Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma

Abstract

Background Activation of Wnt/β-catenin pathway is a frequent event in hepatocellular carcinoma and is associated with enhanced cell survival and proliferation. Therefore, targeting this signaling pathway is discussed as an attractive therapeutic approach for HCC treatment. BCL9 and BCL9L, two homologous coactivators of the β-catenin transcription factor complex, have not yet been comprehensively characterized in HCC. We aimed to elucidate the roles of BCL9 and BCL9L, especially regarding Wnt/β-catenin signaling and their prognostic value in HCC. Methods Expression of BCL9/BCL9L was determined in HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B, and Huh6) and normal liver cell lines (THLE-2 and THLE-3). To analyze proliferation and apoptosis, BCL9 and/or BCL9L were knocked down in Wnt-inactive HLE and Wnt-active HepG2 and Huh6 cells using siRNA. Subsequently, Wnt reporter assays were performed in HepG2 and Huh6 cells. BCL9 and BCL9L expression, clinicopathological and survival data of public HCC datasets were analyzed, taking the Wnt signaling status into account. Results Knockdown of BCL9L, but not of BCL9, reduced Wnt signaling activity. Knockdown of BCL9 and/or BCL9L reduced cell viability and increased apoptosis of Wnt-inactive HCC cells, but had no effect in Wnt-active cells. Expression of BCL9 and BCL9L was upregulated in human HCC and increased with progressing dedifferentiation. For BCL9L, higher expression was observed in tumors of larger size. Overexpression of BCL9 and BCL9L correlated with poor overall survival, especially in HCC without activated Wnt signaling. Conclusion Oncogenic BCL9 proteins represent promising targets for cancer therapy and inhibiting them may be particularly beneficial in Wnt-inactive HCCs. Nicole Huge and Maria Sandbothe have contributed equally to this work. Beate Vajen and Britta Skawran supervised this work equally.

Deficiency of Mettl3 in Bladder Cancer Stem Cells Inhibits Bladder Cancer Progression and Angiogenesis

“…The reduced expression of Mettl3 and Ki67 with the increased level of Caspase-3 was detected by randomized double-blind IHC scoring in Upk3a CreER ; Mettl3 flox/flox mice, manifesting the role of Mettl3 in promoting proliferation and inhibiting apoptosis in vivo ( Figure 1F ). A significant reduction in AKT1 (a proliferation-related factor) ( Wang et al, 2019 ) and BCL9L (an inhibitor of apoptosis) ( Huge et al, 2020 ) was observed by the loss of Mettl3 in Upk3a + BCa cells ( Figure 1G ). These results indicate that Mettl3 is essential for cellular proliferation and survival in BBN-induced BCa.…”

miR-766-3p Targeting BCL9L Suppressed Tumorigenesis, Epithelial-Mesenchymal Transition, and Metastasis Through the β-Catenin Signaling Pathway in Osteosarcoma Cells

“…B-Cell Lymphoma 9-Like Protein (BCL9L), as a cofactor for canonical Wnt signaling, is a component of BCL9 family and mediates EMT ( Gay et al, 2019 ). It has been reported that BCL9L induces early phases of human intestinal cancer progress by regulating the β-catenin function switch between adhesion and transcription ( Brembeck et al, 2004 ; Huge et al, 2020 ). Moreover, BCL9L is demonstrated to enhance β-catenin–mediated transcriptions and increase the abilities of proliferation and metastasis in breast and colon cancer cell lines ( Brembeck et al, 2011 ; El-Hage et al, 2015 ).…”

Long non-coding RNA LINC00665 promotes gemcitabine resistance of Cholangiocarcinoma cells via regulating EMT and stemness properties through miR-424-5p/BCL9L axis

“…Moreover, simultaneously BCL9/BCL9L depletion completely suppresses β-Catenin driven intestinal and hepatocellular transformation in mouse models 39 . BCL9L overexpression is positively correlated with poor overall survival in hepatocellular carcinoma patients, and silencing BCL9L, but not BCL9, reduced Wnt signaling, and suppressed cell growth and induced apoptosis of Wnt-inactive hepatocellular carcinoma cells 40 . In pancreatic cancer, BCL9L knockdown decreases cell proliferation, migration, invasion, and liver metastasis, and increases E-cadherin expression even in the presence of TGF-β, suggesting a role of BCL9L in regulating EMT 31 .…”