Date on Senior Honors Thesis

5-2018

Document Type

Senior Honors Thesis

Degree Name

B.S.

Department

Biology

Author's Keywords

Hepatocellular Carcinoma; Cancer Stem Cells; Wnt pathway

Abstract

Hepatocellular carcinoma is the most common type of liver cancer that, when diagnosed at advanced stage, has a 5-year survival rate of less than 12%. Alarmingly, the recurrence rate of HCC after curative and palliative treatment is 70% in the first 14 months. Cancer Stem Cells are a subpopulation in the tumor mass. Accumulating evidence suggests that the CSC subpopulation can initiate cancer and drives tumor recurrence, drug resistance, and metastasis. The Wnt/β-catenin pathway is a cardinal pathway contributing to stem-cell organogenesis during embryo development. The objective of the project was to identify canonical Wnt/β-catenin pathway components and/or downstream targets that contribute to activation of CSCs. We hypothesized that “β-catenin protein regulates CSCs activation in HCC via the canonical Wnt/β-catenin pathway”. We tested this hypothesis with the following experiments: 1) Stabilizing β-catenin in the canonical Wnt pathway and expected an increase in oncogenic Wnt downstream products and subsequently a increase in cancer stem cell properties in HCC cells. 2) Inhibiting Wnt/β-catenin signaling and expected a decrease oncogenic Wnt downstream products and subsequently a decrease in cancer stem cell properties in HCC cells.MG132 induces spheroid formation in a dose dependent manner in Hep3B and Hepa1-6 cell lines. LiCl showed a dose dependent increase in β-catenin in Hep3B and HepG2 cell lines. LiCl treatment induced an increase in oncogenic downstream targets in both control and spheroid-culture Hepa1-6 cells. MG132 induces spheroid formation in a dose dependent manner in Hep3B and Hepa1-6 cell lines. LiCl showed a dose dependent increase in β-catenin in Hep3B and HepG2 cell lines. LiCl treatment induced an increase in oncogenic downstream targets in both control and spheroid-culture Hepa1-6 cells. Inhibiting proteasome degradation in the Canonical Wnt/β-catenin pathway induces an increase in β-catenin expression and spheroid formation characteristic of cancer stem cells in Hep3B and Hepa1-6. Inhibiting GSK3β, a key component of the Canonical Wnt/β-catenin pathway, induces an increase in both β-catenin expression as well as an increase in downstream targets of the Wnt/β-catenin pathway that are oncogenic properties of cancer stem cells in the Hepa1-6 cell line. Research was supported by the NIH: National Cancer Institute Grant R25-CA-134283.

Lay Summary

This study explored the role that aberrant Wnt/β-catenin signaling plays in cancer stem cell (CSC) activation in hepatocellular carcinoma (HCC). CSCs can initiate cancer and drives tumor recurrence, drug resistance, and metastasis. Multiple studies have identified dysregulation of the Wnt/β-catenin signaling components in epithelial tumors including HCC. It is important to establish a correlation between β-catenin, downstream Wnt/β-catenin pathway targets, and cancer stem cell properties in order to help identify HCC patients at risk for metastasis and reoccurrence.The results suggest that stabilizing β-catenin in HCC cells lines may induce CSC-like properties in the cells.

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