Kindlin-2 induced by TGF-β signaling promotes pancreatic ductal adenocarcinoma progression through downregulation of transcriptional factor HOXB9

Jun Zhan; Jiagui Song; Peng Wang; Xiaochun Chi; Yunling Wang; Yongqing Guo; Weigang Fang; Hongquan Zhang

doi:10.1016/j.canlet.2015.02.039

Kindlin-2 induced by TGF-β signaling promotes pancreatic ductal adenocarcinoma progression through downregulation of transcriptional factor HOXB9

Cancer Lett. 2015 May 28;361(1):75-85. doi: 10.1016/j.canlet.2015.02.039. Epub 2015 Feb 24.

Authors

Jun Zhan¹, Jiagui Song¹, Peng Wang¹, Xiaochun Chi¹, Yunling Wang¹, Yongqing Guo², Weigang Fang³, Hongquan Zhang⁴

Affiliations

¹ Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Health Science Center, Peking University, Beijing 100191, China; Department of Anatomy, Histology and Embryology, Laboratory of Molecular Cell Biology and Tumor Biology, Beijing 100191, China.
² Department of Thoracic Surgery, Sino-Japan Friendship Hospital, Beijing 100123, China.
³ Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Health Science Center, Peking University, Beijing 100191, China; Department of Pathology, Health Science Center, Peking University, Beijing 100191, China. Electronic address: wgfang@bjmu.edu.cn.
⁴ Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Health Science Center, Peking University, Beijing 100191, China; Department of Anatomy, Histology and Embryology, Laboratory of Molecular Cell Biology and Tumor Biology, Beijing 100191, China. Electronic address: hongquan.zhang@bjmu.edu.cn.

PMID: 25724625
DOI: 10.1016/j.canlet.2015.02.039

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths with no effective therapeutics. Invasion and metastasis are the major characteristics of PDAC. However, mechanisms underlying PDAC invasion and metastasis are elusive. In this report, we found that Kindlin-2 is a target protein of transforming growth factor β (TGF-β) signaling and is upregulated by TGF-β1 in PDAC cells. TGF-β1-upregulated Kindlin-2 promotes PDAC cell growth, migration and invasion, whereas Kindlin-2 upregulates transforming growth factor receptor I (TβRI), a key component of TGF-β signaling. Thereby Kindlin-2 and TGF-β signaling constitute a positive feedback loop. Mechanistically, Kindlin-2 promotes PDAC progression by downregulation of HOXB9 and E-cadherin. For clinical relevance, enhanced expression of Kindlin-2 predicts a poor overall survival for PDAC patients. Gene expression levels of Kindlin-2, TGF-β, TβRI and HOXB9 are all correlated with the overall survival of PDAC patients in an Oncomine dataset. Taken together, our findings demonstrated that TGF-β1-induced Kindlin-2 expression promotes PDAC progression by downregulation of HOXB9 and E-cadherin.

Keywords: E-cadherin; HOXB9; Kindlin-2; Pancreatic cancer; TGF-β1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Blotting, Western
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / mortality
Carcinoma, Pancreatic Ductal / pathology*
Cell Movement
Cell Proliferation
Cytoskeletal Proteins / physiology*
Disease Progression
Gene Expression Regulation, Neoplastic*
Homeodomain Proteins / antagonists & inhibitors
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
Immunoenzyme Techniques
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Muscle Proteins / physiology*
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / mortality
Pancreatic Neoplasms / pathology*
Prognosis
RNA, Small Interfering / genetics
Receptors, Transforming Growth Factor beta / metabolism
Survival Rate
Transforming Growth Factor beta / pharmacology*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Cytoskeletal Proteins
FERMT3 protein, human
HOXB9 protein, human
Homeodomain Proteins
Membrane Proteins
Muscle Proteins
Neoplasm Proteins
RNA, Small Interfering
Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta
kindlin-2 protein, mouse