Tumor Biology

, Volume 37, Issue 8, pp 11299–11309 | Cite as

Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro

  • Shao-jie Chen
  • Yin-ting Chen
  • Lin-juan Zeng
  • Qiu-bo Zhang
  • Guo-da Lian
  • Jia-jia Li
  • Ke-ge Yang
  • Chu-mei Huang
  • Ya-qing Li
  • Zhong-hua Chu
  • Kai-hong Huang
Original Article

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.

Keywords

Pancreatic cancer Bmi1 KRAS Snail EMT 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81302140, 81572396, 81502503), Science and Technology Planning Project of Guangdong Province, China (Grant No. 2013B021800233), National Natural Science Foundation of Guangdong, China (Grant No. 2014A030313050), and Specialized Research Fund for the Doctoral Program of Higher Education (Grant No. 20130171120093). Grant [2013]163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology and grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes were acknowledged.

Compliance with ethical standards

Conflicts of interest

None

Supplementary material

13277_2016_4840_Fig6_ESM.gif (106 kb)
Fig. S1

PANC-1 cells were able to form colonies in soft agar (GIF 106 kb)

13277_2016_4840_MOESM1_ESM.tif (3.8 mb)
High Resolution Image (TIF 3857 kb)
13277_2016_4840_Fig7_ESM.gif (118 kb)
Fig. S2

Both HPNE-Bmi1-Vector and HPNE-Bmi1-KRASG12D cells failed to form tumors in nude mice for up to 8 weeks following inoculation (GIF 117 kb)

13277_2016_4840_MOESM2_ESM.tif (1.2 mb)
High Resolution Image (TIF 1269 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Shao-jie Chen
    • 1
    • 2
  • Yin-ting Chen
    • 1
    • 2
  • Lin-juan Zeng
    • 3
  • Qiu-bo Zhang
    • 4
  • Guo-da Lian
    • 1
    • 2
  • Jia-jia Li
    • 1
    • 2
  • Ke-ge Yang
    • 1
    • 2
  • Chu-mei Huang
    • 1
    • 2
  • Ya-qing Li
    • 1
    • 2
  • Zhong-hua Chu
    • 5
  • Kai-hong Huang
    • 1
    • 2
  1. 1.Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  2. 2.Department of Gastroenterology, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  3. 3.Department of OncologyThe Fifth Affiliated Hospital of Sun Yat-Sen UniversityZhuhaiChina
  4. 4.Department of GastroenterologyLihuili Hospital of Ningbo Medical CenterNingboChina
  5. 5.Department of Gastroenteropancreatic Surgery, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina

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