MFSD2A Overexpression Inhibits Hepatocellular Carcinoma Through TGF-β/Smad Signaling

被引:1
作者
Xiao, Chaowen [1 ]
Zhao, Xinyang [1 ]
Hu, Zouxiao [1 ]
Long, Guanbao [1 ]
机构
[1] Huazhong Univ Sci & Technol, Cent Hosp Wuhan, Tongji Med Coll, Dept Hepatobiliary Surg, Wuhan, Hubei, Peoples R China
关键词
hepatocellular carcinoma; MFSD2A; RNA-binding protein; TGF-beta; 1/Smad; EPITHELIAL-MESENCHYMAL TRANSITION; PROTEIN; BETA; METASTASIS; SUPPRESSES; REGULATOR; ENCODES; CANCER; GENES; CELLS;
D O I
10.1002/mc.23875
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver and has a high mortality. Major facilitator superfamily domain containing 2 (MFSD2A) was previously demonstrated to inhibit tumor progression in several cancers. Here, we elucidated the association between MFSD2A expression and HCC progression and also investigated the underlying mechanism. The online tools were utilized to evaluate MFSD2A expression in HCC samples and predict the prognostic significance of MFSD2A in HCC patients. The biological role of MFSD2A in HCC cellular processes was examined by colony formation, wound healing, transwell, and western blotting. The in vivo role of MFSD2A in HCC was investigated in a xenograft tumor model. The miRNAs and RNA-binding proteins potentially targeting MFSD2A were identified using bioinformatics prediction tools. Luciferase reporter, RNA immunoprecipitation, actinomycin D, and immunofluorescence assays were performed to investigate the molecule mechanisms of MFSD2A. Transforming growth factor (TGF)-beta 1/Small mothers against decapentaplegic (Smad) signaling was detected using western blot analysis. We found that MFSD2A expression was significantly downregulated in HCC patients and cells and its downregulation predicted a poor prognosis. MFSD2A overexpression repressed HCC cell proliferation, migration, invasion, the epithelial-to-mesenchymal transition in vitro, as well as inhibited HCC tumor growth in vivo. MFSD2A was targeted by miR-3189-3p. High-density lipoprotein binding protein (HDLBP) inhibited MFSD2A expression by binding to and destabilizing MFSD2A mRNA. MFSD2A significantly suppressed activation of TGF-beta/Smad signaling in HCC cells. Knockdown of MFSD2A abrogated the inhibitory effect of miR-3189-3p inhibitor on HCC cellular processes, and overexpression of MFSD2A reversed the tumor-promoting effect of HDLBP overexpression. Overall, MFSD2A exerts a tumor-inhibiting effect in HCC via suppression of TGF-beta/Smad signaling, suggesting that MFSD2A may be a promising target for HCC therapy.
引用
收藏
页码:597 / 611
页数:15
相关论文
共 48 条
[1]   A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome [J].
Alakbarzade, Vafa ;
Hameed, Abdul ;
Quek, Debra Q. Y. ;
Chioza, Barry A. ;
Baple, Emma L. ;
Cazenave-Gassiot, Amaury ;
Nguyen, Long N. ;
Wenk, Markus R. ;
Ahmad, Arshia Q. ;
Sreekantan-Nair, Ajith ;
Weedon, Michael N. ;
Rich, Phil ;
Patton, Michael A. ;
Warner, Thomas T. ;
Silver, David L. ;
Crosby, Andrew H. .
NATURE GENETICS, 2015, 47 (07) :814-+
[2]  
Aliya Sheik, 2021, Critical Reviews in Oncogenesis, V26, P51, DOI 10.1615/CritRevOncog.2020036027
[3]   Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis [J].
Angers, Martin ;
Uldry, Marc ;
Kong, Dong ;
Gimble, Jeffrey M. ;
Jetten, Anton M. .
BIOCHEMICAL JOURNAL, 2008, 416 (347-355) :347-355
[4]   The mRNA-Bound Proteome and Its Global Occupancy Profile on Protein-Coding Transcripts [J].
Baltz, Alexander G. ;
Munschauer, Mathias ;
Schwanhaeusser, Bjoern ;
Vasile, Alexandra ;
Murakawa, Yasuhiro ;
Schueler, Markus ;
Youngs, Noah ;
Penfold-Brown, Duncan ;
Drew, Kevin ;
Milek, Miha ;
Wyler, Emanuel ;
Bonneau, Richard ;
Selbach, Matthias ;
Dieterich, Christoph ;
Landthaler, Markus .
MOLECULAR CELL, 2012, 46 (05) :674-690
[5]   Management of Hepatocellular Carcinoma A Review [J].
Brown, Zachary J. ;
Tsilimigras, Diamantis I. ;
Ruff, Samantha M. ;
Mohseni, Alireza ;
Kamel, Ihab R. ;
Cloyd, Jordan M. ;
Pawlik, Timothy M. .
JAMA SURGERY, 2023, 158 (04) :410-420
[6]   Cytoplasmic PML promotes TGF-β-associated epithelial-mesenchymal transition and invasion in prostate cancer [J].
Buczek, M. E. ;
Miles, A. K. ;
Green, W. ;
Johnson, C. ;
Boocock, D. J. ;
Pockley, A. G. ;
Rees, R. C. ;
Hulman, G. ;
van Schalkwyk, G. ;
Parkinson, R. ;
Hulman, J. ;
Powe, D. G. ;
Regad, T. .
ONCOGENE, 2016, 35 (26) :3465-3475
[7]   MicroRNA functions [J].
Bushati, Natascha ;
Cohen, Stephen M. .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 2007, 23 :175-205
[8]   A 5′-region polymorphism modulates promoter activity of the tumor suppressor gene MFSD2A [J].
Colombo, Francesca ;
Falvella, Felicia S. ;
Galvan, Antonella ;
Frullanti, Elisa ;
Kunitoh, Hideo ;
Ushijima, Toshikazu ;
Dragani, Tommaso A. .
MOLECULAR CANCER, 2011, 10
[9]   Is it time to refine HCC surveillance strategies in HCV cured patients? [J].
D'Ambrosio, Roberta ;
Lampertico, Pietro .
HEPATOLOGY, 2022, 76 (01) :9-11
[10]   Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma [J].
Devan, Aswathy R. ;
Pavithran, Keechilat ;
Nair, Bhagyalakshmi ;
Murali, Maneesha ;
Nath, Lekshmi R. .
WORLD JOURNAL OF GASTROENTEROLOGY, 2022, 28 (36) :5250-5264