Downregulation of microRNA‑146a inhibits ovarian granulosa cell apoptosis by simultaneously targeting interleukin‑1 receptor‑associated kinase and tumor necrosis factor receptor‑associated factor 6

Chen,Xi; Xie,Mingxuan; Liu,Da; Shi,Ke

doi:10.3892/mmr.2015.4036

Downregulation of microRNA‑146a inhibits ovarian granulosa cell apoptosis by simultaneously targeting interleukin‑1 receptor‑associated kinase and tumor necrosis factor receptor‑associated factor 6

Authors:
- Xi Chen
- Mingxuan Xie
- Da Liu
- Ke Shi
View Affiliations

Affiliations: Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: July 3, 2015 https://doi.org/10.3892/mmr.2015.4036
Pages: 5155-5162

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Premature ovarian failure (POF), an ovarian disorder of multifactorial origin, is defined as the occurrence of amenorrhea, hypergonadotropism and hypoestrogenism in females <40 years old. Apoptosis of ovarian granulosa cells is important in POF and understanding the regulatory mechanism underlying ovarian granulosa cell apoptosis may be beneficial for the management of POF. Increasing evidence suggests that microRNAs (miRs) have a regulatory function in oocyte maturation and ovarian follicular development. In the present study, the expression of miR‑146a in plasma and ovarian granulosa cells obtained from patients with POF, its effect on the apoptosis of ovarian granulosa cells and the possible underlying mechanisms were examined. The present study demonstrated that compared with the control groups, the expression of miR‑146a in the plasma and in ovarian granulosa cells of patients with POF was significantly upregulated. Furthermore, it was found that miR‑146a simultaneously targeted interleukin‑1 receptor‑associated kinase (IRAK1) and tumor necrosis factor receptor‑associated factor 6 (TRAF6), which regulated the activity of nuclear factor‑κB and IκBα. In addition, the results demonstrated that inhibition of the caspase cascade by caspase inhibitors attenuated the effects of miR‑146a on ovarian granulosa cell apoptosis. Taken together, these results suggest that miR‑146a has an important promoting effect on the apoptosis of granulosa cells by targeting IRAK1 and TRAF6 via the caspase cascade pathway. These results may be useful for the management of POF.

View Figures

View References

1	Beck-Peccoz P and Persani L: Premature ovarian failure. Orphanet J Rare Dis. 1:92006. View Article : Google Scholar : PubMed/NCBI
2	Mittal M, Savvas M, Arya R, McEniery C, Narvekar N, Cardozo L, Panay N and Hamoda H: A randomised controlled trial comparing the effects of micronized progesterone to medroxyprogesterone acetate on cardiovascular health, lipid metabolism and the coagulation cascade in women with premature ovarian insufficiency: Study protocol and review of the literature. Menopause Int. 19:127–132. 2013.PubMed/NCBI
3	Morgan S, Anderson RA, Gourley C, Wallace WH and Spears N: How do chemotherapeutic agents damage the ovary? Hum Reprod Update. 18:525–535. 2012. View Article : Google Scholar : PubMed/NCBI
4	Knet M, Tabarowski Z, Slomczynska M and Duda M: The effects of the environmental antiandrogen vinclozolin on the induction of granulosa cell apoptosis during follicular atresia in pigs. Theriogenology. 81:1239–1247. 2014. View Article : Google Scholar : PubMed/NCBI
5	Ford JH: Reduced quality and accelerated follicle loss with female reproductive aging - does decline in theca dehydroepiandrosterone (DHEA) underlie the problem? J Biomed Sci. 20:932013. View Article : Google Scholar : PubMed/NCBI
6	Sirotkin AV, Lauková M, Ovcharenko D, Brenaut P and Mlyncek M: Identification of microRNAs controlling human ovarian cell proliferation and apoptosis. J Cell Physiol. 223:49–56. 2010.
7	Toloubeydokhti T, Bukulmez O and Chegini N: Potential regulatory functions of microRNAs in the ovary. Semin Reprod Med. 26:469–478. 2008. View Article : Google Scholar : PubMed/NCBI
8	Yang X, Zhou Y, Peng S, Wu L, Lin HY, Wang S and Wang H: Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir-23a in granulosa cell apoptosis. Reproduction. 144:235–244. 2012. View Article : Google Scholar : PubMed/NCBI
9	Fiedler SD, Carletti MZ, Hong X and Christenson LK: Hormonal regulation of MicroRNA expression in periovulatory mouse mural granulosa cells. Biol Reprod. 79:1030–1037. 2008. View Article : Google Scholar : PubMed/NCBI
10	Zilahi E, Tarr T, Papp G, Griger Z, Sipka S and Zeher M: Increased microRNA-146a/b, TRAF6 gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjögren's syndrome. Immunol Lett. 141:165–168. 2012. View Article : Google Scholar
11	Hung PS, Liu CJ, Chou CS, Kao SY, Yang CC, Chang KW, Chiu TH and Lin SC: miR-146a enhances the oncogenicity of oral carcinoma by concomitant targeting of the IRAK1, TRAF6 and NUMB genes. PLoS One. 8:e799262013. View Article : Google Scholar : PubMed/NCBI
12	Woods DC, White YA, Dau C and Johnson AL: TLR4 activates NF-κB in human ovarian granulosa tumor cells. Biochem Biophys Res Commun. 409:675–680. 2011. View Article : Google Scholar : PubMed/NCBI
13	Park EJ, Shin JW, Seo YS, Kim DW, Hong SY, Park WI and Kang BM: Gonadotropin-releasing hormone-agonist induces apoptosis of human granulosa-luteal cells via caspase-8, -9 and -3 and poly-(ADP-ribose)-polymerase cleavage. Biosci Trends. 5:120–128. 2011. View Article : Google Scholar
14	Ebrahimi M and Akbari Asbagh F: Pathogenesis and causes of premature ovarian failure: An update. Int J Fertil Steril. 5:54–65. 2011.PubMed/NCBI
15	Kim YJ, Ku SY, Kim YY, Liu HC, Chi SW, Kim SH, Choi YM, Kim JG and Moon SY: MicroRNAs transfected into granulosa cells may regulate oocyte meiotic competence during in vitro maturation of mouse follicles. Hum Reprod. 28:3050–3061. 2013. View Article : Google Scholar : PubMed/NCBI
16	Jin L, Zhao J, Jing W, Yan S, Wang X, Xiao C and Ma B: Role of miR-146a in human chondrocyte apoptosis in response to mechanical pressure injury in vitro. Int J Mol Med. 34:451–463. 2014.PubMed/NCBI
17	Dong S, Xiong W, Yuan J, Li J, Liu J and Xu X: MiRNA-146a regulates the maturation and differentiation of vascular smooth muscle cells by targeting NF-κB expression. Mol Med Rep. 8:407–412. 2013.PubMed/NCBI
18	Chen G, Umelo IA, Lv S, Teugels E, Fostier K, Kronenberger P, Dewaele A, Sadones J, Geers C and De Grève J: miR-146a inhibits cell growth, cell migration and induces apoptosis in non-small cell lung cancer cells. PLoS One. 8:e603172013. View Article : Google Scholar : PubMed/NCBI
19	Sha M, Ye J, Zhang LX, Luan ZY and Chen YB: Celastrol induces apoptosis of gastric cancer cells by miR-146a inhibition of NF-κB activity. Cancer Cell Int. 13:502013. View Article : Google Scholar
20	Elsarraj HS, Stecklein SR, Valdez K and Behbod F: Emerging functions of microRNA-146a/b in development and breast cancer: MicroRNA-146a/b in development and breast cancer. J Mammary Gland Biol Neoplasia. 17:79–87. 2012. View Article : Google Scholar : PubMed/NCBI
21	Woods DC, Schorey JS and Johnson AL: Toll-like receptor signaling in hen ovarian granulosa cells is dependent on stage of follicle maturation. Reproduction. 137:987–996. 2009. View Article : Google Scholar : PubMed/NCBI
22	Li S, Yue Y, Xu W and Xiong S: MicroRNA-146a represses mycobacteria-induced inflammatory response and facilitates bacterial replication via targeting IRAK-1 and TRAF-6. PLoS One. 8:e814382013. View Article : Google Scholar : PubMed/NCBI
23	Liu M, John CM and Jarvis GA: Induction of endotoxin tolerance by pathogenic Neisseria is correlated with the inflammatory potential of lipooligosaccharides and regulated by microRNA-146a. J Immunol. 192:1768–1777. 2014. View Article : Google Scholar : PubMed/NCBI
24	Quinn EM, Wang JH, O'Callaghan G and Redmond HP: MicroRNA-146a is upregulated by and negatively regulates TLR2 signaling. PLoS One. 8:e622322013. View Article : Google Scholar : PubMed/NCBI
25	Dong W, Liu Y, Peng J, Chen L, Zou T, Xiao H, Liu Z, Li W, Bu Y and Qi Y: The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4. J Biol Chem. 281:26029–26040. 2006. View Article : Google Scholar : PubMed/NCBI
26	Kim SJ and Li J: Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia. Cell Death Dis. 4:e7162013. View Article : Google Scholar : PubMed/NCBI
27	Grimstad Ø, Husebye H and Espevik T: TLR3 mediates release of IL-1β and cell death in keratinocytes in a caspase-4 dependent manner. J Dermatol Sci. 72:45–53. 2013. View Article : Google Scholar : PubMed/NCBI
28	Antonopoulos C, El Sanadi C, Kaiser WJ, Mocarski ES and Dubyak GR: Proapoptotic chemotherapeutic drugs induce noncanonical processing and release of IL-1β via caspase-8 in dendritic cells. J Immunol. 191:4789–4803. 2013. View Article : Google Scholar : PubMed/NCBI