Significance of integrin αvβ5 and erbB3 in enhanced cell migration and liver metastasis of colon carcinomas stimulated by hepatocyte-derived heregulin

被引：39

作者：

Yoshioka, Toshiaki ^{[1
]}

Nishikawa, Yuji ^{[1
]}

Ito, Reiko ^{[1
]}

Kawamata, Makiko ^{[1
]}

Doi, Yuko ^{[1
]}

Yamamoto, Yohei ^{[1
]}

Yoshida, Masayuki ^{[1
]}

Omori, Yasufumi ^{[1
]}

Kotanagi, Hitoshi ^{[2
]}

Masuko, Takashi ^{[3
]}

Enomoto, Katsuhiko ^{[1
]}

机构：

[1] Akita Univ, Grad Sch Med, Dept Mol Pathol & Tumor Pathol, Akita 010, Japan

[2] Akita Red Cross Hosp, Dept Surg, Akita, Japan

[3] Kinki Univ, Sch Pharmaceut Sci, Dept Cell Biol, Osaka, Japan

来源：

CANCER SCIENCE | 2010年 / 101卷 / 09期

基金：

日本学术振兴会;

关键词：

COLORECTAL-CANCER; HEPATIC METASTASIS; GROWTH; ADHESION; RECEPTOR; EXPRESSION; PARACRINE; KINASE; VITRONECTIN; SUPPRESSES;

D O I：

10.1111/j.1349-7006.2010.01640.x

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

To study the mechanisms of the highly liver-metastatic character of colon carcinoma cells, we studied the expression pattern of surface integrins on LS-LM6 (a highly liver-metastatic human colon cancer cell line) and the effects of hepatocyte-derived soluble factors on cell migration. LS-LM6 showed significantly higher expression of integrin alpha v beta 5, a ligand for vitronectin (VN), as compared with its parental cell line (LS174T). A conditioned medium of cultured mouse hepatocytes enhanced VN-mediated cell migration of LS-LM6, which was blocked by neutralizing antibody against integrin alpha v beta 5, while the medium did not affect cell adhesion to VN-coated plastic surfaces. The conditioned medium induced phosphorylation of erbB3 and its heterodimeric partner, erbB2. Heregulin (HRG), a ligand for erbB3, exerted similar effects on VN-mediated cell migration and phosphorylation of erbB3 and erbB2. The conditioned medium contained HRG, and depletion of HRG from the medium by pre-absorption with HRG antibody abolished its effects on cell migration. Heregulin (HRG) was expressed in some hepatocytes in the liver with carcinoma cell metastasis. Furthermore, knockdown of integrin alpha v and erbB3 by small-interfering RNAs significantly inhibited cell migration induced by HRG as well as liver metastasis in vivo. Finally, we found that HRG-induced cell migration was associated with marked phosphorylation of Akt and that cell migration was suppressed by treatment with specific inhibitors of phosphatidylinositol 3-kinase. Our study suggests that hepatocyte-derived HRG might participate in a highly liver-metastatic phenotype of LS-LM6 through enhancement of integrin alpha v beta 5-mediated cell migration and erbB3/erbB2 signaling. (Cancer Sci 2010).

引用

页码：2011 / 2018

页数：8