Abstract
Galectin-1 (Gal-1) is involved in several pathological activities associated with tumor progression and chemoresistance, however, the role and molecular mechanism of Gal-1 activity in hepatocellular carcinoma (HCC) epithelial–mesenchymal transition (EMT) and sorafenib resistance remain enigmatic. In the present study, forced Gal-1 expression promoted HCC progression and sorafenib resistance. Gal-1 elevated αvβ3-integrin expression, leading to AKT activation. Moreover, Gal-1 overexpression induced HCC cell EMT via PI3K/AKT cascade activation. Clinically, our data revealed that Gal-1 overexpression is correlated with poor HCC survival outcomes and sorafenib response. These data suggest that Gal-1 may be a potential therapeutic target for HCC and a biomarker for predicting response to sorafenib treatment.
Highlights
The epithelial–mesenchymal transition (EMT) is well known to have a pivotal role in the dissemination of malignant hepatocytes during Hepatocellular carcinoma (HCC) progression,[6,7] elucidation of the molecular mechanism underlying EMT may aid in the development of innovative therapeutic strategies against HCC
We found that Gal-1 protein expression was significantly increased in highly metastatic cell lines (MHCC97H and HCCLM3) compared with low metastatic HCC cell lines (Hep3B and Huh-7; Figure 1a)
Gal-1 increases αvβ3-integrin expression and activates FAK/ PI3K/AKT signaling in HCC cells, we examined whether the oncogenic effects of Gal-1 could be reversed by loss of either the αv- or β3-integrin subunits
Summary
The epithelial–mesenchymal transition (EMT) is well known to have a pivotal role in the dissemination of malignant hepatocytes during HCC progression,[6,7] elucidation of the molecular mechanism underlying EMT may aid in the development of innovative therapeutic strategies against HCC. Galectin-1 (Gal-1), a 14.5-kDa protein, is regulated by HIF-1 and has vital protumorigenic roles within the tumor microenvironment.[11] Dysregulation of Gal-1 expression is associated with resistance to chemotherapy through H-Ras/Raf/extracellular signal-regulated kinase (ERK) pathway activation.[12] Gal-1 overexpression mediates migration and invasion via increased phosphorylation of AKT, mTOR and p70 kinases in cancer cells.[13] sorafenib response is impaired in HCC with dysregulated p-ERK and p-AKT activation.[14,15].
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