circ-PRKCI targets miR-1294 and miR-186-5p by downregulating FOXK1 expression to suppress glycolysis in hepatocellular carcinoma

Chen,Wenqi; Li,Yuehua; Zhong,Jing; Wen,Gebo

doi:10.3892/mmr.2021.12103

circ-PRKCI targets miR-1294 and miR-186-5p by downregulating FOXK1 expression to suppress glycolysis in hepatocellular carcinoma

Authors:
- Wenqi Chen
- Yuehua Li
- Jing Zhong
- Gebo Wen
View Affiliations

Affiliations: Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China, Institute of Clinical Medicine, First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
Published online on: April 19, 2021 https://doi.org/10.3892/mmr.2021.12103
Article Number: 464
Copyright: © Chen 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

Numerous human circular RNAs (circRNAs/circ) have been functionally characterized. However, the potential role of circ-protein kinase C iota (PRKCI) in hepatocellular carcinoma (HCC) remains unknown. The effects of each transfection and expression levels of circ-PRKCI, microRNA (miR)-1294, miR-186-5p and forkhead box K1 (FOXK1) in HCC cells were analyzed using reverse transcription-quantitative PCR analysis. The interactions between circ-PRKCI and miR-1294 or miR-186-5p, and miR-1294 or miR-186-5p and FOXK1 were validated using dual luciferase reporter assays. The viability, invasion and migration of HCC cells were determined using Cell Counting Kit-8, Transwell and wound healing assays, respectively. The expression levels of FOXK1, hexokinase-2 (HK2), glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA) in HCC cells were analyzed using western blotting. The levels of glucose and lactic acid in the cultured supernatant were detected using commercially available kits. The results of the present study revealed that miR-1294 and miR-186-5p expression levels were downregulated in the HCC cell line, HCCLM3, and were subsequently downregulated by circ-PRKCI overexpression and upregulated by the knockdown of circ-PRKCI. circ-PRKCI overexpression promoted the viability, invasion and migration of HCCLM3 cells, which was also reversed by the overexpression of miR-1294 and miR-186-5p. In addition, the overexpression of circ-PRKCI upregulated FOXK1 expression levels, while the overexpression of miR-1294 and miR-186-5p downregulated FOXK1 expression levels. Conversely, the knockdown of circ-PRKCI expression downregulated FOXK1 expression levels, while the knockdown of miR-1294 and miR-186-5p upregulated FOXK1 expression levels. Furthermore, circ-PRKCI was identified to target miR-1294 and miR-186-5p, and miR-1294 and miR-186-5p were subsequently found to target FOXK1. The overexpression of circ-PRKCI also increased glucose and lactic acid levels, while the knockdown of FOXK1 decreased glucose and lactic acid levels. The knockdown of circ-PRKCI decreased glucose and lactic acid levels, which were reversed by FOXK1 overexpression. In conclusion, the findings of the present study suggested that circ-PRKCI may promote the viability, invasion and migration of HCC cells by sponging miR-1294 and miR-186-5p to upregulate FOXK1 expression levels.

View Figures

View References

1	Forner A, Reig M and Bruix J: Hepatocellular carcinoma. Lancet. 391:1301–1314. 2018. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Gingold JA, Zhu D, Lee DF, Kaseb A and Chen J: Genomic profiling and metabolic homeostasis in primary liver cancers. Trends Mol Med. 24:395–411. 2018. View Article : Google Scholar : PubMed/NCBI
4	Invenizzi F, Iavarone M, Donato MF, Mazzucco A, Torre M, Conforti S, Rimessi A, Zavaglia C, Schiavon M, Comacchio G, et al: Pulmonary resection for metastasis of hepatocellular carcinoma recurring after liver transplant: An Italian multicenter experience. Front Oncol. 10:3812020. View Article : Google Scholar : PubMed/NCBI
5	Wei CY, Chen PC, Chau GY, Lee RC, Chen PH, Huo TI, Huang YH, Su YH, Hou MC, Wu JC, et al: Comparison of prognosis between surgical resection and transarterial chemoembolization for patients with solitary huge hepatocellular carcinoma. Ann Transl Med. 8:2382020. View Article : Google Scholar : PubMed/NCBI
6	Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF and Sharpless NE: Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 19:141–157. 2013. View Article : Google Scholar : PubMed/NCBI
7	Wu L, Li Y, Xu XM and Zhu X: Circular RNA circ-PRKCI promotes cell proliferation and invasion by binding to microRNA-545 in gastric cancer. Eur Rev Med Pharmacol Sci. 23:9418–9426. 2019.PubMed/NCBI
8	Shi N, Shan B, Gu B, Song Y, Chu H and Qian L: Circular RNA circ-PRKCI functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-3680-3p in esophageal squamous cell carcinoma. J Cell Biochem. 120:10021–10030. 2019. View Article : Google Scholar : PubMed/NCBI
9	Qi SX, Sun H, Liu H, Yu J, Jiang ZY and Yan P: Role and mechanism of circ-PRKCI in hepatocellular carcinoma. World J Gastroenterol. 25:1964–1974. 2019. View Article : Google Scholar : PubMed/NCBI
10	Cai X, Yu L, Chen Z, Ye F, Ren Z and Jin P: Arsenic trioxide-induced upregulation of miR-1294 suppresses tumor growth in hepatocellular carcinoma by targeting TEAD1 and PIM1. Cancer Biomark. 28:221–230. 2020. View Article : Google Scholar : PubMed/NCBI
11	Shan Y and Li P: Long intergenic non-protein coding RNA 665 regulates viability, apoptosis, and autophagy via the MiR-186-5p/MAP4K3 axis in hepatocellular carcinoma. Yonsei Med J. 60:842–853. 2019. View Article : Google Scholar : PubMed/NCBI
12	Lan T, Yan X, Li Z, Xu X, Mao Q, Ma W, Hong Z, Chen X and Yuan Y: Long non-coding RNA PVT1 serves as a competing endogenous RNA for miR-186-5p to promote the tumorigenesis and metastasis of hepatocellular carcinoma. Tumour Biol. 39:10104283177053382017. View Article : Google Scholar : PubMed/NCBI
13	Wang Y, Liu G, Sun S and Qin J: miR-1294 alleviates epithelial-mesenchymal transition by repressing FOXK1 in gastric cancer. Genes Genomics. 42:217–224. 2020. View Article : Google Scholar : PubMed/NCBI
14	Zhang Z, Zhang W, Mao J, Xu Z and Fan M: miR-186-5p functions as a tumor suppressor in human osteosarcoma by targeting FOXK1. Cell Physiol Biochem. 52:553–564. 2019. View Article : Google Scholar : PubMed/NCBI
15	Cui H, Gao Q, Zhang L, Han F and Wang L: Knockdown of FOXK1 suppresses liver cancer cell viability by inhibiting glycolysis. Life Sci. 213:66–73. 2018. View Article : Google Scholar : PubMed/NCBI
16	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. 2001. View Article : Google Scholar : PubMed/NCBI
17	Kawauchi K, Araki K, Tobiume K and Tanaka N: p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol. 10:611–618. 2008. View Article : Google Scholar : PubMed/NCBI
18	Shi D, Zhao D, Niu P, Zhu Y, Zhou J and Chen H: Glycolysis inhibition via mTOR suppression is a key step in cardamonin-induced autophagy in SKOV3 cells. BMC Complement Altern Med. 18:3172018. View Article : Google Scholar : PubMed/NCBI
19	Gillies RJ and Gatenby RA: Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev. 26:311–317. 2007. View Article : Google Scholar : PubMed/NCBI
20	Ding Z, Yang L, Xie X, Xie F, Pan F, Li J, He J and Liang H: Expression and significance of hypoxia-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cells. J Cancer Res Clin Oncol. 136:1697–1707. 2010. View Article : Google Scholar : PubMed/NCBI
21	Liberti MV and Locasale JW: The Warburg effect: How does it benefit cancer cells? Trends Biochem Sci. 41:211–218. 2016. View Article : Google Scholar : PubMed/NCBI
22	Benjamin DI, Cravatt BF and Nomura DK: Global profiling strategies for mapping dysregulated metabolic pathways in cancer. Cell Metab. 16:565–577. 2012. View Article : Google Scholar : PubMed/NCBI
23	Orang AV, Petersen J, McKinnon RA and Michael MZ: Micromanaging aerobic respiration and glycolysis in cancer cells. Mol Metab. 23:98–126. 2019. View Article : Google Scholar : PubMed/NCBI
24	Guo W, Qiu Z, Wang Z, Wang Q, Tan N, Chen T, Chen Z, Huang S, Gu J, Li J, et al: MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer. Hepatology. 62:1132–1144. 2015. View Article : Google Scholar : PubMed/NCBI
25	Iansante V, Choy PM, Fung SW, Liu Y, Chai JG, Dyson J, Del Rio A, D'Santos C, Williams R, Chokshi S, et al: PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation. Nat Commun. 6:78822015. View Article : Google Scholar : PubMed/NCBI
26	Liang Y, Zhang D, Zheng T, Yang G, Wang J, Meng F, Liu Y, Zhang G, Zhang L, Han J, et al: lncRNA-SOX2OT promotes hepatocellular carcinoma invasion and metastasis through miR-122-5p-mediated activation of PKM2. Oncogenesis. 9:542020. View Article : Google Scholar : PubMed/NCBI
27	Xiao Q, Wei Z, Li Y, Zhou X, Chen J, Wang T, Shao G, Zhang M and Zhang Z: miR-186 functions as a tumor suppressor in osteosarcoma cells by suppressing the malignant phenotype and aerobic glycolysis. Oncol Rep. 39:2703–2710. 2018.PubMed/NCBI
28	Liu Y, Jiang Y, Xu L, Qu C, Zhang L, Xiao X, Chen W, Li K, Liang Q and Wu H: circ-NRIP1 promotes glycolysis and tumor progression by regulating miR-186-5p/MYH9 axis in gastric cancer. Cancer Manag Res. 12:5945–5956. 2020. View Article : Google Scholar : PubMed/NCBI
29	Sukonina V, Ma H, Zhang W, Bartesaghi S, Subhash S, Heglind M, Foyn H, Betz MJ, Nilsson D, Lidell ME, et al: FOXK1 and FOXK2 regulate aerobic glycolysis. Nature. 566:279–283. 2019. View Article : Google Scholar : PubMed/NCBI
30	Zhang Z, Lin W, Gao L, Chen K, Yang C, Zhuang L, Peng S, Kang M and Lin J: Hsa_circ_0004370 promotes esophageal cancer progression through miR-1294/LASP1 pathway. Biosci Rep. 39:BSR201823772019. View Article : Google Scholar : PubMed/NCBI
31	Guo TY, Xu HY, Chen WJ, Wu MX and Dai X: Downregulation of miR-1294 associates with prognosis and tumor progression in epithelial ovarian cancer. Eur Rev Med Pharmacol Sci. 22:7646–7652. 2018.PubMed/NCBI
32	Kan XQ, Li YB, He B, Cheng S, Wei Y and Sun J: MiR-1294 acts as a tumor inhibitor in cervical cancer by regulating FLOT1 expression. J Biol Regul Homeost Agents. Apr 24–2020.(Epub ahead of print).