MIR-147B REGULATED PROLIFERATION AND APOPTOSIS OF GASTRIC CANCER CELLS BY TARGETING CPEB2 VIA THE PTEN PATHWAY
Tao K.1,2, Dong J-H.2, Wang D.1, Li F.2#, Zhang Z-T.#1*
*Corresponding Author: Zhong-Tao Zhang, MD, Email: sxzhangzhongtao@sina.com, ORCID ID: 0000-0002-1184-2591 #: Zhong-Tao Zhang and Feng Li contributed equally to the article : Co-corresponding author: Feng Li, Email: sxlifengwobuxin@sina.com, ORCID: 0000-0002-7322-422X
page: 10

DISCUSSION

MicroRNA (miRNA), a well-known noncoding RNA subtype has recently appeared as gene expression regulators by combining its target messenger 3 ʹ- Non translation area (3ʹ- UTR) which transcriptionally regulates the gene expression of the messenger RNA (mRNA) 11. The interaction of miRNA and mRNA generate RNA and induce a silencing complex, which is an event promoting mRNA degradation and translation inhibition 11. Therefore, miRNA is believed to promote tumorigenesis 12,13. Various studies have suggested that numerous miRNAs disorders are involved in regulating tumor malignant growth and invasive metastasis; therefore, they act as oncogenes or tumor suppressors 14,15. In addition, itis used significantly as a biomarker, in prognosis, as well as a therapeutic target 16,17. miR-147b has been also associated with a variety of cancers 1820. In this study, differentially expressed miRNAs were screened from 3 pairs of samples by miRNA chip. The cut-off point of multiple changes was 1.50 or 0.67. An miRNA microarray detected that the concentration of 14 miRNAs in GC tissues was up-regulated, among which hsa-miR-147b was more significant. Further extraction of miR-147b in gastric cancer tissues was established as extensively elevated when compared to neighboring tissues, thus confirming that miR-147b was highly expressed in gastric cancer tissues. miR-147b was also highly expressed in GC cell lines. Our further functional assay showed that the addition of miR-147b inhibitor considerably repressed the propagation and incursion of gastric cancer cells. Similarly, miR-147b is up-regulated in hepatitis-C virus related diffuse large B-cell lymphoma, and patients with elevated miR-147b usually have a low prognosis17. In addition, the expression of miR-147b increased abnormally in hepatocellular carcinoma tissues. This was related to tumor severity, and also thus promoted the growth of hepatocellular carcinoma in vitro 19. These findings support the carcinogenic effect of miR-147b. These results are consistent with this study, but it was also found that the addition of exogenous miR-147b inhibitor does not significantly inhibit viability and incursion of gastric cancer cells in in vitro, indicating that there are other related microRNAs at the same time. On the contrary, some studies have shown that miR- 147b is found to be reduced in tumor samples and functions as a tumor suppressor. The level of miR-147b expression was found low in rectal cancer tissues and reduce the propagation and incursion of colorectal cancer cells 19,20. miR-147b can be used as a protecting predictive indicator in patients with ovarian cancer 16, where its function may vary from tumor to tumor 21. Therefore, the exact role of miR-147b in tumorigenesis needs to be further studied in different tumor types. The gene silencing, and the abnormal expression of downstream genes in tumor tissues may be caused by dysregulated miRNA. It promotes or inhibits eukaryotic mRNA translation by engaging the dynamic change of poly (A) tail length in cytoplasm 22. In the cytoplasm, the lengthening or shortening of poly (A) is arbitrated by the interaction of the cytoplasmic polyadenylation element (CPE, a cis factor) and RNA binding protein (CPEB, a trans factor). This phenomenon is called cytoplasmic polyadenylation by CPEB protein 23. CPEB2, a member of the CPEB protein family is found concentrated in cytoplasm during transfection and connects to poly (U) RNA oligomers 24. It functions as a translation regulator. In the human genome database, it was found that theCPEB2 nucleotide sequence was a potential target gene of miR-147b in gastric cancer, which was confirmed by luciferase experiment. Western blotting showed that miR-147b negatively regulated CPEB2 and then affected the expression of the PTEN protein. The results of the study suggest that the expression of CPEB2 was not considerably associated with gender, age, tumor location, tumor size and histological type, but with tumor cell differentiation, TNM stage and lymph node metastasis. The lower the expression of CPEB2, the worse the tumor differentiation, accompanied by the increase of TNM stage and the aggravation of lymph node metastasis load. Patients with high expression of miR-147b and low expression of CPEB2 had poor 5-year overall survival.



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