الفهرس 
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Abstract
Colorectal cancer is prevalent in Egypt, with nearly 14.0 % of all colonoscopies revealing the presence of the disease. In 2020, CRC represented 10% of global cancer incidence and 9.4% of cancer fatalities. Colon tumors often develop over long periods of time through accumulation of histological, morphological and genetic changes. The routinely used tumor markers for diagnosis and prognosis of CRC such as CEA - CA19.9 aren’t significant for malignant tumors.
MiRNAs are a large family of single-stranded, short, non-coding endogenous RNAs that are guided to specific target sites located in the 3’-untranslated region (3’-UTR) of mRNAs, then direct their post- transcriptional repression effects with the mode of mRNA degradation or translational repression.
MiR-133a has been proposed as a tumor suppressor and a biomarker for prognosis of numerous cancers. It can be detected in body fluids, like blood and gastric juice, suggesting its value as a non-invasive biomarker.
MiR-574-3p was found to exert tumor suppressive function in various cancers and diseases. Over expression of miR-574-3p inhibited proliferation and promoted apoptosis of cancer cells in vitro.
MiR-27a acts as oncogenic miRNA that is up-regulated and overexpressed in many tumors. MiR-27a was found to play vital clinical significance in drug sensitivity, treatment of cancer and patient’s prognosis.
MiRNA-based biomarkers have been shown promise as CRC-specific prognostic tests due to their high sensitivity and specificity. Thus the aim of the study was to evaluate the expression levels of miR-133a, miR-574-3p and miR-27a as non-invasive biomarkers for CRC and correlate their expression to clinicopathological factors.
Patients enrolled are attending GI oncology unit -Ain Shams University hospital and Endoscopy unit -Ain Shams University hospital from 2018-2020. The study included 70 CRC patients, 30 patients with benign polyps and 20 normal volunteers. The study was conducted at High Throughput Molecular and Genetic laboratory, Central Laboratories Network and the Centers of Excellence, National Research Centre
Subjects in this study were categorized into three groups
• Control group contained 13 females and 7 males with age range of 18-86 years and mean age of 45 ± 17 years.
• Benign group contained 19 females and 11 males whose ages range from 18 to 86 years with mean age of 45±18 years.
• Malignant group contained 38 females and 32 males whose ages range from 28 years to 90 years with mean age of 48 ±13 years.
Patients in this study were questioned about their lifestyle, medical history and reproductive statue for female patients. A histopathological assessment of tumor after tumor biopsy was done. This included the histopathological grade and evaluation of lymph node status. MiRNAs were assessed by Quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR). Then results were calculated and statistically analyzed.
By plotting the ROC curve, the diagnostic efficacy was determined using the calculated cutoff point as 36.5, 46.5 and 18.5 fold change for miRNAs 133a, 574-3p and 27a respectively. The sensitivity for miR-133a was 98.6%, specificity was 88%, The PPV was 92%, NPV was100% and ACC was 95%.
For miR-574-3p sensitivity was 98.6%, specificity was 86%, The PPV was 90.7%, NPV was 97.7% and ACC was 93%.
While for miR-27a sensitivity was 87.1%, specificity was 76%, The PPV was 83.5%, NPV was 80.8% and ACC was 82.5% respectively.
The miRNAs 133a and 574-3p showed high significance when related to CRC stages, different grades, tumor size and lymph node metastasis with the lowest fold expressed in malignant group. The fold change of mir-133a and mir-574-3p showed significant decrease upon progression of stage, grades, increase in tumor size and upon lymph node metastasis. While miR-27a expressed highest fold change in malignant group and was significally increased upon progression of stage, grades, increase in tumor size and upon lymph node metastasis.
The combination of the three miRNAs (miR-133a, miR-574-3p, miR-27a) in a single test would significantly increase sensitivity (to 100%), which would be essential for early diagnosis of CRC.
In conclusion, studying novel tumor markers with better sensitivities and specificities will help in early detection of CRC and with less invasive or surgical interference for such widely spread malignancy which could result in better prognosis and higher survival rate for CRC patients. Here we found that evaluating expression levels of miR-133a, miR-574-3p and miR-27a would provide novel markers for CRC diagnosis and combining these three miRNAs would provide more precise marker for diagnosis and prognosis of CRC and could be used as future therapeutic targets.
Recommendations
Further studies with larger cohorts and more comparability tests are required to confirm the linkage of serum miRs-133a, 27a and 574-3p with CRC and their targeted pathway.
More studies are needed to utilize these miRNA as future therapeutic targets for CRC.