Targeting endogenous DLK1 exerts antitumor effect on hepatocellular carcinoma through initiating cell differentiation.
Cancer stem cells (CSCs) are responsible for tumor initiation and progression. We previously showed that Delta-like homolog 1 (DLK1) may be a therapeutic target against the CSCs of human hepatocellular carcinoma (HCC). However, the therapeutic efficacy and underlying mechanism remain unclear. Here we demonstrated that knockdown of DLK1 using a tet-inducible short hairpin RNA (shRNA) system significantly inhibited proliferation, spheroid formation and in vivo xenograft tumor growth of human HCC cells. Furthermore, in an orthotopic xenograft mouse model, adenovirus-mediated DLK1 knockdown could significantly reduce tumor size, as shown by in vivo imaging approach. Subsequently, an adenoviral vector harboring mouse Dlk1 shRNA was applied. The results showed that Dlk1 knockdown also could inhibit tumor progression in a diethylnitrosamine (DEN) induced mouse HCC model. At cellular mechanism, DLK1 knockdown delayed the cell cycle G1-S transition, along with the decreased expression of cyclin E1 and D1. Significantly, DLK1 knockdown resulted in the decrease of molecular markers such as AFP and EpCAM for hepatic progenitor cells, but the increase of KRT18 and KRT19 for the differentiated hepatocytes. The collective data indicated that targeting endogenous DLK1 may exert antitumor effect on HCCs possibly through initiating cell differentiation.
Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.
Chun-Miao
CM
Cai
Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.
Xu
X
Xiao
Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.|Shanghai Center of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
Bing-Hao
BH
Wu
Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.
Bao-Feng
BF
Wei
Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.|Shanghai Center of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
Ze-Guang
ZG
Han
D000818:Animals; D002135:Calcium-Binding Proteins; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000628:therapy; D002453:Cell Cycle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology* / Q000628:therapy; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000166:cytology*; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D004318:Doxycycline
DLK1; RNA interference; cell differentiation; hepatocellular carcinoma
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