Identification of the roles played by IKKε in hepatocellular and colorectal carcinogenesis

Abstract

Hepatocellular carcinomas (HCC) and colorectal carcinomas (CRC) are among the most common cancers worldwide with high mortality rates. While HCC affecting mostly underdeveloped countries, CRC is a disease that mainly occur in more developed countries. As is known, CRC is the third most common cancer and the surgical removal of tumors upon early diagnosis is still the best tool in our hands, developing better strategies to cure patients with an advanced CRC has utmost importance. Furthermore, survival rates of HCC patients are very low as a result of poor prognosis and the most efficient therapy for HCC is organ transplantation. Sorafenib, a multikinase inhibitor, is the most effective chemotherapeutic agent in use for HCC leading drug resistance in HCC cells. Thus, alternative strategies should be developed to extend disease-free survival and to treat this cancer. One of the major risk factor for cancer is chronic inflammation and HCC is a good example of inflammation related cancer due to the fact that 90% of HCC cases are stem from inflammation and hepatic injury. As a result of unresolved chronic inflammation, sequential development of HCC occurs from fibrosis and cirrhosis. Moreover, tumor-associated inflammation can encourage tumor development in the gut, indicating central role for inflammation in the development of both sporadic CRC and CAC. In this thesis, our aim was to understand the roles played by IKKε in hepatocellular and colorectal carcinogenesis. Our preliminary bioinformatics analysis with publicly available data has shown high amplification of IKKε in HCC patients in silico. Also, we showed that IKKε plays important roles in HCC cell proliferation and viability. Specifically, upon IKKε depletion, we observed reductions in HCC cell proliferation both in vivo and in vitro. Furthermore, increase epithelial markers upon IKKε loss was suggesting reversed EMT process in HEP3B cells. Consequently, IKKε could be a valuable prognostic biomarker and targeting IKKε may be a potential therapeutic strategy against HCC tumors. On the other hand, in CRC, we demonstrated that IKKε depletion conferred a growth advantage to IKKε depleted DLD1 and SW480 cells and resulted in an increased proliferation in vivo and in vitro, and induced formation of partial-EMT like features in DLD1 cells. Therefore, IKKε complementation may be a valuable potential therapeutic strategy against CRC tumors.