الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Colorectal Carcinoma (CRC) is one of the most prevalent malignant tumors of the digestive system. Colorectal cancer is the third most common cancer in the United States and the 7th commonest cancer in Egypt. An interest in Egyptian CRC has been raised as higher incidence of the disease among young Egyptian population was noted. DNL has been reported to play a central role in progression of various human cancers including CRC. Therefore, targeting lipogenic pathway emerges as a novel approach in cancer treatment
Sterol Regulatory Element Binding Proteins (SREBPs) family includes SREBP1, c and SREBP2 are the key regulators of DNL pathway. Their activation increases the expression of FASN and c-MYC.
The aim of this study was to characterize the immunohistochemical (IHC) expression of SREBP1, SREBP2, FASN and c-MYC in colonic adenoma and CRC to delineate the correlation between these markers in the studied groups. In addition, the current study aimed to correlate markers expression with each others and with the clinico-pathological data and overall survival to identify their clinical significance.
This was a retrospective case control study. The study included 183 colorectal cases including 58 corresponding non-neoplastic colonic tissues, 38 adenoma cases and 87 CRC. All specimens were obtained from Egyptian patients.
The present study found significant overexpression of SREBP1, SREBP2, FASN and c-MYC in CRC cases in comparison with adenoma and normal control groups. In addition, they were overexpressed in the adenomatous lesions in comparison to non-neoplastic colonic tissue.
SREBP1, SREBP2 and c-MYC nucleocytoplasmic expressions were significantly associated with poor prognostic parameters manifested with non-conventional subtypes of CRC, tumor grade, nodal metastasis and high grade of tumor budding regarding SREBP1 and with non-conventional subtypes of CRC regarding SREBP2 and c-MYC.
In CRC, Epithelial SREBP1 overexpression was significantly associated with poor prognostic parameters as high grade, nodal metastasis, presence of tumor budding and high grade of tumor budding. Moreover, stromal SREBP1 overexpression regarding H-score was significantly associated with poor prognostic parameters as non-conventional subtypes of CRC, high tumor grade, nodal metastasis, presence of tumor budding and high grade of tumor. Epithelial SREBP 2 overexpression (high values of H score) was significantly associated with annular gross morphology and poor prognostic parameters as nodal metastasis, advanced pathological stage, presence of tumor budding and high grade of tumor budding.
Moreover, stromal SREBP2 overexpression regarding H-score was significantly associated with poor prognostic parameters as nodal metastasis and advanced pathological stage. Epithelial FASN overexpression was significantly associated with poor prognostic parameters as high grade, nodal metastasis, advanced pathological stage, LVI, presence of tumor budding and high grade of tumor budding. Epithelial c-MYC overexpression (high H-score values) was significantly associated with poor prognostic parameters as high grade, nodal
Summary
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metastasis, advanced pathological stage, LVI presence of tumor budding and high grade of tumor budding. Moreover, stromal c-MYC overexpression regarding H-score overexpression of C-MYC in stromal cells was significantly associated with poor prognostic parameters as nodal metastasis and advanced stage.
There was a significant positive correlation between SREBP1 (epithelial and stromal), SREBP2 (epithelial and stromal), FASN epithelial and c-MYC (epithelial and stromal) expressions. This could suggest the synergistic effect of these proteins in activating DNL pathway in CRC pathogenesis.
There was significant association between the overexpression of the four markers and poor survival outcome by univariate analysis. Moreover, SREBP1 was an independent factor affecting the overall survival for the studied CRC cases.
In conclusion, the four markers were overexpressed in adenoma and CRC and may have a poor prognostic role in progression of CRC cases. The four markers may have a poor prognostic role in progression of CRC. Therefore, targeting lipogenic pathway may have a possible preventive and therapeutic target for patients at high risk of CRC.