Abstract
Meningioma-associated protein 30 (MAC30) has been recently identified as a new tumor-associated protein that is implicated in multiple tumor types. However, the role of MAC30 in hepatocellular carcinoma (HCC) has not been studied. In the current study, we explored the expression, biological function and underlying mechanism of MAC30 in HCC. We found that MAC30 expression was significantly elevated in HCC tissues and cell lines. Functional in vitro assays demonstrated that the knockdown of MAC30 inhibited the proliferation and invasion of HCC cells, while MAC30 overexpression facilitated these biological behaviors. Moreover, the knockdown of MAC30 decreased glycogen synthase kinase (GSK)-3β phosphorylation level and β-catenin expression, leading to the inactivation of Wnt/β-catenin signaling in HCC cells. The inhibition of GSK-3β or reactivation Wnt/β-catenin signaling markedly reversed MAC30 knockdown-mediated inhibitory effects on the proliferation and invasion of HCC cells. Notably, the inhibition of Wnt/β-catenin signaling abrogated the MAC30-evoked oncogenic role in HCC cells. In addition, the knockdown of MAC30 impeded tumor formation and the growth rate of HCC cells in vivo. Taken together, our data recognized MAC30 as a potential tumor-promotion factor in HCC, which accelerated the proliferation and invasion of HCC through the up-regulation of Wnt/β-catenin signaling. Our study suggests MAC30 as a potential anticancer target for HCC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The data and material used to support the findings of this study are available from the corresponding author upon request.
References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424
Chen R, Fen Y, Lin X, Ma T, Cai H, Ding H (2016) Overexpression of MAC30 is resistant to platinum-based chemotherapy in patients with non-small cell lung cancer. Technol Cancer Res Treat 15:815–820
Ding H, Gui X, Lin X, Chen R, Ma T, Sheng Y, Cai H, Fen Y (2017) The prognostic effect of MAC30 expression on patients with non-small cell lung cancer receiving adjuvant chemotherapy. Technol Cancer Res Treat 16:645–653
Forner A, Reig M, Bruix J (2018) Hepatocellular carcinoma. Lancet 391:1301–1314
Fujiwara N, Friedman SL, Goossens N, Hoshida Y (2018) Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 68:526–549
Gravitz L (2014) Liver cancer. Nature 516:S1
Grinchuk OV, Motakis E, Kuznetsov VA (2010) Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression. BMC Genomics 11(Suppl 1):S9
Hasan S, Abel S, Uemura T, Verma V, Koay EJ, Herman J, Thai N, Kirichenko A (2019) Liver transplant mortality and morbidity following preoperative radiotherapy for hepatocellular carcinoma. HPB (Oxford) 22:770–778
Ikeda M, Morizane C, Ueno M, Okusaka T, Ishii H, Furuse J (2018) Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Jpn J Clin Oncol 48:103–114
Kayed H, Kleeff J, Ding J, Hammer J, Giese T, Zentgraf H, Buchler MW, Friess H (2004) Expression analysis of MAC30 in human pancreatic cancer and tumors of the gastrointestinal tract. Histol Histopathol 19:1021–1031
Klaus A, Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8:387–398
Labeur TA, Achterbergh R, Takkenberg B, Van Delden O, Mathot R, Klumpen HJ (2019) Sorafenib for patients with hepatocellular carcinoma and child-pugh B liver cirrhosis: lessons learned from a terminated study. Oncologist 2019:0718
Lachenmayer A, Alsinet C, Savic R, Cabellos L, Toffanin S, Hoshida Y, Villanueva A, Minguez B, Newell P, Tsai HW, Barretina J, Thung S, Ward SC, Bruix J, Mazzaferro V, Schwartz M, Friedman SL, Llovet JM (2012) Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin Cancer Res 18:4997–5007
Malhotra K, Luehrsen KR, Costello LL, Raich TJ, Sim K, Foltz L, Davidson S, Xu H, Chen A, Yamanishi DT, Lindemann GW, Cain CA, Madlansacay MR, Hashima SM, Pham TL, Mahoney W, Schueler PA (1999) Identification of differentially expressed mRNAs in human fetal liver across gestation. Nucleic Acids Res 27:839–847
Moparthi SB, Arbman G, Wallin A, Kayed H, Kleeff J, Zentgraf H, Sun XF (2007) Expression of MAC30 protein is related to survival and biological variables in primary and metastatic colorectal cancers. Int J Oncol 30:91–95
Murphy M, Pykett MJ, Harnish P, Zang KD, George DL (1993) Identification and characterization of genes differentially expressed in meningiomas. Cell Growth Differ 4:715
Nusslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287:795–801
Oyer HM, Sanders CM, Kim FJ (2019) Small-molecule modulators of sigma1 and sigma2/TMEM97 in the context of cancer: foundational concepts and emerging themes. Front Pharmacol 10:1141
Qu T, Zhao Y, Chen Y, Jin S, Fang Y, Jin X, Sun L, Ma Y (2019) Down-regulated MAC30 expression inhibits breast cancer cell invasion and EMT by suppressing Wnt/beta-catenin and PI3K/Akt signaling pathways. Int J Clin Exp Pathol 12:1888–1896
Sanchez-Pulido L, Ponting CP (2014) TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease. Front Genet 5:439
Schmit K, Michiels C (2018) TMEM proteins in cancer: a review. Front Pharmacol 9:1345
Song GQ, Zhao Y (2018) MAC30 knockdown involved in the activation of the hippo signaling pathway in breast cancer cells. Biol Chem 399:1305–1311
White BD, Chien AJ, Dawson DW (2012) Dysregulation of Wnt/beta-catenin signaling in gastrointestinal cancers. Gastroenterology 142:219–232
Wu X, Zhou F, Ji X, Ren K, Shan Y, Mao X, Fen Y, Chen R, Ding H, Fu X (2017) The prognostic role of MAC30 in advanced gastric cancer patients receiving platinum-based chemotherapy. Future Oncol 13:2691–2696
Wu X, Zhang Y, Guo J, Yan X, Shen L, Zhou J, Zhao J, Zhuang M, Cao Z (2020) MAC30 knockdown inhibits proliferation and enhance apoptosis of gastric cancer by suppressing Wnt/beta-catenin signaling pathway. Gastroenterol Res Pract 2020:6358685
Xiao M, Li H, Yang S, Huang Y, Jia S, Wang H, Wang J, Li Z (2013) Expression of MAC30 protein is related to survival and clinicopathological variables in breast cancer. J Surg Oncol 107:456–462
Xu XY, Zhang LJ, Yu YQ, Zhang XT, Huang WJ, Nie XC, Song GQ (2014) Down-regulated MAC30 expression inhibits proliferation and mobility of human gastric cancer cells. Cell Physiol Biochem 33:1359–1368
Yan BY, Wang DW, Zhu ZL, Yang YH, Wang MW, Cui DS, Zhang H, Sun XF (2010) Overexpression of MAC30 in the cytoplasm of oral squamous cell carcinoma predicts nodal metastasis and poor differentiation. Chemotherapy 56:424–428
Yang S, Li H, Liu Y, Ning X, Meng F, Xiao M, Wang D, Lou G, Zhang Y (2013) Elevated expression of MAC30 predicts lymph node metastasis and unfavorable prognosis in patients with epithelial ovarian cancer. Med Oncol 30:324
Zhan T, Rindtorff N, Boutros M (2017) Wnt signaling in cancer. Oncogene 36:1461–1473
Zhang PP, Wang PQ, Qiao CP, Zhang Q, Zhang JP, Chen F, Zhang X, Xie WF, Yuan ZL, Li ZS, Chen YX (2016) Differentiation therapy of hepatocellular carcinoma by inhibiting the activity of AKT/GSK-3beta/beta-catenin axis and TGF-beta induced EMT with sophocarpine. Cancer Lett 376:95–103
Zhao ZR, Zhang LJ, He XQ, Zhang ZY, Zhang F, Li F, Pei YB, Hu YM, Wang MW, Sun XF (2011) Significance of mRNA and protein expression of MAC30 in progression of colorectal cancer. Chemotherapy 57:394–401
Author information
Authors and Affiliations
Contributions
Yu Zhang designed the study, performed the experiments and drafted the manuscript. Hui Li performed the experiments. Jixin Wang interpreted the data. Xilin Geng interpreted the data. Jun Hai designed the study and revised the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Ethics approval
The use of clinical tissues was approved by Ethics Committee of Shaanxi Provincial People’s Hospital, and experimental procedures were undertaken in line with the guidelines set forth by the Declaration of Helsinki. The animal experiments were approved by the Ethics Committee of Shaanxi Provincial People’s Hospital and carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Consent to participate
Not applicable.
Consent for publication
All authors have approved for the publication of this paper.
Code availability
Not applicable.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
ESM 1
(DOCX 16 kb)
Rights and permissions
About this article
Cite this article
Zhang, Y., Li, H., Wang, J. et al. Meningioma-associated protein 30 accelerates the proliferation and invasion of hepatocellular carcinoma by modulating Wnt/GSK-3β/β-catenin signaling. J Bioenerg Biomembr 53, 73–83 (2021). https://doi.org/10.1007/s10863-020-09864-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10863-020-09864-2