and Hspb1 were highly expressed in LuM1 cells compared to NM11 cells. The knockdown of MMP3 attenuated cell viability, migration, and invasion in vitro and lung metastasis potential in vivo. Immunohistochemical analysis of MMP3 showed localization to nuclei and the nuclear margins in LuM1 cells. Furthermore, Hspa2 gene expression was downregulated by siRNA knockdown of MMP3. These results suggest that MMP3 involves cancer progression and metastasis through promoting Hspa2 gene expression in LuM1 cell.
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