title: Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro.
abstract: It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC.
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Shao-Jie
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yin-Ting
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China.
authors.forename: Lin-Juan
authors.initials: LJ
authors.lastname: Zeng
authors.affiliation: Department of Gastroenterology, Lihuili Hospital of Ningbo Medical Center, Ningbo, China.
authors.forename: Qiu-Bo
authors.initials: QB
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Guo-da
authors.initials: GD
authors.lastname: Lian
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Ke-Ge
authors.initials: KG
authors.lastname: Yang
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Chu-Mei
authors.initials: CM
authors.lastname: Huang
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Ya-Qing
authors.initials: YQ
authors.lastname: Li
authors.affiliation: Department of Gastroenteropancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China. sumschuzhonghua@hotmail.com.
authors.forename: Zhong-Hua
authors.initials: ZH
authors.lastname: Chu
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China. huangkh@mail.sysu.edu.cn.|Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. huangkh@mail.sysu.edu.cn.
authors.forename: Kai-Hong
authors.initials: KH
authors.lastname: Huang
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C069077:BMI1 protein, human; C117307:KRAS protein, human; D063150:Polycomb Repressive Complex 1; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Bmi1; EMT; KRAS; Pancreatic cancer; Snail