LOXL2 promotes vasculogenic mimicry and tumour aggressiveness in hepatocellular carcinoma

Abstract

Lysyl oxidase‐like 2 (LOXL2) has shown to promote metastasis and poor prognosis in hepatocellular carcinoma (HCC). Also, we have previously reported that vasculogenic mimicry (VM) is associated with invasion, metastasis and poor survival in HCC patients. In the present study, we investigated molecular function of LOXL2 in HCC and VM. We used the immunohistochemical and CD31/periodic acid‐Schiff double staining to detect the relationship between LOXL2 and VM formation. We performed the gain and loss of function studies and analysed the migratory, invasion and tube formation in HCC cell lines. We analysed the function of LOXL2 in VM formation and HCC metastasis both in vitro and in vivo. We have showed that LOXL2 was overexpression in HCC and was positively correlated with tumour grade, metastasis, VM formation and poor survival in 201 HCC patients. Secondly, our studies have showed that LOXL2 overexpression in HCC cells significantly promoted migration, invasion and tube formation. Finally, we found that LOXL2 may increase SNAIL expression, thereby enabling VM. Our study indicated that LOXL2 may promote VM formation and tumour metastasis by collaborating with SNAIL in HCC. What's more, the overexpression of LOXL2 indicated a poor prognosis in HCC patients.

Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models

“…Our bio-informatic analysis identified 25 hypoxia upregulated genes in chronic HBV infected patients, including LOXL2, SMIM3, TNS1, and IGFBP1. Notably, LOXL2 overexpression in HCC was previously associated with high tumour grade, metastasis, and poor patient overall and disease-free survival 59 . LOXL2 was shown to mediate its pathogenic effects in HCC angiogenesis via vasculogenic mimicry signalling, cytoskeleton reorganization, and bone-marrow derived cell recruitment 59,60 .…”

“…Notably, LOXL2 overexpression in HCC was previously associated with high tumour grade, metastasis, and poor patient overall and disease-free survival 59 . LOXL2 was shown to mediate its pathogenic effects in HCC angiogenesis via vasculogenic mimicry signalling, cytoskeleton reorganization, and bone-marrow derived cell recruitment 59,60 . In fact, hypoxia and HIF-1α signalling have been identified as key regulators of LOXL2 and driver of its pathogenesis, consistent with our observations 60,61 .…”

Hypoxic gene expression in chronic hepatitis B infected patients is not observed in state-of-artin vitroand mouse infection models

“…Our bio-informatic analysis identified 25 hypoxia upregulated genes in chronic HBV infected patients, including LOXL2, SMIM3, TNS1 , and IGFBP1 . Notably, LOXL2 overexpression in HCC was previously associated with high tumour grade, metastasis, and poor patient overall and disease-free survival 52 . LOXL2 was shown to mediate its pathogenic effects in HCC angiogenesis via vasculogenic mimicry signalling, cytoskeleton reorganization, and bone-marrow derived cell recruitment 52,53 .…”

“…Notably, LOXL2 overexpression in HCC was previously associated with high tumour grade, metastasis, and poor patient overall and disease-free survival 52 . LOXL2 was shown to mediate its pathogenic effects in HCC angiogenesis via vasculogenic mimicry signalling, cytoskeleton reorganization, and bone-marrow derived cell recruitment 52,53 . In fact, hypoxia and HIF-1α signalling have been identified as key regulators of LOXL2 and driver of its pathogenesis, consistent with our observations 53,54 .…”

Involvement of Actin and Actin-Binding Proteins in Carcinogenesis

“…In recent years, more and more importance has been attributed to the phenomenon called vasculogenic mimicry (VM). Although the prevalence and importance of VM in cancer still divides the scientific community [ 141 , 142 ], evidence confirms that this process is associated with poor prognosis in cancer patients [ 143 , 144 , 145 ]. However, there is no detailed description of changes in the actin structure in the course of this phenomenon so far.…”