Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancers and a leading cause of cancer-related deaths worldwide. In the past two decades, HCC mortality rate has been on a rise both globally and in the U.S., and despite the heightened efforts to target the disease, we have yet seen a major breakthrough since the development of sorafenib. A key reason for this setback resides in our approach in studying HCC. HCC is a highly heterogeneous disease with the mean numbers of somatic mutations in coding sequence ranging from 40 to 80 per tumor, but we have limited understanding of the molecular complexity of HCC and its consequences. The inherent intra- and inter-heterogeneity of HCC and its resulting cancer transcriptome—which is unlike any other major cancers—makes it challenging for us to determine the mechanisms of action of the principal drivers of HCC. In addition, HCC expresses a high number of unique prognostic hallmark genes but shares very few with other cancer. This further highlights the fact that the molecular mechanism of HCC pathogenesis is different from that of other cancers and that a prominent driver of other cancers may play a different role in HCC.
β-catenin is a dual-function protein that is a critical component of the adherens junction (AJ) complex and canonical Wnt/β-catenin signaling pathway. β-catenin is often considered to be a major oncogenic driver of HCC due to the fact that Wnt/β-catenin signaling pathway is the second most frequently altered pathway in HCC. However, activated β-catenin alone is insufficient to initiate HCC and therefore its oncogenic potential and the nature of its contribution to HCC progression require thorough investigation. In our study, we reveal a strikingly elaborate role for β-catenin by taking advantage of a clinically relevant and tractable mouse model of HCC and cell lines derived from this model for mechanistic studies. Our data show that β-catenin is predominantly located in the AJ complex in HCC, only transitioning to the Wnt pathway during the latest stages of the disease. More importantly, we show that the AJ complex is a critical promoter of HCC development by supporting the signaling activity of growth factor receptors such as EGFR, a pathway that is currently under investigation for its potential clinical benefit for HCC patients. Therefore, our work reveals the evolving nature of β-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease.
Kim, Eunsun, "A Novel Perspective On The Role Of Β-Catenin In Hepatocellular Carcinoma" (2019). Publicly Accessible Penn Dissertations. 3312.