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PU.1 Is Identified as a Novel Metastasis Suppressor in Hepatocellular Carcinoma Regulating the miR-615-5p/IGF2 Axis

  • Song, Li-Jie (Department of Oncology, the First Affiliated Hospital of Zhengzhou University) ;
  • Zhang, Wei-Jie (Department of Oncology, the First Affiliated Hospital of Zhengzhou University) ;
  • Chang, Zhi-Wei (Department of Oncology, the First Affiliated Hospital of Zhengzhou University) ;
  • Pan, Yan-Feng (Department of Oncology, the First Affiliated Hospital of Zhengzhou University) ;
  • Zong, Hong (Department of Oncology, the First Affiliated Hospital of Zhengzhou University) ;
  • Fan, Qing-Xia (Department of Oncology, the First Affiliated Hospital of Zhengzhou University) ;
  • Wang, Liu-Xing (Department of Oncology, the First Affiliated Hospital of Zhengzhou University)
  • Published : 2015.05.18

Abstract

Invasion and metastasis is the major cause of tumor recurrence, difficulty for cure and low survival rate. Excavating key transcription factors, which can regulate tumor invasion and metastasis, are crucial to the development of therapeutic strategies for cancers. PU.1 is a master hematopoietic transcription factor and a vital regulator in life. Here, we report that, compared to adjacent non-cancerous tissues, expression of PU.1 mRNA in metastatic hepatocellular carcinoma (HCC), but not primary HCC, was significantly down-regulated. In addition, levels of PU.1 mRNA in metastatic hepatoma cell lines MHCC97L and MHCC97H were much lower than in non-metastatic Hep3B cells. Transwell invasion assays after PU.1 siRNA transfection showed that the invasion of hepatoma cell lines was increased markedly by PU.1 knockdown. Oppositely, overexpression of PU.1 suppressed the invasion of these cells. However, knockdown and overexpression of PU.1 did not influence proliferation. Finally, we tried to explore the potential mechanism of PU.1 suppressing hepatoma cell invasion. ChIP-qPCR analysis showed that PU.1 exhibited a high binding capacity with miR-615-5p promoter sequence. Overexpression of PU.1 caused a dramatic increase of pri-, pre- and mature miR-615-5p, as well as a marked decrease of miR-615-5p target gene IGF2. These data indicate that PU.1 inhibits invasion of human HCC through promoting miR-615-5p and suppressing IGF2. These findings improve our understanding of PU.1 regulatory roles and provided a potential target for metastatic HCC diagnosis and therapy.

Keywords

PU.1;miR-615-5p;hepatocellular carcinoma;invasion and metastasis

References

  1. Bruix J, Sherman M (2011). Management of hepatocellular carcinoma: an update. Hepatol, 53, 1020-2. https://doi.org/10.1002/hep.24199
  2. Christie DA, Xu LS, Turkistany SA, et al (2015). PU. 1 opposes IL-7-dependent proliferation of developing B cells with involvement of the direct target gene bruton tyrosine kinase. J Immunol, 194, 595-605. https://doi.org/10.4049/jimmunol.1401569
  3. Drusco A, Nuovo GJ, Zanesi N, et al (2014). MicroRNA profiles discriminate among colon cancer metastasis. PloS one, 9, 96670. https://doi.org/10.1371/journal.pone.0096670
  4. El Tayebi H, Hosny K, Esmat G, Breuhahn K, Abdelaziz AI (2012). MiR-615-5p is restrictedly expressed in cirrhotic and cancerous liver tissues and its overexpression alleviates the tumorigenic effects in hepatocellular carcinoma. FEBS Lett, 586, 3309-16. https://doi.org/10.1016/j.febslet.2012.06.054
  5. Fornari F, Gramantieri L, Giovannini C, et al (2009). MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res, 69, 5761-7. https://doi.org/10.1158/0008-5472.CAN-08-4797
  6. Guan J (2015). Cholesterol-conjugated let-7a miRNA mimics: promising tools for HCC systemic. RNA and DISEASE, 2, doi.org/10.14800/rd.630. https://doi.org/10.14800/rd.630
  7. Kudo M, Matsui O, Izumi N, et al (2014). JSH consensusbased clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by the liver cancer study group of Japan. Liver Cancer, 3, 458-68. https://doi.org/10.1159/000343875
  8. Kutay H, Bai S, Datta J, et al (2006). Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem, 99, 671-8. https://doi.org/10.1002/jcb.20982
  9. Landgraf P, Rusu M, Sheridan R, et al (2007). A mammalian microRNA expression atlas based on small RNA library sequencing. Cell, 129, 1401-14. https://doi.org/10.1016/j.cell.2007.04.040
  10. Lin L, Pang W, Chen K, et al (2012). Adipocyte expression of PU. 1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production. Am J Physiol-Endoc M, 302, 1550-9.
  11. Liu AM, Xu Z, Shek FH, et al (2014). miR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma. PloS one, 9, 86872. https://doi.org/10.1371/journal.pone.0086872
  12. Llovet JM, Hernandez-Gea V (2014). Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res, 20, 2072-9. https://doi.org/10.1158/1078-0432.CCR-13-0547
  13. Loffreda S, Yang S, Lin H, et al (1998). Leptin regulates proinflammatory immune responses. FASEB J, 12, 57-65.
  14. Metcalf D, Dakic A, Mifsud S, et al (2006). Inactivation of PU. 1 in adult mice leads to the development of myeloid leukemia. Proc Natl Acad Sci USA, 103, 1486-91. https://doi.org/10.1073/pnas.0510616103
  15. Olena AF, Patton JG (2014). MiRNA biogenesis and function. in: microRNA in development and in the progression of cancer, pp, 3-28.
  16. Pang WJ, Lin LG, Xiong Y, et al (2013). Knockdown of PU. 1 AS lncRNA inhibits adipogenesis through enhancing PU. 1 mRNA translation. J Cell Biochem, 114, 2500-12. https://doi.org/10.1002/jcb.24595
  17. Shimizu S, Takehara T, Hikita H, et al (2010). The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol, 52, 698-704. https://doi.org/10.1016/j.jhep.2009.12.024
  18. Toiyama Y, Tanaka K, Kitajima T, et al (2014). Elevated serum angiopoietin-like protein 2 correlates with the metastatic properties of colorectal cancer: a serum biomarker for early diagnosis and recurrence. Clin Cancer Res, 20, 6175-86. https://doi.org/10.1158/1078-0432.CCR-14-0007
  19. Wang F, Tong Q (2008). Transcription factor PU. 1 is expressed in white adipose and inhibits adipocyte differentiation. Am J Physiol-Cell Ph, 295, 213-20. https://doi.org/10.1152/ajpcell.00422.2007
  20. Wei N, Pang W, Wang Y, et al (2014). Knockdown of PU. 1 mRNA and AS lncRNA regulates expression of immune-related genes in zebrafish danio rerio. Dev Comp Immunol, 44, 315-9. https://doi.org/10.1016/j.dci.2014.01.015
  21. Wei N, Wang Y, Xu RX, et al (2015). PU. 1 antisense lncRNA against its mRNA translation promotes adipogenesis in porcine preadipocytes. Anim Genet, 46, 133-40. https://doi.org/10.1111/age.12275

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