Oncogenic dependency on β-catenin in liver cancer cell lines correlates with pathway activation.

Zhihu Ding,Sabine Scheidler,Joern Hopke,Dinesh S Bangari,Mikhail Levit,Chaomei Shi,Douglas D Fang,Dietmar Hoffmann,Christopher Winter,Liang Schweizer,Karl Mamaat,Taiguang Jin,Jack Pollard,Qunyan Yu,Hui Cao,Dmitri Wiederschain,Lan Jiang,Mike W Helms,Tatiana Tolstykh,Fangxian Sun,May Cindhuchao,Susan Ryan,Kerstin Jahn‐Hofmann ,Hui Qü

doi:10.18632/oncotarget.21298

Abstract

Hepatocellular carcinoma (HCC) represents a serious public health challenge with few therapeutic options available to cancer patients.Wnt/β-catenin pathway is thought to play a significant role in HCC pathogenesis. In this study, we confirmed high frequency of CTNNB1 (β-catenin) mutations in two independent cohorts of HCC patients and demonstrated significant upregulation of β-catenin protein in the overwhelming majority of HCC patient samples, patient-derived xenografts (PDX) and established cell lines. Using genetic tools validated for target specificity through phenotypic rescue experiments, we went on to investigate oncogenic dependency on β-catenin in an extensive collection of human HCC cells lines. Our results demonstrate that dependency on β-catenin generally tracks with its activation status. HCC cell lines that harbored activating mutations in CTNNB1 or displayed elevated levels of non-phosphorylated (active) β-catenin were significantly more sensitive to β-catenin siRNA treatment than cell lines with wild-type CTNNB1 and lower active β-catenin. Finally, significant therapeutic benefit of β-catenin knock-down was demonstrated in established HCC tumor xenografts using doxycycline-inducible shRNA system. β-catenin downregulation and tumor growth inhibition was associated with reduction in AXIN2, direct transcriptional target of β-catenin, and decreased cancer cell proliferation as measured by Ki67 staining. Taken together, our data highlight fundamental importance of aberrant β-catenin signaling in the maintenance of oncogenic phenotype in HCC.

Highlights

Wnt/β-catenin signaling is an important developmental pathway that is often hijacked by cancer cells to sustain their unrestricted proliferation, promote survival and facilitate metastatic spread
Significant therapeutic benefit of β-catenin knockdown was demonstrated in established Hepatocellular carcinoma (HCC) tumor xenografts using doxycyclineinducible shRNA system. β-catenin downregulation and tumor growth inhibition was associated with reduction in AXIN2, direct transcriptional target of β-catenin, and decreased cancer cell proliferation as measured by Ki67 staining
HCC is a complex human malignancy characterized by deregulation of multiple signaling pathways, among which Wnt/β-catenin occupies the place of central importance

Summary

Introduction

Wnt/β-catenin signaling is an important developmental pathway that is often hijacked by cancer cells to sustain their unrestricted proliferation, promote survival and facilitate metastatic spread. Frequent somatic alterations in CTNNB1, gene that encodes β-catenin, or components of its regulatory network, such as APC and AXIN, have been detected in human cancers. Somatic activating mutations in CTNNB1 have been detected in a number of tumors, but the highest frequency is observed in hepatocellular carcinoma (HCC) [6]. These mutations frequently disrupt normal protein turnover of β-catenin and result in its aberrant accumulation in cancer cells. Multi-factorial nature of HCC coupled with incomplete understanding of critical drivers of this disease continue to hamper development of new therapeutic modalities for HCC patients [12]

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