Radiation enhances long-term metastasis potential of residual hepatocellular carcinoma in nude mice through TMPRSS4-induced epithelial-mesenchymal transition

• Published in: Cancer gene therapy Vol. 18; no. 9; pp. 617 - 626
• Main Authors: Li, T, Zeng, Z-C, Wang, L, Qiu, S-J, Zhou, J-W, Zhi, X-T, Yu, H-H, Tang, Z-Y
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2011; Nature Publishing Group
• Subjects: 692/699/67/1504/1610; 692/699/67/322; 692/700/565/485; Animals; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cadherins - genetics; Cadherins - metabolism; Carcinoma, Hepatocellular - complications; Care and treatment; Cell Line, Tumor; Development and progression; E-cadherin; Epithelial-Mesenchymal Transition - genetics; Epithelial-Mesenchymal Transition - radiation effects; Gelatinase A; Gene Expression; Gene Therapy; Health aspects; Hepatocellular carcinoma; Hepatoma; Immunohistochemistry; Invasiveness; Liver cancer; Male; Matrix metalloproteinase; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; original-article; Physiological aspects; Radiation; Radiation therapy; Radiotherapy; Reverse Transcriptase Polymerase Chain Reaction; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; siRNA; Smad protein; Transcription; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; X-Rays; Xenograft Model Antitumor Assays; Xenografts; China; epithelial–mesenchymal transition; radiation; metastasis; hepatocellular carcinoma; TMPRSS4
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/cgt.2011.29

Recurrence and metastasis are frequently observed after radiotherapy for hepatocellular carcinoma (HCC), although upregulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) induced by radiation has been claimed to be involved, the mechanism is not clarified yet. In the present study, by using MHCC97L, a human HCC cell line with metastatic potential, and its xenograft in nude mice, we found that radiation induced a 48- to 72-h temporary increase in the expression of MMP-2 and VEGF both in vitro and in vivo , but only the in vitro invasiveness of MHCC97L cells was enhanced, while the in vivo metastatic potential of tumors was suppressed. Whereas, 30 days after radiation, when the expression of MMP-2 and VEGF decreased to unirradiated control levels, the in vivo dissemination and metastatic potential of residual tumors have just begun to increase with overexpression of TMPRSS4, which induced loss of E-cadherin through induction of Smad-Interacting Protein 1 (SIP1), an E-cadherin transcriptional repressor, and led to epithelial–mesenchymal transition (EMT). This process was blocked by treatment of siRNA-TMPRSS4. In conclusion, our study revealed novel findings regarding the biphasic effect of radiation on the metastatic potential of residual HCC. Overexpression of TMPRSS4 has a critical role in radiation-induced long-term dissemination and metastasis of residual HCC by facilitating EMT. These findings may provide new clues to suppress the radiation-induced dissemination and metastasis, thereby improve the prognosis of HCC patients.