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Inhibiting roles of FOXA2 in liver cancer cell migration and invasion by transcriptionally suppressing microRNA-103a-3p and activating the GREM2/LATS2/YAP axis

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Abstract

Forkhead box A2 (FOXA2) has emerged as a tumor inhibitor in several human malignancies. This work focused on the effect of FOXA2 on liver cancer (LC) cell invasion and migration and the involving molecules. FOXA2 expression in LC tissues and cell lines was determined. The potential target microRNA (miRNA) of FOXA2 was predicted via bioinformatic analysis and validated through a ChIP assay. The mRNA target of miRNA-103a-3p was predicted via bioinformatic analysis and confirmed via a luciferase assay. Altered expression of FOXA2, miR-103a-3p and GREM2 was introduced in cells to identify their roles in LC cell migration and invasion. Consequently, FOXA2 and GREM2 were poorly expressed while miR-103a-3p was highly expressed in LC samples. Overexpression of FOXA2 or GREM2 suppressed migration and invasion of LC cells, while up-regulation of miR-103a-3p led to inverse trends. FOXA2 transcriptionally suppressed miR-103a-3p to increase GREM2 expression. Silencing of GREM2 blocked the effects of FOXA2. GREM2 increased LATS2 activity and YAP phosphorylation and degradation. To conclude, this study demonstrated that FOXA2 suppressed miR-103a-3p transcription to induce GREM2 upregulation, which increased LATS2 activity and YAP phosphorylation to inhibit migration and invasion of LC cells.

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References

  • Augeri DJ, Langenfeld E, Castle M, Gilleran JA, Langenfeld J (2016) Inhibition of BMP and of TGFbeta receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death. Mol Cancer 15:27

    Article  Google Scholar 

  • Bach DH, Long NP, Luu TT, Anh NH, Kwon SW, Lee SK (2018) The Dominant Role of Forkhead Box Proteins in Cancer. Int J Mol Sci 19

  • Bow YD et al (2020) Silencing of FOXA2 decreases E-cadherin expression and is associated with lymph node metastasis in oral cancer. Oral Dis 26:756–765

    Article  Google Scholar 

  • Callegari E, Gramantieri L, Domenicali M, D’Abundo L, Sabbioni S, Negrini M (2015) MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches. Cell Death Differ 22:46–57

    Article  CAS  Google Scholar 

  • Chen W et al (2016) Cancer statistics in China. CA Cancer J Clin 66:115–132

    Article  Google Scholar 

  • Chen Z et al (2021) Epigenetically silenced linc00261 contributes to the metastasis of hepatocellular carcinoma via inducing the deficiency of FOXA2 transcription. Am J Cancer Res 11:277–296

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cho JW, Lee CY, Ko Y (2012) Therapeutic potential of mesenchymal stem cells overexpressing human forkhead box A2 gene in the regeneration of damaged liver tissues. J Gastroenterol Hepatol 27:1362–1370

    Article  CAS  Google Scholar 

  • Condrat CE et al. (2020) miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis Cells 9

  • Convertini P et al. (2019) Transcriptional regulation factors of the human mitochondrial aspartate/glutamate carrier gene, isoform 2 (SLC25A13): USF1 as Basal Factor and FOXA2 as activator in liver cells. Int J Mol Sci 20

  • De Mattia E et al (2019) Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J Gastroenterol 25:3870–3896

    Article  Google Scholar 

  • Di L et al (2019) Discovery of a natural small-molecule compound that suppresses tumor EMT, stemness and metastasis by inhibiting TGFbeta/BMP signaling in triple-negative breast cancer. J Exp Clin Cancer Res 38:134

    Article  Google Scholar 

  • Diaz-Gonzalez A, Reig M, Bruix J (2016) Treatment of Hepatocellular Carcinoma. Dig Dis 34:597–602

    Article  Google Scholar 

  • Friedman JR, Kaestner KH (2006) The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci 63:2317–2328

    Article  CAS  Google Scholar 

  • Fu J, Wang H (2018) Precision diagnosis and treatment of liver cancer in China. Cancer Lett 412:283–288

    Article  CAS  Google Scholar 

  • Ge J et al. (2020) miR-103a-3p suppresses cell proliferation and invasion by targeting tumor protein D52 in prostate cancer. J Invest Surg:1–9

  • Hu X et al (2018) miRNA-103a-3p promotes human gastric cancer cell proliferation by targeting and suppressing ATF7 in vitro. Mol Cells 41:390–400

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang C, Liu J, Xiong B, Yonemura Y, Yang X (2019) Expression and prognosis analyses of forkhead box A (FOXA) family in human lung cancer. Gene 685:202–210

    Article  CAS  Google Scholar 

  • Jagle S, Busch H, Freihen V, Beyes S, Schrempp M, Boerries M, Hecht A (2017) SNAIL1-mediated downregulation of FOXA proteins facilitates the inactivation of transcriptional enhancer elements at key epithelial genes in colorectal cancer cells. PLoS Genet 13:e1007109

    Article  Google Scholar 

  • Kai K, Dittmar RL, Sen S (2018) Secretory microRNAs as biomarkers of cancer. Semin Cell Dev Biol 78:22–36

    Article  CAS  Google Scholar 

  • Li JH et al (2018) microRNA-141–3p fosters the growth, invasion, and tumorigenesis of cervical cancer cells by targeting FOXA2. Arch Biochem Biophys 657:23–30

    Article  CAS  Google Scholar 

  • Li Y et al (2019) Artemisinin suppresses hepatocellular carcinoma cell growth, migration and invasion by targeting cellular bioenergetics and Hippo-YAP signaling. Arch Toxicol 93:3367–3383

    Article  CAS  Google Scholar 

  • McFadden VC et al (2017) Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation. PLoS Pathog 13:e1006239

    Article  Google Scholar 

  • Momin B, Millman AJ, Nielsen DB, Revels M, Steele CB (2018) Promising practices for the prevention of liver cancer: a review of the literature and cancer plan activities in the National Comprehensive Cancer Control Program. Cancer Causes Control 29:1265–1275

    Article  Google Scholar 

  • Nolan K, Kattamuri C, Rankin SA, Read RJ, Zorn AM, Thompson TB (2016) Structure of gremlin-2 in complex with GDF5 gives insight into DAN-family-mediated BMP antagonism. Cell Rep 16:2077–2086

    Article  CAS  Google Scholar 

  • Okumura N, Ikeda M, Satoh S, Dansako H, Sugiyama M, Mizokami M, Kato N (2015) Negative regulation of hepatitis B virus replication by forkhead box protein A in human hepatoma cells. FEBS Lett 589:1112–1118

    Article  CAS  Google Scholar 

  • Ou H et al (2019) Frizzled 2-induced epithelial-mesenchymal transition correlates with vasculogenic mimicry, stemness, and Hippo signaling in hepatocellular carcinoma. Cancer Sci 110:1169–1182

    Article  CAS  Google Scholar 

  • Peng Q et al (2020) FOXA1 suppresses the growth, migration, and invasion of nasopharyngeal carcinoma cells through repressing miR-100–5p and miR-125b-5p. J Cancer 11:2485–2495

    Article  CAS  Google Scholar 

  • Pinter M, Peck-Radosavljevic M (2018) Review article: systemic treatment of hepatocellular carcinoma. Aliment Pharmacol Ther 48:598–609

    Article  Google Scholar 

  • Razaghi-Moghadam Z, Nikoloski Z (2020) Supervised learning of gene regulatory networks. Curr Protoc Plant Biol 5:e20106

    Article  Google Scholar 

  • Shaalan UF, Ibrahim NL, Ehsan NA, Sultan MM, Naser GM, Abd El-Fatah MO (2019) Reduced Immunohistochemical Expression of Hnf1beta and FoxA2 in Liver Tissue Can Discriminate Between Biliary Atresia and Other Causes of Neonatal Cholestasis. Appl Immunohistochem Mol Morphol 27:e32–e38

    Article  CAS  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA Cancer J Clin 70:7–30

    Article  Google Scholar 

  • Song Y, Washington MK, Crawford HC (2010) Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res 70:2115–2125

    Article  CAS  Google Scholar 

  • Thanan R et al. (2020) Opposing roles of FoxA1 and FoxA3 in intrahepatic cholangiocarcinoma progression. Int J Mol Sci 21

  • Wang J et al (2014) FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloproteinase-9 inhibition. Carcinogenesis 35:2576–2583

    Article  CAS  Google Scholar 

  • Wang K (2015) Molecular mechanisms of hepatic apoptosis regulated by nuclear factors. Cell Signal 27:729–738

    Article  CAS  Google Scholar 

  • Wang L, Wu J, Xie C (2017) miR-92a promotes hepatocellular carcinoma cells proliferation and invasion by FOXA2 targeting. Iran J Basic Med Sci 20:783–790

    PubMed  PubMed Central  Google Scholar 

  • Wang S, Gu M, Jiang H, Zheng X (2019) BMP-2 upregulates the AKT/mTOR pathway in breast cancer with microcalcification and indicates a poor prognosis. Clin Transl Oncol

  • Wennmann DO et al (2014) Evolutionary and molecular facts link the WWC protein family to Hippo signaling. Mol Biol Evol 31:1710–1723

    Article  CAS  Google Scholar 

  • Yamashita H et al (2017) On a FOX hunt: functions of FOX transcriptional regulators in bladder cancer. Nat Rev Urol 14:98–106

    Article  CAS  Google Scholar 

  • Zhang G, Chen Z, Zhang Y, Li T, Bao Y, Zhang S (2020) Inhibition of miR-103a-3p suppresses the proliferation in oral squamous cell carcinoma cells via targeting RCAN1 Neoplasma

  • Zhang H et al (2019) A panel of seven-miRNA signature in plasma as potential biomarker for colorectal cancer diagnosis. Gene 687:246–254

    Article  CAS  Google Scholar 

  • Zhang S, Zhou D (2019) Role of the transcriptional coactivators YAP/TAZ in liver cancer. Curr Opin Cell Biol 61:64–71

    Article  CAS  Google Scholar 

  • Zhao Y, Li Z (2015) Interplay of estrogen receptors and FOXA factors in the liver cancer. Mol Cell Endocrinol 418:334–339

    Article  CAS  Google Scholar 

  • Zheng Y, Pan D (2019) The hippo signaling pathway in development and disease. Dev Cell 50:264–282

    Article  CAS  Google Scholar 

Download references

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Author notes

  1. Guangzhen Ma and Jirong Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, The Second People’s Hospital of Liaocheng, The Second Hospital of Liaocheng Affiliated to Shandong First Medical University), Liaocheng, 252601, Shandong, People’s Republic of China

    Guangzhen Ma

  2. Department of General Surgery, Suizhou Hospital, Hubei University of Medicine, No.60, Longmen Street, Jiefang Road, Suizhou, 441300, Hubei, People’s Republic of China

    Jirong Chen, Tiantian Wei, Jia Wang & Wenshan Chen

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  1. Guangzhen Ma
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  2. Jirong Chen
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  3. Tiantian Wei
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  4. Jia Wang
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  5. Wenshan Chen
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Correspondence to Wenshan Chen.

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Ma, G., Chen, J., Wei, T. et al. Inhibiting roles of FOXA2 in liver cancer cell migration and invasion by transcriptionally suppressing microRNA-103a-3p and activating the GREM2/LATS2/YAP axis. Cytotechnology 73, 523–537 (2021). https://doi.org/10.1007/s10616-021-00475-2

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