Krüppel-like Factor 8 Induces Epithelial-to-mesenchymal Transition and Promotes Invasion of Pancreatic Cancer Cells Through Transcriptional Activation of Four and a Half LIM-only Protein 2

Overview

Journal Oncol Lett

Specialty Oncology

Date 2017 Sep 26

PMID 28943967

Citations 9

Authors

Xiaoping Yi

Hongyan Zai

Xueying Long

Xiaoyi Wang

Wenzheng Li

Yixiong Li

Affiliations

Soon will be listed here.

Abstract

Pancreatic cancer (PC) is one of the most aggressive types of cancer with an extremely poor prognosis. Invasive growth and early metastasis is one of the greatest challenges to overcome for the treatment of PC. Numerous previous studies have indicated that the transcription factor Krüppel-like factor 8 (KLF8) and nuclear cofactor four and a half LIM-only protein 2 (FHL2) serve important roles in tumorigenesis and tumor progression; however, their roles in PC remain elusive. The present study revealed that KLF8 and FHL2 expression is aberrantly co-overexpressed in PC tissue samples and associated with tumor metastasis. Furthermore, a positive correlation between the expression levels of KLF8 and FHL2 was observed. Subsequently, the present study identified KLF8 as a critical inducer of epithelial-to-mesenchymal transition (EMT) and invasion. Of note, the present study demonstrated that KLF8 overexpression induced a strong increase in FHL2 expression, and subsequent promoter reporter assays determined that KLF8 directly bound and activated the FHL2 gene promoter. Furthermore, FHL2 knockdown in KLF8-overexpressing cells partially reversed the EMT and invasive phenotypes. The present study identified KLF8-induced FHL2 activation as a novel and critical signaling mechanism underlying human PC invasion.

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References

Ding L, Wang Z, Yan J, Yang X, Liu A, Qiu W . Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway. J Clin Invest. 2009; 119(2):349-61. PMC: 2631293. DOI: 10.1172/JCI35930. View

Liu L, Liu N, Xu M, Liu Y, Min J, Pang H . Lentivirus-delivered Krüppel-like factor 8 small interfering RNA inhibits gastric cancer cell growth in vitro and in vivo. Tumour Biol. 2011; 33(1):53-61. DOI: 10.1007/s13277-011-0245-7. View

Qiao L, Wang Y, Pang R, Wang J, Dai Y, Ma J . Oncogene functions of FHL2 are independent from NF-kappaBIalpha in gastrointestinal cancer. Pathol Oncol Res. 2008; 15(1):31-6. DOI: 10.1007/s12253-008-9085-1. View

Lloyd J . KLF8 sets the pace for the cell cycle through interactions with p300 and PCAF. Cell Cycle. 2010; 9(4):650-1. View

Wang X, Zheng M, Liu G, Xia W, McKeown-Longo P, Hung M . Krüppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res. 2007; 67(15):7184-93. DOI: 10.1158/0008-5472.CAN-06-4729. View

Yan Q, Zhang W, Wu Y, Wu M, Zhang M, Shi X . KLF8 promotes tumorigenesis, invasion and metastasis of colorectal cancer cells by transcriptional activation of FHL2. Oncotarget. 2015; 6(28):25402-17. PMC: 4694840. DOI: 10.18632/oncotarget.4517. View

Zhao J, Bian Z, Yee K, Chen B, Chien S, Guan J . Identification of transcription factor KLF8 as a downstream target of focal adhesion kinase in its regulation of cyclin D1 and cell cycle progression. Mol Cell. 2003; 11(6):1503-15. DOI: 10.1016/s1097-2765(03)00179-5. View

Wang X, Urvalek A, Liu J, Zhao J . Activation of KLF8 transcription by focal adhesion kinase in human ovarian epithelial and cancer cells. J Biol Chem. 2008; 283(20):13934-42. DOI: 10.1074/jbc.M709300200. View

Lu X, Shi Y, Chen J, Ma S . Krüppel-like factors in hepatocellular carcinoma. Tumour Biol. 2015; 36(2):533-41. DOI: 10.1007/s13277-015-3127-6. View

10.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

11.

Thiery J, Acloque H, Huang R, Nieto M . Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139(5):871-90. DOI: 10.1016/j.cell.2009.11.007. View

12.

Beuran M, Negoi I, Paun S, Ion A, Bleotu C, Negoi R . The epithelial to mesenchymal transition in pancreatic cancer: A systematic review. Pancreatology. 2015; 15(3):217-25. DOI: 10.1016/j.pan.2015.02.011. View

13.

Yang T, Cai S, Zhang J, Lu J, Lin C, Zhai J . Krüppel-like factor 8 is a new Wnt/beta-catenin signaling target gene and regulator in hepatocellular carcinoma. PLoS One. 2012; 7(6):e39668. PMC: 3384617. DOI: 10.1371/journal.pone.0039668. View

14.

Gullotti L, Czerwitzki J, Kirfel J, Propping P, Rahner N, Steinke V . FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer. Lab Invest. 2011; 91(12):1695-705. DOI: 10.1038/labinvest.2011.109. View

15.

Chen G, Yang W, Jin W, Wang Y, Tao C, Yu Z . Lentivirus-mediated gene silencing of KLF8 reduced the proliferation and invasion of gastric cancer cells. Mol Biol Rep. 2012; 39(10):9809-15. DOI: 10.1007/s11033-012-1847-x. View

16.

Urvalek A, Wang X, Lu H, Zhao J . KLF8 recruits the p300 and PCAF co-activators to its amino terminal activation domain to activate transcription. Cell Cycle. 2010; 9(3):601-11. PMC: 2888133. DOI: 10.4161/cc.9.3.10606. View

17.

Lahiri S, Zhao J . Krüppel-like factor 8 emerges as an important regulator of cancer. Am J Transl Res. 2012; 4(3):357-63. PMC: 3426389. View

18.

Zhang P, Basu P, Redmond L, Morris P, Rupon J, Ginder G . A functional screen for Krüppel-like factors that regulate the human gamma-globin gene through the CACCC promoter element. Blood Cells Mol Dis. 2005; 35(2):227-35. DOI: 10.1016/j.bcmd.2005.04.009. View

19.

McGrath M, Binge L, Sriratana A, Wang H, Robinson P, Pook D . Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer. Cancer Res. 2013; 73(16):5066-79. DOI: 10.1158/0008-5472.CAN-12-4520. View

20.

Deer E, Gonzalez-Hernandez J, Coursen J, Shea J, Ngatia J, Scaife C . Phenotype and genotype of pancreatic cancer cell lines. Pancreas. 2010; 39(4):425-35. PMC: 2860631. DOI: 10.1097/MPA.0b013e3181c15963. View