Kindlin-2 induced by TGF-β signaling promotes pancreatic ductal adenocarcinoma progression through downregulation of transcriptional factor HOXB9.
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.
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.
Jun
J
Zhan
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.
Jiagui
J
Song
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.
Peng
P
Wang
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.
Xiaochun
X
Chi
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.
Yunling
Y
Wang
Department of Thoracic Surgery, Sino-Japan Friendship Hospital, Beijing 100123, China.
Yongqing
Y
Guo
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.
Weigang
W
Fang
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.
Hongquan
H
Zhang
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000502:physiology*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009124:Muscle Proteins / Q000502:physiology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D003598:Cytoskeletal Proteins; C477322:FERMT3 protein, human; C491257:HOXB9 protein, human; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C527802:kindlin-2 protein, mouse
E-cadherin; HOXB9; Kindlin-2; Pancreatic cancer; TGF-β1