Bmi1 plays an important role in colorectal cancer tumorgenesis through the regulation of mir-200c
Mitra Karimi mazraeh shah,
1,* Massoud saidijam,
2 Seyed mohammad tavangar,
3 Rezvan najafi,
4 Razieh amini,
5 Fatemeh karimi dermani,
6
1. Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
2. Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
3. Department of Pathology, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
4. Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
5. Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
6. Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
Abstract
Introduction
Colorectal cancer (crc) is one of the most leading cancer deaths throughout the world. surgery, chemotherapy and radiotherapy are the current treatment for crc. despite advances in diagnosis and treatment, the mortality rate is high. therefore, finding appropriate biomarkers for timely detection and treatment is necessary. in cancer, recurrence after treatment has often been a critical clinical limitation indicative of another emerging stem cell category that evade the existing therapy, classified as cancer initiating cells (cics) or cancer stem cells (cscs). colorectal cancer stem cells are theorized but poorly characterized. cell population believed to be crucial for tumor growth, spread, and tenacity. crc stem cell share many similar characteristics of normal intestinal stem cells and are hypothesized originate from them.
bmi1 surfaces as a bio-signature of cics/cscs. bmi1 is a member of polycomb repressive complex that has multiple role in gene silencing by regulating chromatin structure, and is indispensable for self-renewal of both normal and cancer stem cell, moreover dna damage repair, beyond its capacity as a transcriptional repressor of the ink/arf pathway. as a new paradigm for therapy resistance, the role of bmi1 in this perspective is also highlighted. the wide spectrum of malignancies that implicate bmi1 as a signature for stemness and oncogenesis also make it suitable candidate for a prognostic marker and therapeutic marker.
mirnas are small endogenous noncoding rnas that regulated gene expression. up regulated mirna are considered as oncogene and down regulated mirna are tumor suppressors. mir-200c has been shown that has a critical role in cancer initiation and progression. in this study, we investigated the mir-200c expression in crc tissues and its effects in crc cell lines that mediated by bmi1.
Methods
Qrt-pcr and immunohistochemistry were employed to detect mir-200c and bmi1 expression in tumor tissues from 38 patients with crc and 38 non-cancerous tissues. hct-116 and sw-48 cells were transfected by lna-anti-mir-200c. western blot and real-time pcr were applied to determine the bmi1 protein and mirna levels. the apoptosis was analyzed via annexin/ pi staining and cell invasion was evaluated by transwell assay.
Results
Mir-200c was markedly down regulated in crc tissues whereas protein expression of bmi1 in crc tissues was up regulated compared with non-cancerous tissues. in the colon cancer cell lines, transfection of lna-anti-mir-200c increased bmi1 gene and protein expression as well as the cell invasion. down regulation of mir-200c by lna decreased the apoptotic cells.
Conclusion
The present study focused on mir-200c expression in crc and its role in apoptosis and cell invasion. our results showed the down regulation of mir-200c increases the invasion of tumor cells and decrease the rate of apoptosis. moreover, the expression of mir-200c has a reverse relationship with bmi1. finally, our finding indicates that mir-200c acts as tumor suppressor in crc through inhibiting of bmi1 expression.
Keywords
Colorectal cancer; cancer stem cell; bmi1; mir-200c; apoptosis
