CUB-Domain-Containing Protein 1 Regulates Peritoneal Dissemination of Gastric Scirrhous Carcinoma

Abstract

CUB-domain-containing protein 1 (CDCP1) is a type-I transmembrane protein that is highly expressed in colon, breast, and lung cancers. We recently revealed that CDCP1 is associated with and phosphorylated by Src family kinases and is involved in the regulation of anchorage independence of certain lung cancer cell lines. In this study, we examined whether CDCP1 is involved in the regulation of tumor progression of scirrhous gastric cancer, which is a diffusely infiltrative carcinoma with high invasion potential. Expression and phosphorylation levels of CDCP1 correlated with the invasive potential of scirrhous gastric cancers. Reduction of CDCP1 expression by siRNA suppressed migration, invasion, and anchorage independence without affecting the proliferation of highly invasive scirrhous gastric cancer cells. However, CDCP1 overexpression promoted gastric cancer cell migration with low potential of invasion. Loss of CDCP1 suppressed invasion and dissemination of cancer cells that were orthotopically implanted in the gastric wall of nude mice. Expression and phosphorylation of CDCP1 were also detected in cancer cells of surgically resected tissues of human scirrhous gastric cancer by immunohistochemical analysis. Our results suggest that CDCP1 promotes invasion and peritoneal dissemination of cancer cells through the regulation of cell migration and anchorage independence. Therefore, it is both a potential prognostic and therapeutic target in certain types of gastrointestinal cancers, and suppression of its phosphorylation might be a useful strategy for modulating cancer metastasis. (Am J Pathol

CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

“…In addition, reduced expression of CDCP1 significantly suppressed invasion of MDA-MB-231 cells through Matrigel (Fig. 1F), which is consistent with our results obtained with gastric and pancreatic cancer cell lines (8,12). Taken together, these results indicate that CDCP1 is an essential regulator of invadopodia-mediated ECM degradation during cancer cell invasion.…”

“…We previously reported that CDCP1, a substrate of SFKs, is an essential regulator of anoikis resistance and controls cancer cell migration and invasion (6,8,11,12). CDCP1 expression is positively correlated with poor prognosis in patients with lung, renal, or pancreatic cancer (8)(9)(10).…”

“…We showed that knockdown of CDCP1 resulted in the inhibition of extracellular matrix (ECM) degradation by pancreatic cancer cells (8). Tyrosine phosphorylation of CDCP1, especially at tyrosine 734 residue, plays an essential role in these oncogenic processes (8,11,12). However, the exact molecular mechanisms by which CDCP1 regulates cancer cell invasion remain to be determined.…”

“…Two sets of siRNA against CDCP1 were synthesized and purchased from Life Technologies Corporation as described elsewhere (12). The control siRNA for CDCP1 was synthesized as follows: CDCP1 control siRNA-1, 5 0 -GCUAC-CGGAGCGAAACAACAUCUUA-3 0 (sense), and 5 0 -UA-AGAUGUUGUUUCGCUCCGGUAGC-3 0 (antisense).…”

“…CDCP1 expression is strongly associated with cancer progression and poor prognosis in renal cell carcinoma, lung adenocarcinoma, and pancreatic cancer (8)(9)(10). We previously reported that CDCP1 is a critical regulator of anoikis resistance in lung cancer cells (11), peritoneal dissemination of gastric scirrhous carcinoma (12), and invasion of pancreatic cancer cells (8). We showed that knockdown of CDCP1 resulted in the inhibition of extracellular matrix (ECM) degradation by pancreatic cancer cells (8).…”