Trefoil factor 3 mediation of oncogenicity and chemoresistance in hepatocellular carcinoma is AKT-BCL-2 dependent
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Ming-Liang You1,*, Yi-Jun Chen1,*, Qing-Yun Chong1, Ming-Ming Wu2,3, Vijay Pandey1, Ru-Mei Chen1, Liang Liu4, Lan Ma5, Zheng-Sheng Wu6, Tao Zhu2,3 and Peter E. Lobie1,5
1Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore
2Hefei National Laboratory for Physical Sciences at Microscale Hefei, Anhui, China
3The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China
4Department of Oncology and Department of Radiology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
5Tsinghua Berkeley Shenzhen Institute (TBSI), Shenzhen, China
6Department of Pathology, Anhui Medical University, Hefei, Anhui, China
*These authors have contributed equally to this work
Peter E Lobie, email: [email protected]
Tao Zhu, email: [email protected]
Keywords: TFF3, hepatocellular carcinoma, oncogenic, chemoresistance, cancer stem cells
Received: January 12, 2017 Accepted: March 07, 2017 Published: April 07, 2017
The efficacious treatment of hepatocellular carcinoma (HCC) remains a challenge, partially being attributed to intrinsic chemoresistance. Previous reports have observed increased TFF3 expression in HCC. Herein, we investigated the functional role of TFF3 in progression of HCC, and in both intrinsic and acquired chemoresistance. TFF3 expression was observed to be upregulated in HCC and associated with poor clinicopathological features and worse patient survival outcome. Functionally, forced expression of TFF3 in HCC cell lines increased cell proliferation, cell survival, anchorage-independent and 3D matrigel growth, cell invasion and migration, and in vivo tumor growth. In contrast, depleted expression of TFF3 decreased the oncogenicity of HCC cells as indicated by the above parameters. Furthermore, forced expression of TFF3 decreased doxorubicin sensitivity of HCC cells, which was attributed to increased doxorubicin efflux and cancer stem cell-like behavior of Hep3B cells. In contrast, depletion of TFF3 increased doxorubicin sensitivity and decreased cancer stem cell-like behavior of Hep3B cells. Correspondingly, TFF3 expression was markedly increased in Hep3B cells with acquired doxorubicin resistance, while the depletion of TFF3 resulted in re-sensitization of the Hep3B cells to doxorubicin. The increased doxorubicin efflux and enhanced cancer stem cell-like behavior of the doxorubicin-resistant Hep3B cells was observed to be dependent on TFF3 expression. In addition, we determined that TFF3-stimulated oncogenicity and chemoresistance in HCC cells was mediated by AKT-dependent expression of BCL-2. Hence, therapeutic inhibition of TFF3 should be considered to hinder HCC progression and overcome intrinsic and acquired chemoresistance in HCC.
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