Signaling Pathways Targeting Colorectal Cancer in Egypt

Study Overview
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Brief Summary
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Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide. In Egypt, CRC constitutes 4.2% of all cancers with median age is 50 years old.

Detailed Description
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The TP53-induced glycolysis and apoptosis regulator (TIGAR) is a transcriptional target of p53. TIGAR functions as a fructose-2,6-bisphosphatase, decreasing the flux through the main glycolytic pathway. Consequently, glucose metabolism diverted into the pentose phosphate pathway (PPP). This results in TIGAR-mediated increase in cellular NADPH production, which contributes to the scavenging of ROS by reduced glutathione and thus a lower sensitivity of cells to oxidative stress-associated apoptosis. PPP also produce ribose phosphate for DNA synthesis and repair that play a role in tumor development and cell survival in tumor microenvironment. A high expression level of TIGAR was observed in cancers such as breast cancer, hepatocellular carcinoma, intestinal cancer, and glioblastoma. These studies suggested that TIGAR may act as an oncogene that support cancer progression. The tripartite motif containing 59 (TRIM) proteins have been implicated in many biological processes including cell differentiation, apoptosis, transcriptional regulation, and signaling pathways. It is related to several cancers. The oncogenic effect of TRIM59 on tumor proliferation and migration has been studied in various cancers, including gastric cancer, osteosarcoma, lung and CRC. The biological activity of TRIM59 has been observed to be closely associated with the regulation of P53. TRIM59 interacts with P53, leading to P53 ubiquitination and degradation, and consequently promotes tumor growth and migration. TRIM59 functions as an oncogene in CRC progression. It also activates the PI3K/AKT pathway. Increased activity of this pathway is often associated with tumor progression and resistance to cancer therapies. AKT can control TIGAR protein translation by activation of mTOR. Targeting TRIM59 inhibition will inhibit PI3K-Akt pathway downregulate TIGAR protein translation. This is in turn downregulates GSH levels, increases ROS production, leading to cell death and blocks the cellular proliferation and survival of cancer cells leading to tumor regression. Therefore, TRIM59 protein can serve as a new potential therapeutic target for CRC.

Official Title
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Identification of New Signaling Pathways Targeting Colorectal Cancer in Egyptian Patients

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Genetic: Markers in tissue samples: (TIGAR , TRIM59, P53, AKT, GSH)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Patients confirmed histopathologically to have early stages of colorectal cancer. Risky group patients (including those with ulcerative colitis, chron's disease, familial adenomatous polyposis). Exclusion Criteria: Patients with previous history of CRC treated with chemotherapy or presence of other types of cancer.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Colorectal cancer patients<br>50 Patients confirmed histopathologically to have early stages of colorectal cancer. | Genetic: Markers in tissue samples: (TIGAR , TRIM59, P53, AKT, GSH)<br>* The followings markers will be investigated in tissue samples: TIGAR expression using quantitative real-time polymerase chain reaction (q Rt PCR) and immunohistochemistry. TRIM59 expression using quantitative real-time polymerase chain reaction (q Rt PCR) and immunohistochemistry. P53 expression using immunohistochemistry. P53 nuclear localization is essential for its normal function in growth inhibition or induction of apoptosis. Akt expression using western blot. GSH using chemical methods.<br>|
| Risky group<br>20 risky patients (those with ulcerative colitis, chron's disease, familial adenomatous polyposis). | Genetic: Markers in tissue samples: (TIGAR , TRIM59, P53, AKT, GSH)<br>* The followings markers will be investigated in tissue samples: TIGAR expression using quantitative real-time polymerase chain reaction (q Rt PCR) and immunohistochemistry. TRIM59 expression using quantitative real-time polymerase chain reaction (q Rt PCR) and immunohistochemistry. P53 expression using immunohistochemistry. P53 nuclear localization is essential for its normal function in growth inhibition or induction of apoptosis. Akt expression using western blot. GSH using chemical methods.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure TIGAR in the study groups. | Measure TIGAR expression in colorectal cancer patients and risky group patients. | 1 YEAR | 
| Measure TRIM59 in the study groups. | Measure TRIM59 expression in colorectal cancer patients and risky group patients. | 1Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Targeting new prognostic and therapeutic markers for colorectal cancer. | Finding a relationship between TIGAR and TRIM 59 expression and PI3K/AKT pathway as a major signaling mechanism in tumorigenesis for targeting new prognostic and therapeutic markers for colorectal cancer. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal cancer, TIGAR, TRIM59