Introduction: Colorectal cancer (CRC), encompassing both colon and rectal cancer, is the third most common cancer in the world after lung cancer and breast cancer and the fourth leading cause of cancer-related deaths worldwide with 700,000 deaths per year. CRC is the second- and third-most common cancer in women and men, is most prevalent in developed regions of the world such as Western Europe, New Zealand, United States, Japan and Australia and the lowest rates in Africa and south Asia. The highest incidence rates of CRC in Iran were found in the central, northern and western provinces. CRC is a heterogeneous disease, both genetic and environmental factors play an important part in the etiology of colorectal cancer. Several risk factors for the development of CRC have been identified, inherited genetic factors, lifestyle including unhealthy behaviors such as physical inactivity, smoking, red and processed meat as well as alcohol consumption and some diseases including obesity, Diabetes type 2and inflammatory bowel diseases have been also associated with increased risk to develop CRC. About 10% of CRC cases are hereditary and up to 90% are sporadic. The two main forms of hereditary CRC are the Lynch syndrome, which involves mutations in the DNA mismatch repair system, and the familial adenomatotous polyposis coli (FAP), which is caused by germline mutations in the tumor suppressor adenomatouse polyposis coli gene. Most of the changes reported for onset of sporadic colorectal cancer are as follows: The activation of oncogenes, inactivation of tumor suppressor genes such as SMAD-4, chromosomal instability (CIN), microsatellite instability (MSI) and CpG islandmethylator phenotype (CIMP).
SMAD-4 located at 18q21.1 chromosome, encodes protein belonging to the SMAD family. this protein acts as a transcriptional factor, it participates in expression regulation of many genes involved in the cell cycle, apoptosis, proliferation, differentiation and other important cellular processes such as prevention of excessive epithelial cell growth and divisions. SMAD-4 is a key transcriptional factor of TGFβ- signaling. Indeed, smad-4 is an intracellular transducer that mediates the transforming growth factor (TGFβ )-SMAD-dependent signaling pathway and translocation of the TGFβ- complex into the nucleus. Inactivation of this gene is commonly found in pancreatic cancer, acts as a tumor suppressor in colorectal cancer.
Methods: In this study used of 40 pairs samples included 40 tumoral tissues and 40 normal tissues. RNA was extracted from these samples, cDNA synthesized. RT-PCR was performed to investigate of SMAD-4 gene expression, the observations were confirmed by Real Time-PCR.
Results: In this study silencing of SMAD-4 was observed in 50% of the tumors (n=20), Different expression levels was not observed among the tumors with positive expression. The effect of silencing of this tumor suppressor gene and its association with clinicopathology characters such as age, gender, stage, grade and metastasis was examine. No association was found between the silencing/expression of this genes and any clinicopatholy feature.
Conclusion: Based on the above data, SMAd-4 is not either a good diagnostic or prognostic biomarkers in CRR. Although further investigations is required.