rs12976445 variant in the pri-miR-125a correlates with a lower level of hsa-miR-125a and ERBB2 overexpression in breast cancer patients

Watanabe

Clinical and Experimental Immunology

et al. 2014

SummaryIt is important to search the biomarker to predict the development and prognosis of autoimmune thyroid diseases (AITDs) such as Hashimoto's disease (HD) and Graves' disease (GD). MicroRNA (miR) bind directly to the 3′ untranslated region of specific target mRNAs to suppress the expression of proteins, promote the degradation of target mRNAs and regulate immune response. miR-125a is known to be a negative regulator of regulated upon activation normal T cell expressed and secreted (RANTES), interleukin (IL)-6 and transforming growth factor (TGF)-β; however, its association with AITDs remains unknown. To clarify the association between AITDs and miR-125a, we genotyped the rs12976445 C/T, rs10404453 A/G and rs12975333 G/T polymorphisms in the MIR125A gene, which encodes miR125a, using direct sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods in 155 patients with GD, 151 patients with HD and 118 healthy volunteers. We also examined the expression of miR-125a in peripheral blood mononuclear cells (PBMCs) from 55 patients with GD, 79 patients with HD and 38 healthy volunteers using quantitative real-time PCR methods. We determined that the CC genotype and C allele of the rs12976445 C/T polymorphism were significantly more frequent in patients with HD compared with control subjects (P < 0·05) and in intractable GD compared with GD in remission (P < 0·05). The expression of miR-125a was correlated negatively with age (P = 0·0010) and down-regulated in patients with GD compared with control subjects (P = 0.0249). In conclusion, miR-125a expression in PBMCs and the rs12976445 C/T polymorphism were associated with AITD development and prognosis.

Section: Discussioncontrasting

confidence: 72%

Associations of single nucleotide polymorphisms in precursor-microRNA (miR)-125a and the expression of mature miR-125a with the development and prognosis of autoimmune thyroid diseases

Watanabe

Clinical and Experimental Immunology

et al. 2014

J of Cellular Biochemistry

“…6 Currently, multiple miRNAs are known to participate in regulating the proliferation, differentiation, metabolism, and apoptosis of tumor cells. [14][15][16] The study has revealed that miR-125b controls proliferation and apoptosis by downregulating P53 and the genes involved in the P53 pathway including BAK1 and PUMA, which provides for the first time a potential mechanism for the development of secondary hematologic malignancies in patients treated with IMiD compounds. 9,10 Studies have shown that miR-125b acts as a tumor-suppressor gene in chronic lymphocytic leukemia (CLL) and MM, 11,12 whereas miR-125a is a newly discovered member of miR-125, whose precursor can produce two kinds of mature miR-125a-3p and miR-125a-5p, 13 which have also been reported to be tumorsuppressor genes in various malignant tumors, such as prostate tumor, lung tumor, and ovarian tumor.…”

mentioning

confidence: 99%

RETRACTED: miR‐125a suppresses malignancy of multiple myeloma by reducing the deubiquitinase USP5

Wu¹,

Zhang²,

Chen³

et al. 2019

miR‐125a is a microRNA that is frequently diminished in various human malignancies. However, the mechanism by which impaired miR‐125a promotes cancer growth remains undefined. In this study, we investigated the role of miR‐125a in the proliferation and apoptosis of multiple myeloma (MM). To do this, we used MM tissue samples (from 40 anonymous patients), normal matched control samples, and five MM‐derived cell lines. We also established a mouse model of MM xenograft to explore the effect of overexpression of miR‐125a on the MM growth in vivo. Quantitative real‐time polymerase chain reaction revealed that the miR‐125a expression was broadly reduced in MM tissues and cell lines. The impairment of miR‐125a in MM tissues was functionally relevant because the overexpression of miR‐125a remarkably decreased the cell viability and colony‐forming activity, at least in part, by promoting apoptosis in two miR‐125a‐deficient MM cell lines: NCI‐H929 and U266. Interestingly, we also discovered that the human gene encoding the ubiquitin‐specific peptidase 5 (USP5), which is known to promote cellular deubiquitination and ubiquitin/proteasome‐dependent proteolysis, was a direct transcriptional target for miR‐125a to repress. More importantly, the heterologous expression of USP5 significantly reversed the growth‐inhibitory effects of miR‐125a on MM cells in vitro. In the mouse xenograft model, overexpressed miR‐125a prominently inhibited the growth of MM tumors and concomitantly reduced the expression of USP5 in tumor tissues. These results suggest that miR‐125a inhibits the expression of USP5, thereby mitigating the proliferation and survival of malignant MM cells. We propose that USP5 acts as an oncoprotein in miR‐125a‐missing cancers.

“…Two polymorphisms in the miR‐125a gene are associated with breast cancer (Li et al , ; Lehmann et al , ). The variants lead to decreased levels of mature miR‐125a and upregulation of its target ERBB2 (Duan et al , ; Lehmann et al , ).…”

Section: Non‐coding Rnasmentioning

confidence: 99%

The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non‐coding RNA and synonymous mutations

et al. 2016

Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor‐specific mutations not only in protein‐coding sequences but also in non‐coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this “dark matter” of the genome. Malignancy‐driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5′‐UTR and 3′‐UTR. Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non‐coding RNA, such as microRNA, lncRNA, and lincRNA. A synonymous mutation changes the coding region in the DNA and RNA but not the protein sequence. Importantly, oncogenes such as TERT or miR‐21 as well as tumor suppressor genes such as TP53/p53,APC,BRCA1, or RB1 can be affected by these alterations. In summary, coding‐independent mutations can affect gene regulation from transcription, splicing, mRNA stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non‐coding or allegedly silent mutations in tumorigenesis.