SDF-1/CXCR4 axis promotes directional migration of colorectal cancer cells through upregulation of integrin αvβ6.

Colorectal cancer (CRC) displays a predilection for metastasis to liver. Although stromal cell-derived factor-1 (SDF-1)/CXCR4 plays an important role in the liver metastasis, the molecular mechanism still remains obscure. We previously reported that integrin v6 was implicated in the progression of CRC. However, no data are currently available on the cross talk between CXCR4 and v6. In the present study, we first demonstrated the cross talk between CXCR4 and v6 and their role in liver metastasis of CRC. We analyzed 159 human CRC samples and found that expression of CXCR4 and v6 was significantly associated with liver metastasis, and interestingly expression of v6 significantly correlated with expression of CXCR4. Both CXCR4 and v6 were highly expressed in metastatic CRC cell lines HT-29 and WiDr, whereas both of them were exiguous in non-metastatic cell line Caco-2. Furthermore, inhibition of v6 significantly decreased SDF-1-induced cell migration in vitro. SDF-1/CXCR4 could upregulate v6 expression through phosphorylation of ERK and activation of Ets-1 transcription factor. In conclusion, we demonstrate that SDF-1/CXCR4 induces directional migration and liver metastasis of CRC cells by upregulating v6 through ERK/Ets-1 pathway. These data support combined inhibition of CXCR4 and v6 to prevent development of liver metastasis of CRC.