Effect of miR‑29a‑3p in exosomes on glioma cells by regulating the PI3K/AKT/HIF‑1α pathway

Liu,Zeqiang; Yang,Zheng; He,Lu

doi:10.3892/mmr.2023.12959

Effect of miR‑29a‑3p in exosomes on glioma cells by regulating the PI3K/AKT/HIF‑1α pathway

Authors:
- Zeqiang Liu
- Zheng Yang
- Lu He
View Affiliations

Affiliations: Department of Laboratory Medicine, Peking University Third Hospital, Beijing 100191, P.R. China, Department of Neurosurgery, The First People's Hospital of Jiashan, Jiaxing, Zhejiang 314100, P.R. China
Published online on: February 10, 2023 https://doi.org/10.3892/mmr.2023.12959
Article Number: 72
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Exosomes secreted by glioma cells can carry a number of bioactive molecules. As the most abundant noncoding RNA in exosomes, microRNAs (miRNAs) are involved in signaling between tumor cells in a number of ways. In addition, hypoxia is an important feature of the microenvironment of most tumors. The present study investigated the effect of miR‑29a‑3p in glioma exosomes on the proliferation and apoptosis levels of U251 glioma cells under hypoxia. Qualitative PCR results showed that the expression level of miR‑29a‑3p in plasma exosomes of glioma patients was lower than that of normal subjects. By conducting hypoxia experiments in vitro on U251 glioma cells, it was found that the expression level of miR‑29a‑3p decreased following hypoxia, while overexpression of miR‑29a‑3p significantly decreased the proliferation of U251 glioma cells and promoted apoptosis by inhibiting the expression of the antiapoptotic marker Bcl‑2 and increasing the expression of the proapoptotic marker Bax The potential targets of miR‑29a‑3p were predicted by online tools and validated by a dual‑luciferase gene reporter assay. miR‑29a‑3p was found to target and regulate PI3K, which in turn inhibited the activity of the PI3K‑AKT pathway, thereby reducing the expression of hypoxia inducible factor (HIF)‑1α protein. Furthermore, the effects of miR‑29a‑3p on proliferation and apoptosis in glioma cells in those processes could be reversed by the PI3K‑AKT agonist Recilisib. In addition, the inhibitory effect of miR‑29a‑3p on the PI3K/AKT/HIF‑1α regulatory axis could cause a decrease in the expression levels of pyruvate dehydrogenase kinase‑1 and pyruvate dehydrogenase kinase‑2 and eventually lead to a reduction in glycolysis in U251 glioma cells. Similarly, Recilisib slowed the inhibitory effect of miR‑29a‑3p on glycolysis and glycolysis‑related molecules. The results of this study tentatively confirm that miR‑29a‑3p carried by exosomes can be used as a novel diagnostic marker and a potential inhibitory molecule for glioma cells, providing a new theoretical and experimental basis for the precise clinical treatment of glioma.

View Figures

View References

1	Touati S, Djekkoun R, El-Okki ME and Satta D: Epidemiology and survival analyses of 333 adult glioma patients from Eastern Algeria (2008–2016). Afr Health Sci. 20:1250–1258. 2020. View Article : Google Scholar : PubMed/NCBI
2	Domènech M, Hernández A, Plaja A, Martínez-Balibrea E and Balañà C: Hypoxia: The cornerstone of glioblastoma. Int J Mol Sc. 22:126082021. View Article : Google Scholar
3	Mohlin S, Wigerup C, Jögi A and Påhlman S: Hypoxia, pseudohypoxia and cellular differentiation. Exp Cell Res. 356:192–196. 2017. View Article : Google Scholar : PubMed/NCBI
4	Tamai S, Ichinose T, Tsutsui T, Tanaka S, Garaeva F, Sabit H and Nakada M: Tumor microenvironment in glioma invasion. Brain Sci. 12:5052022. View Article : Google Scholar : PubMed/NCBI
5	Ke Q and Costa M: Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 70:1469–1480. 2006. View Article : Google Scholar : PubMed/NCBI
6	Saadatpour L, Fadaee E, Fadaei S, Nassiri Mansour R, Mohammadi M, Mousavi SM, Goodarzi M, Verdi J and Mirzaei H: Glioblastoma: Exosome and microRNA as novel diagnosis biomarkers. Cancer Gene Ther. 23:415–418. 2016. View Article : Google Scholar : PubMed/NCBI
7	Whiteside TL: Tumor-derived exosomes and their role in cancer progression. Adv Clin Chem. 74:103–141. 2016. View Article : Google Scholar : PubMed/NCBI
8	Yu X, Odenthal M and Fries JWU: Exosomes as miRNA carriers: Formation-function-future. Int J Mol Sci. 17:20282016. View Article : Google Scholar : PubMed/NCBI
9	Wang JY, Zhang Q, Wang DD, Yan W, Sha HH, Zhao JH, Yang SJ, Zhang HD, Hou JC, Xu HZ, et al: MiR-29a: A potential therapeutic target and promising biomarker in tumors. Biosci Rep. 38:BSR201712652018. View Article : Google Scholar : PubMed/NCBI
10	Yan B, Guo Q, Fu FJ, Wang Z, Yin Z, Wei YB and Yang JR: The role of miR-29b in cancer: Regulation, function, and signaling. Onco Targets Ther. 8:539–548. 2015.PubMed/NCBI
11	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2021. View Article : Google Scholar : PubMed/NCBI
12	Yahara K, Ohguri T, Udono H, Yamamoto J, Tomura K, Onoda T, Imada H, Nishizawa S and Korogi Y: Radiotherapy using IMRT boosts after hyperbaric oxygen therapy with chemotherapy for glioblastoma. J Radiat Res. 58:351–356. 2017. View Article : Google Scholar : PubMed/NCBI
13	Zhang S, Luo X, Wan F and Lei T: The roles of hypoxia-inducible factors in regulating neural stem cells migration to glioma stem cells and determinating their fates. Neurochem Res. 37:2659–2666. 2012. View Article : Google Scholar : PubMed/NCBI
14	Cheng H, Chang S, Xu R, Chen L, Song X, Wu J, Qian J, Zou Y and Ma J: Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis. Stem Cell Res Ther. 11:2242020. View Article : Google Scholar : PubMed/NCBI
15	Jiang H, Zhao H, Zhang M, He Y, Li X, Xu Y and Liu X: Hypoxia induced changes of exosome cargo and subsequent biological effects. Front Immunol. 13:8241882022. View Article : Google Scholar : PubMed/NCBI
16	Sun H, Meng Q, Shi C, Yang H, Li X, Wu S, Familiari G, Relucenti M, Aschner M, Wang X and Chen R: Hypoxia-inducible exosomes facilitate liver-tropic premetastatic niche in colorectal cancer. Hepatology. 74:2633–2651. 2021. View Article : Google Scholar : PubMed/NCBI
17	Kumar A and Deep G: Exosomes in hypoxia-induced remodeling of the tumor microenvironment. Cancer Lett. 488:1–8. 2020. View Article : Google Scholar : PubMed/NCBI
18	Yaghoubi S, Najminejad H, Dabaghian M, Karimi MH, Abdollahpour-Alitappeh M, Rad F, Mahi-Birjand M, Mohammadi S, Mohseni F, Sobhani Lari M, et al: How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment? IUBMB Life. 72:1286–1305. 2020. View Article : Google Scholar : PubMed/NCBI
19	Sheehan C and D'Souza-Schorey C: Tumor-derived extracellular vesicles: Molecular parcels that enable regulation of the immune response in cancer. J Cell Sci. 132:jcs2350852019. View Article : Google Scholar : PubMed/NCBI
20	Indira Chandran V, Welinder C, Gonçalves de Oliveira K, Cerezo-Magaña M, Månsson AS, Johansson MC, Marko-Varga G and Belting M: Global extracellular vesicle proteomic signature defines U87-MG glioma cell hypoxic status with potential implications for non-invasive diagnostics. J Neurooncol. 144:477–488. 2019. View Article : Google Scholar : PubMed/NCBI
21	van der Vos KE, Abels ER, Zhang X, Lai C, Carrizosa E, Oakley D, Prabhakar S, Mardini O, Crommentuijn MH, Skog J, et al: Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain. Neuro Oncol. 18:58–69. 2016. View Article : Google Scholar : PubMed/NCBI
22	Cai Q, Zhu A and Gong L: Exosomes of glioma cells deliver miR-148a to promote proliferation and metastasis of glioblastoma via targeting CADM1. Bull Cancer. 105:643–651. 2018. View Article : Google Scholar : PubMed/NCBI
23	He PY, Yip WK, Chai BL, Chai BY, Jabar MF, Dusa N, Mohtarrudin N and Seow HF: Inhibition of cell migration and invasion by miR-29a-3p in a colorectal cancer cell line through suppression of CDC42BPA mRNA expression. Oncol Rep. 38:3554–3566. 2017.PubMed/NCBI
24	Wang J, Chen X, Xie C, Sun M, Hu C, Zhang Z, Luan L, Zhou J, Zhou J, Zhu X, et al: MicroRNA miR-29a inhibits colon cancer progression by downregulating B7-H3 expression: Potential molecular targets for colon cancer therapy. Mol Biotechnol. 63:849–861. 2021. View Article : Google Scholar : PubMed/NCBI
25	Kuo TY, Hsi E, Yang IP, Tsai PC, Wang JY and Juo SHH: Computational analysis of mRNA expression profiles identifies microRNA-29a/c as predictor of colorectal cancer early recurrence. PLoS One. 7:e315872012. View Article : Google Scholar : PubMed/NCBI
26	Yamada A, Horimatsu T, Okugawa Y, Nishida N, Honjo H, Ida H, Kou T, Kusaka T, Sasaki Y, Yagi M, et al: Serum miR-21, miR-29a, and miR-125b are promising biomarkers for the early detection of colorectal neoplasia. Clin Cancer Res. 21:4234–4242. 2015. View Article : Google Scholar : PubMed/NCBI
27	Uratani R, Toiyama Y, Kitajima T, Kawamura M, Hiro J, Kobayashi M, Tanaka K, Inoue Y, Mohri Y, Mori T, et al: Diagnostic potential of cell-free and exosomal MicroRNAs in the identification of patients with high-risk colorectal adenomas. PLoS One. 11:e01607222016. View Article : Google Scholar : PubMed/NCBI
28	Marcuello M, Duran-Sanchon S, Moreno L, Lozano JJ, Bujanda L, Castells A and Gironella M: Analysis of A 6-Mirna signature in serum from colorectal cancer screening participants as non-invasive biomarkers for advanced adenoma and colorectal cancer detection. Cancers (Basel). 11:15422019. View Article : Google Scholar : PubMed/NCBI
29	Huang Z, Huang D, Ni S, Peng Z, Sheng W and Du X: Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer. 127:118–126. 2010. View Article : Google Scholar : PubMed/NCBI
30	Guo X, Qiu W, Wang J, Liu Q, Qian M, Wang S, Zhang Z, Gao X, Chen Z, Guo Q, et al: Glioma exosomes mediate the expansion and function of myeloid-derived suppressor cells through microRNA-29a/Hbp1 and microRNA-92a/Prkar1a pathways. Int J Cancer. 144:3111–3126. 2019. View Article : Google Scholar : PubMed/NCBI
31	Huang YH, Lian WS, Wang FS, Wang PW, Lin HY, Tsai MC and Yang YL: MiR-29a curbs hepatocellular carcinoma incidence via targeting of HIF-1α and ANGPT2. Int J Mol Sci. 23:16362022. View Article : Google Scholar : PubMed/NCBI
32	Agani F and Jiang BH: Oxygen-independent regulation of HIF-1: Novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets. 13:245–251. 2013. View Article : Google Scholar : PubMed/NCBI
33	Wang J, Chen X, Hu H, Yao M, Song Y, Yang A, Xu X, Zhang N, Gao J and Liu B: PCAT-1 facilitates breast cancer progression via binding to RACK1 and enhancing oxygen-independent stability of HIF-1α. Mol Ther Nucleic Acids. 24:310–324. 2021. View Article : Google Scholar : PubMed/NCBI
34	Currie E, Schulze A, Zechner R, Walther TC and Farese RV Jr: Cellular fatty acid metabolism and cancer. Cell Metab. 18:153–161. 2013. View Article : Google Scholar : PubMed/NCBI
35	Tang Y, Xiao G, Shen Z, Zhuang C, Xie Y, Zhang X, Yang Z, Guan J, Shen Y, Chen Y, et al: Noninvasive detection of extracellular pH in human benign and malignant liver tumors using CEST MRI. Front Oncol. 10:5789852020. View Article : Google Scholar : PubMed/NCBI
36	Xu L, Wang L, Zhou L, Dorfman RG, Pan Y, Tang D, Wang Y, Yin Y, Jiang C, Zou X, et al: The SIRT2/cMYC pathway inhibits peroxidation-related apoptosis in cholangiocarcinoma through metabolic reprogramming. Neoplasia. 21:429–441. 2019. View Article : Google Scholar : PubMed/NCBI
37	Zong WX, Rabinowitz JD and White E: Mitochondria and cancer. Mol Cell. 61:667–676. 2016. View Article : Google Scholar : PubMed/NCBI
38	Guerra F, Arbini AA and Moro L: Mitochondria and cancer chemoresistance. Biochim Biophys Acta Bioenerg. 1858:686–699. 2017. View Article : Google Scholar : PubMed/NCBI
39	Porporato PE, Filigheddu N, Pedro JMB, Kroemer G and Galluzzi L: Mitochondrial metabolism and cancer. Cell Res. 28:265–280. 2018. View Article : Google Scholar : PubMed/NCBI
40	Księżakowska-Łakoma K, Żyła M and Wilczyński JR: Mitochondrial dysfunction in cancer. Prz Menopauzalny. 13:136–144. 2014.PubMed/NCBI
41	Beltrà M, Pin F, Ballarò R, Costelli P and Penna F: Mitochondrial dysfunction in cancer cachexia: Impact on muscle health and regeneration. Cells. 10:31502021. View Article : Google Scholar : PubMed/NCBI
42	Hsu CC, Tseng LM and Lee HC: Role of mitochondrial dysfunction in cancer progression. Exp Biol Med (Maywood). 241:1281–1295. 2016. View Article : Google Scholar : PubMed/NCBI
43	Liu ZZ, Tian YF, Wu H, Ouyang SY and Kuang WL: LncRNA H19 promotes glioma angiogenesis through miR-138/HIF-1α/VEGF axis. Neoplasma. 67:111–118. 2020. View Article : Google Scholar : PubMed/NCBI
44	Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, Zhang P, Panek WK, Cordero A, Han Y, et al: HIF-1α Is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep. 27:226–237.e4. 2019. View Article : Google Scholar : PubMed/NCBI
45	Wang Z, Li Q, Xia L, Li X, Sun C, Wang Q, Cai X and Yang G: Borneol promotes apoptosis of human glioma cells through regulating HIF-1a expression via mTORC1/eIF4E pathway. J Cancer. 11:4810–4822. 2020. View Article : Google Scholar : PubMed/NCBI
46	Gabriely G, Wheeler MA, Takenaka MC and Quintana FJ: Role of AHR and HIF-1α in glioblastoma metabolism. Trends Endocrinol Metab. 28:428–436. 2017. View Article : Google Scholar : PubMed/NCBI
47	Yang D, Fan L, Song Z, Fang S, Huang M and Chen P: The KMT1A/TIMP3/PI3K/AKT circuit regulates tumor growth in cervical cancer. Reprod Biol. 22:1006442022. View Article : Google Scholar : PubMed/NCBI
48	Ma Y, Ran D, Zhao H, Song R, Zou H, Gu J, Yuan Y, Bian J, Zhu J and Liu Z: Cadmium exposure triggers osteoporosis in duck via P2X7/PI3K/AKT-mediated osteoblast and osteoclast differentiation. Sci Total Environ. 750:1416382021. View Article : Google Scholar : PubMed/NCBI
49	Zhang W, Hou J, Yan X, Leng J, Li R, Zhang J, Xing J, Chen C, Wang Z and Li W: Platycodon grandiflorum saponins ameliorate cisplatin-induced acute nephrotoxicity through the NF-κB-mediated inflammation and PI3K/Akt/apoptosis signaling pathways. Nutrients. 10:13282018. View Article : Google Scholar : PubMed/NCBI
50	Iheagwam FN, Iheagwam OT, Onuoha MK, Ogunlana OO and Chinedu SN: Terminalia catappa aqueous leaf extract reverses insulin resistance, improves glucose transport and activates PI3K/AKT signalling in high fat/streptozotocin-induced diabetic rats. Sci Rep. 12:107112022. View Article : Google Scholar : PubMed/NCBI
51	Zhang Z, Yao L, Yang J, Wang Z and Du G: PI3K/Akt and HIF-1 signaling pathway in hypoxia-ischemia (review). Mol Med Rep. 18:3547–3554. 2018.PubMed/NCBI
52	Zheng HL, Wang LH, Sun BS, Li Y, Yang JY and Wu CF: Oligomer procyanidins (F2) repress HIF-1α expression in human U87 glioma cells by inhibiting the EGFR/AKT/mTOR and MAPK/ERK1/2 signaling pathways in vitro and in vivo. Oncotarget. 8:85252–85262. 2017. View Article : Google Scholar : PubMed/NCBI
53	D'Alessandro G, Quaglio D, Monaco L, Lauro C, Ghirga F, Ingallina C, De Martino M, Fucile S, Porzia A, Di Castro MA, et al: ¹H-NMR metabolomics reveals the glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma. Cell Commun Signal. 17:1082019. View Article : Google Scholar : PubMed/NCBI
54	Mao XG, Xue XY, Wang L, Wang L, Li L and Zhang X: Hypoxia regulated gene network in glioblastoma has special algebraic topology structures and revealed communications involving Warburg effect and immune regulation. Cell Mol Neurobiol. 39:1093–1114. 2019. View Article : Google Scholar : PubMed/NCBI
55	Kim JW, Tchernyshyov I, Semenza GL and Dang CV: HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3:177–185. 2006. View Article : Google Scholar : PubMed/NCBI