Browsing by Subject "CRC"

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Open Access
Identification of the roles played by IKKε in hepatocellular and colorectal carcinogenesis
(2018-07) Kahya, Uğur
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.
Open Access
Identification of theranostic gene markers in cancers and prognostic validation in colorect al cancer
(2015-01) İşbilen, Murat
Colorectal cancer (CRC) is the fourth most prevalent cancer type worldwide. Although the 5-year survival rate of CRC is higher than many cancer types, prediction of prognosis and identification of accurate biomarkers still maintain their importance for chemotherapy benefits, thus survival of the patients. Current techniques to identify biomarkers for clinical use are based on building models with multi-gene signatures. However, the accuracy rates of such signatures are not high enough due to heterogeneity of the tumors and low sensitivity of gene expression measurement techniques, although cell lines can be predicted very well with such signatures. There has also been sufficient evidence that multi-gene signatures may not be better predictors than random signatures with the same size. Therefore, in this study, we aimed to develop two R-based statistical analysis tools, SSAT and USAT, to identify single-gene expression markers for prognosis with chemotherapy benefit prediction power. We identified two genes, ULBP2 and SEMA5A, with SSAT and 6 genes, PTRF, TGFB1I1, DUSP10, KLF9, CLCN7 and CLDN3, with USAT for colon cancer and CRC, respectively. We were able to validate independent prognostic power of ULBP2 and SEMA5A in an independent cohort. However, we could only validate CLCN7 among 6 genes that we identified by USAT. Those results showed that SSAT may be a better tool to identify prognostic gene markers and USAT needs to be improved to identify better candidate genes. We could also reveal the chemotherapy benefit prediction power of ULBP2 and SEMA5A in CCLE and CGP drug databases, although these in silico results should be validated by in vitro experiments. We believe that the approach that we used in this study may pioneer the studies to develop commercial theranostic tools for clinical use in various types of cancer.
Open Access
Receptor for advanced glycation end products acts as a fuel to colorectal cancer development
(Frontiers Media S.A., 2020-09-29) Azizian-Farsani, F.; Abedpoor, N.; Sheikhha, M. H.; Güre, Ali Osmay; Nasr-Esfahani, M. H.; Ghaedi, K.
Receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein taken in diverse chronic inflammatory conditions. RAGE behaves as a pattern recognition receptor, which binds and is engaged in the cellular response to a variety of damage-associated molecular pattern molecules, as well as HMGB1, S100 proteins, and AGEs (advanced glycation end-products). The RAGE activation turns out to a formation of numerous intracellular signaling mechanisms, resulting in the progression and prolongation of colorectal carcinoma (CRC). The RAGE expression correlates well with the survival of colon cancer cells. RAGE is involved in the tumorigenesis, which increases and develops well in the stressed tumor microenvironment. In this review, we summarized downstream signaling cascade activated by the multiligand activation of RAGE, as well as RAGE ligands and their sources, clinical studies, and tumor markers related to RAGE particularly in the inflammatory tumor microenvironment in CRC. Furthermore, the role of RAGE signaling pathway in CRC patients with diabetic mellitus is investigated. RAGE has been reported to drive assorted signaling pathways, including activator protein 1, nuclear factor-κB, signal transducer and activator of transcription 3, SMAD family member 4 (Smad4), mitogen-activated protein kinases, mammalian target of rapamycin, phosphoinositide 3-kinases, reticular activating system, Wnt/β-catenin pathway, and Glycogen synthase kinase 3β, and even microRNAs.