PCa is currently the most commonly diagnosed cancer and the second leading cause of cancer death in men in the United States [10]. Despite recent progress in the identification of genetic and molecular alterations in PCa, the global management and life quality of PCa patients are still far from ideal. Thus, understanding the molecular mechanism involved in PCa is still extremely important to develop better effective diagnostic and therapeutic strategies. In the present study, we identified 565 target genes of miR-101-3p using bioinformatics analysis. Among these genes, MAPK1, PIKFYVE, EGFR, SMARCA4, TOP2B, GSK3B, FOS, RAC1, BCL2 and TAF1 were defined as hub genes that might provide new ideas for further studies in PCa.
To date, there have been fewer studies concerning the characteristics of miR-101-3p in PCa. Varambally was the first to report that the expression of miR-101-3p was lower in clinically localized PCas and metastatic PCas, and one of miR-101-3p target gene, EZH2, tended to be uniformly elevated in samples with the miR-101-3p genomic loci copy number loss [11]. Later, studies further confirm that miR-101-3p targets EZH2 and suppresses proliferation and migration of PCa cells [12, 13]. After thoroughly reviewing published literature on PCa, we found that ten target genes including SOD1 [14], SUB1 [15], TIGAR [16], NR2F2 [17], RLIP76 [9], COX-2 [18], Glyoxalase 1 [19], ZEB1 [20], Slug [20] as well as EZH2 [11, 13, 21, 22] were truly inhibited by miR-101-3p in PCa tissues or cells. Furthermore, we found that the target genes of miR-101-3p were enriched in many biological processes, such as positive regulation of transcription, intracellular signal transduction, protein autophosphorylation, activation of MAPKK activity. In KEGG pathway analysis, miR-101-3p target genes were mainly located in MAPK signaling pathway, non-small cell lung cancer, colorectal cancer, neurotrophin signaling pathway, pathways in cancer, proteoglycans in cancer, inositol phosphate metabolism and adherens junction.
In the present study, we further identified that candidate target genes for miR-101-3p were involved in the regulation of crucial biological processes in PCa, including MAPK1, PIKFYVE, EGFR, SMARCA4, TOP2B, GSK3B, FOS, RAC1, BCL2 and TAF1. MAPK1 is involved in a number of biochemical signals and cellular processes such as proliferation, differentiation, transcription regulation and development of various cancers [23–25]. Chen demonstrate that miR-378 inhibits PCa cell growth through directly suppresses of MAPK1 in vitro and in vivo [26]. PIKFYVE, a lipid kinase that converts PI(3)P into PI(3,5)P2 in the endocytic pathway [27], has been reported to promote several cancer cells migration and invasion [28, 29]. To our knowledge, no studies have been done to evaluate possible involvement of the PIKFYVE gene in clinical PCa. For EGFR, which is aberrantly expressed in both androgen independent and metastatic PCa, are closely associated with aggressive phenotype, poor clinical prognosis, high Gleason scores, reduced survival rate, then contributing to castrate resistant PCa and progression to metastasis [30, 31]. Shao find that SMARCA4 (also known as BRG1) expression is significantly higher in malignant tissues compared to their benign compartments, especially in high-grade PCa, suggesting increased SMARCA4 expression might promote cell growth and invasion in PCa [32]. TOP2B has been found mediated androgen-induced the double-strand breaks and prostate cancer gene rearrangements [33]. It has been suggested that higher levels of cytoplasmic GSK3B expression are associated with aggressive PCa [34, 35]. Recently, Barrett and colleagues shown that the proto-oncogenes FOS is required for migration and invasion in PCa cells [36]. RAC1, a member of the Rho family GTPases, has been found hyperactivated in the metastatic PCa cells [37] and inhibition of RAC1 activity blocks the migration and invasion of PCa cells [38]. It has been reported an association of high BCL2 expression with higher Gleason scores and lower biochemical recurrence-free survival in patients with advanced PCa undergoing androgen deprivation therapy [39]. A previous study proved that TAF1, a coactivator of androgen receptor, increased expression is associated with progression of human PCa to the lethal castration-resistant state [40]. These results indicate that most of miR-101-3p hub genes were involved in the development of PCa.