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

Abstract

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.

Radiation therapy for hepatocellular carcinoma: current status and perspectives from our experience

“…This effect was mediated by suppression of COX-2 expression by the residual tumor and an increase in E-cadherin production, which reverses the enhancement of epithelial-mesenchymal transition (EMT) and metastasis, where overexpresssion of TMPRSS4 is induced. This study confirmed the clinical value of inhibition of radiation-induced late-stage metastasis and dissemination by administration of low doses of IFN-a and aspirin [30]. In the future, we plan to carry out prospective, randomized clinical trails in HCC patients with Child-Pugh liver function class A or B who have been treated with EBRT.…”

Let-7c Governs the Acquisition of Chemo- or Radioresistance and Epithelial-to-Mesenchymal Transition Phenotypes in Docetaxel-Resistant Lung Adenocarcinoma

“…Tumor volumes were calculated by using the equation: V ¼ A Â B 2 /2 (mm 3 ), wherein A is the largest diameter and B is the perpendicular diameter. When the average tumor size reached about 50 mm 3 , docetaxel was given through intraperitoneal injection with a concentration of 1.0 mg/kg, 1 dose every other day with 3 doses totally. After 5 weeks, all mice were killed, and necropsies were carried out.…”

“…However, due to development of resistance to chemo-or radiotherapy, the prognosis of patients with LAD still remains poor. Chemotherapy-or radiotherapyinduced epithelial-to-mesenchymal transition (EMT) in tumor cells has been linked to chemo-or radiotherapeutic resistance (3)(4)(5). Therefore, a better understanding of the nature of chemoradiotherapy resistance and the molecular mechanisms that govern chemotherapy-induced EMT in LAD could lead to exploration of novel molecular targets.…”

The mutually regulatory loop of epithelial–mesenchymal transition and immunosuppression in cancer progression

“…1 For example, an increasing number of studies suggest that radiotherapy and chemotherapy induce an epithelialmesenchymal transition (EMT), and that the mesenchymal tumor cells have stem cell properties, including resistance to killing by chemotherapeutics and radiotherapy. 2,3 Immunotherapies can also create selective pressures that lead to outgrowth of resistant tumor cells through immunoediting. 1 Obviously, the interplay between tumor cells and immune cells is a common feature during tumor progression and therapy resistance, but its biological basis has remained obscure.…”