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Sublethal irradiation promotes the metastatic potential of hepatocellular carcinoma cells.

ABSTRACT: Radiotherapy (RT) represents one of the major treatment methods for cancers. However, many studies have observed that in descendant surviving tumor cells, sublethal irradiation can promote metastatic ability, which is closely related to the tumor microenvironment. We therefore investigated the functions and mechanisms of sublethal irradiated liver nonparenchymal cells (NPCs) in hepatocellular carcinoma (HCC). In this study, primary rat NPCs and McA-RH7777 hepatoma cells were irradiated with 6 Gy X-ray. Conditioned media (CM) from nonirradiated (SnonR), irradiated (SR), or irradiated plus radiosensitizer celecoxib-treated (S[R + D]) NPCs were collected and added to sublethal irradiated McA-RH7777 cells. We showed that CM from sublethal irradiated NPCs significantly promoted the migration and invasion ability of sublethal irradiated McA-RH7777 cells, which was reversed by celecoxib. The differentially expressed genes in differently treated McA-RH7777 cells were enriched mostly in the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. SR increased the migration and invasion ability of HCC cells by inhibiting AMPK/mTOR signaling, which was enhanced by the AMPK inhibitor compound C and blocked by the AMPK activator GSK-621. Analyses of HCC tissues after neoadjuvant radiotherapy confirmed the effects of radiation on the AMPK/mTOR pathway. Cytokine antibody arrays and further functional investigations showed that matrix metalloproteinase-8 (MMP-8) partly mediates the promotion effects of SR on the migration and invasion ability of HCC cells by regulating AMPK/mTOR signaling. In summary, our data indicate that MMP-8 secreted by irradiated NPCs enhanced the migration and invasion of HCC by regulating AMPK/mTOR signaling, revealing a novel mechanism mediating sublethal irradiation-induced HCC metastasis at the level of the tumor microenvironment.

SUBMITTER: Cao Y

PROVIDER: S-EPMC7780048 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Sublethal irradiation promotes the metastatic potential of hepatocellular carcinoma cells.

Cao Yulin Y Yin Yuan Y Wang Xue X Wu Zhifeng Z Liu Yuhang Y Zhang Fuzheng F Lin Junhua J Huang Zhaohui Z Zhou Leyuan L

Cancer science 20201129 1

Radiotherapy (RT) represents one of the major treatment methods for cancers. However, many studies have observed that in descendant surviving tumor cells, sublethal irradiation can promote metastatic ability, which is closely related to the tumor microenvironment. We therefore investigated the functions and mechanisms of sublethal irradiated liver nonparenchymal cells (NPCs) in hepatocellular carcinoma (HCC). In this study, primary rat NPCs and McA-RH7777 hepatoma cells were irradiated with 6 Gy ...[more]

PMID: 33155388

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Project description:To investigate the function of Pea3 in colorectal carcinoma (CRC) invasion and metastatic potential.The expression of Pea3 during clinical progression of human CRC was investigated using Oncomine Research Edition. To assay Pea3 expression in established CRC cell lines, we performed western blotting of cell lysates. We employed shRNA-mediated knockdown of Pea3 in HCT116 (HCT) and LS174T CRC cells which was confirmed by real-time quantitative PCR (qPCR) and western blotting. Transwell invasion assays, MTS proliferation assays, anoikis assays, and fluorometric matrix metalloprotease (MMP) assays were performed to determine the effects of Pea3 knockdown on invasion, proliferation, anoikis and MMP activity in CRC cells in vitro. Alterations in epithelial-mesenchymal transition (EMT) and matrix metalloprotease (MMP) mRNA levels were determined by qPCR. CRC cells were injected into the flanks of nude mice to generate xenografts and tumor growth monitored with serial calliper measurements. To assay metastatic potential, CRC cells were injected into the spleen of nude mice, and histological analysis performed on the livers 21 d later.We demonstrated that reduction of Pea3 expression in CRC cells significantly impaired their invasive capacity (HCT.shPea3, 0.28 ± 0.04 fold, P < 0.01; LS.shPea3, 0.15 ± 0.04 fold; SW.shPea3, 0.23 ± 0.03, P < 0.01), reduced anoikis resistance (HCT.shPea3 75.4% ± 1.9% viable cells vs HCT.shCtrl 88.6% ± 0.6% viable cells, P < 0.01; LS.shPea3 71.7% ± 0.5% viable cells vs LS.Ctrl 89.6% ± 0.3% viable cells, P < 0.005, but had no effect on proliferation (HCT.shCtrl AUC 5098 ± 123 vs HCT.shPea3 5689 ± 151, P < 0.05; LS.shCtrl AUC 5600 ± 324.1 vs LS.shPea3 6423 ± 400, P < 0.05). In vivo, HCT.shPea3 and HCT.shCtrl tumour xenografts grew at a similar rate (HCT.shPea3 2.64 ± 0.82 fold vs HCT.shCtrl 2.88 ± 0.80 fold, P > 0.05). In keeping with a pro-metastatic function for Pea3 in CRC, several EMT markers and MMPs were downregulated in shPea3-expressing cells, suggesting that Pea3 may exert its effects through these processes. A reduction in overall MMP activity was observed in HCT.shPea3 cells compared to their control counterparts (HCT.shPea3 0.61 ± 0.04 fold, P < 0.005). This translated in vivo to the complete absence of metastases in the livers of mice that were grafted with CRC cells lacking Pea3. Conversely, CRC cells expressing Pea3 formed liver metastases in all mice.Our study implicates Pea3 as a mediator of metastases, and provides a biological rationale for the adverse prognosis associated with elevated Pea3 expression in human CRC.

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Sublethal irradiation promotes the metastatic potential of hepatocellular carcinoma cells.

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Sublethal irradiation promotes the metastatic potential of hepatocellular carcinoma cells.

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