Cadherin-17 interacts with α2β1 integrin to regulate cell proliferation and adhesion in colorectal cancer cells causing liver metastasis

Abstract

Liver metastasis is the major cause of death associated to colorectal cancer. Cadherin-17 (CDH17) is a non-classical, seven domain, cadherin lacking the conserved cytoplasmic domain of classical cadherins. CDH17 was overexpressed in highly metastatic human KM12SM and present in many other colorectal cancer cells. Using tissue microarrays, we observed a significant association between high expression of CDH17 with liver metastasis and poor survival of the patients. On the basis of these findings, we decided to study cellular functions and signaling mechanisms mediated by CDH17 in cancer cells. In this report, loss-of-function experiments demonstrated that CDH17 caused a significant increase in KM12SM cell adhesion and proliferation. Coimmunoprecipitation experiments demonstrated an interaction between CDH17 and α2β1 integrin with a direct effect on β1 integrin activation and talin recruitment. The formation of this complex, together with other proteins, was confirmed by mass spectrometry analysis. CDH17 modulated integrin activation and signaling to induce specific focal adhesion kinase and Ras activation, which led to the activation of extracellular signal-regulated kinase and Jun N-terminal kinase and the increase in cyclin D1 and proliferation. In vivo experiments showed that CDH17 silencing in KM12 cells suppressed tumor growth and liver metastasis after subcutaneous or intrasplenic inoculation in nude mice. Collectively, our data reveal a new function for CDH17, which is to regulate α2β1 integrin signaling in cell adhesion and proliferation in colon cancer cells for liver metastasis.

An RGD Motif Present in Cadherin 17 Induces Integrin Activation and Tumor Growth

“…In agreement with our data, it has been described that ␣2 integrin mediates collagen type IV-dependent activation of FAK and mediates selective liver metastasis (9). We also noticed strong binding of KM12SM cells to collagen IV but not to collagen type I (7).…”

“…Expression of ␣2␤1 integrin was not affected by altering CDH17 expression levels in colorectal cancer cells (7). However, CDH17-WT increased the high-affinity conformation of ␤1 integrin in RKO and KM12SM cells, as shown by using the HUTS21 antibody, which specifically recognizes this conformation (Fig.…”

“…In primary colon cancer tumors, poorly differentiated tumors, and lymph nodes, CDH17 is expressed at low levels (5). However, CDH17 expression is increased in patients with metastasis and is correlated with a poor prognosis, suggesting an association between CDH17 expression and final hepatic colonization during late stages of metastasis (6,7).…”

“…No expression of other integrins in epithelial colon cancer cells has been described, except for some ␤6 integrin constructs. CDH17 was part of a large protein complex containing, among other proteins, ␣2␤1 and ␣6␤4 integrins in colorectal cancer cells (7). After immunoprecipitation of CDH17, only ␣2, ␣6, ␤1, and ␤4 were found, but not ␣v.…”

β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication (Review)

“…While in certain tumors, β1 integrin may also induce anoikis resistance of cancer cells in suspension by phosphorylating FAKs and AKT (14,15). Additionally, β1 integrin may promote the proliferation of cells by phosphorylating FAKs and regulating SRC/mitogen-activated protein kinase (MAPK) to facilitate the expression of v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) and cyclin D1 in cancer cells (16,17). Additionally, although the characteristics of the association between β1 integrin and cancer stem cells are unclear, a previous study has identified that the expression of β1 integrin in cancer stem cells is upregulated (18).…”