Adrenomedullin mediates lung metastasis of colorectal cancer through CRLR receptor

Purpose: The current study investigated adrenomedullin (ADM) as a potential autocrine regulator of colorectal cancer (CRC) cells. Methods: : The expression levels of ADM and calcitonin receptor–like receptor (CRLR) mRNA in 26 primary colorectal tumor and adjacent non-tumor tissues were analyzed by quantitative real time (qRT)-PCR. And CRLR expression in 7 CRC cell lines was tested by qRT-PCR and Western blot analysis. Cell migration, invasion and lung metastasis were detected in vitro and in vivo after exogenous ADM stimulation and silencing of CRLR. Results: : We found that the expression levels of ADM and CRLR were significantly higher in colon cancers than those in adjacent nontumorous tissues. In addition, the expression levels of ADM and CRLR in CRC were correlated with UICC stage, 7lymph node metastasis and differentiated degree. Exogenous ADM promoted the migration of RKO and HT-29 cells, and RNA silencing of CRLR in colon cancer cells blocked ADM-induced migration and invasion, suggesting that CRLR might be involved in the autocrine actions of ADM. Xenograft tumors with CRLR knockdown had dramatically reduced lung metastasis compared to control cells. Conclusions: : This study describes the important roles of ADM in potentiating the aggressive characteristics of CRC, and the CRLR receptor was identified as being critical for these effects. These observations provide significant insights into the multifaceted role of ADM in CRC. Combined with the known importance of ADM as an angiogenic factor, these data generally support the further development of CRLR as a potential therapeutic target of CRC.