Hypoxia activates Wnt/β-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma

Abstract

The Wnt/β-catenin signaling is abnormally activated in the progression of hepatocellular carcinoma (HCC). BCL9 is an essential co-activator in the Wnt/β-catenin signaling. Importantly, BCL9 is absent from tumors originating from normal cellular counterparts and overexpressed in many cancers including HCC. But the mechanism for BCL9 overexpression remains unknown. Ample evidence indicates that hypoxia inducible factors (HIFs) play a role in the development of HCC. It was found in our study that BCL9 was overexpressed in both primary HCC and bone metastasis specimens; loss of BCL9 inhibited the proliferation, migration and angiogenesis of HCC; and that that hypoxia mechanically induced the expression of BCL9. BCL9 induction under the hypoxic condition was predominantly mediated by HIF-1α but not HIF2α. In vitro evidence from xenograft models indicated that BCL9 promoter/gene knockout inhibited HCC tumor growth and angiogenesis. Notably, we found that BCL9 and HIF-1α were coordinately regulated in human HCC specimen. The above findings suggest that hypoxia may promote the expression of BCL9 and associate with the development of HCC. Specific regulation of BCL9 expression by HIF-1α may prove to be an underlying crosstalk between Wnt/β-catenin signaling and hypoxia signaling pathways.

Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer

“…BCL9 represents an unexpected addition to previous findings, as a conserved miR-122 target harboring seven miRNA binding sites in coding exons where half contain non-canonical G-bulges. Previous work has shown that BCL9 promotes proliferation and metastases in myeloma and colon cancer cells (Mani et al, 2009), while in HCC, BCL9 inhibition results in reduced proliferation and migration (Xu et al, 2017). We functionally demonstrated that β-catenin transcriptional activity could be repressed by miR-122 through regulation of downstream effector BCL9.…”

Retracted: Effect of the Wnt/β‐catenin signaling pathway on apoptosis, migration, and invasion of transplanted hepatocellular carcinoma cells after transcatheter arterial chemoembolization in rats

“…Importantly, hypoxia can increase expressions of β‐catenin, vimentin, VEGF, and c‐met . Nevertheless, the Wnt/β‐catenin signaling pathway activation is associated with hypoxia . Zhi et al provided overwhelming evidence that downregulation of lysosomal degradation of E‐cadherin induced the formation of E‐cadherin/β‐catenin complex and membrane translocation of β‐catenin, indirectly leading to the down‐regulation of cyclin D1 and VEGF, and decline of their malignant functions proliferation, metastasis, and angiogenesis.…”

WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure

“…WNT signaling is highly conserved from planarians to humans and serves as a communication system between myriad cell types. [19][20][21] WNT reactivation drives a regenerative or repair response to wounding, either returning the tissue to a fully functional preinjury state or producing nonfunctional fibrotic scar tissue, respectively. 18 WNT signaling can be reactivated locally and transiently as a response to wounding in the kidney and many other tissues.…”