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Pigment epithelium-derived factor promotes tumor metastasis through an interaction with laminin receptor in hepatocellular carcinomas.

ABSTRACT: Pigment epithelium-derived factor (PEDF) has complex functions in tumor metastasis, but little is known about the roles of PEDF and its receptors in hepatocellular carcinoma (HCC). Here we found that high expression of PEDF is associated with shorter overall survival in HCC patients. Forced expression of PEDF enhanced HCC cell aggressive behavior in vitro and in vivo, whereas silencing PEDF expression reduced migration and invasion. Furthermore, PEDF expression led to changes in cell morphology and the expression of epithelial-mesenchymal transition (EMT)-related markers via ERK1/2 signaling pathway, including the upregulation of N-cadherin and slug, and the downregulation of E-cadherin in HCC cells. Our results further showed that PEDF could interact with laminin receptor (LR) and LR knockdown attenuated PEDF-induced migration, invasion and the change of EMT-related markers. More importantly, in clinical HCC specimens, we found that PEDF expression was correlated with subcellular localization of LR, and that high expression of PEDF and positive expression of LR predicted a poor prognosis. In conclusion, our results demonstrate a novel functional role of PEDF/LR axis in driving metastasis through ERK1/2-mediated EMT in HCC and provided a promising prognostic marker in HCC.

SUBMITTER: Hou J

PROVIDER: S-EPMC5596550 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale: The peripheral nervous system (PNS) plays an important role in tumor growth and progression. Schwann cells (SCs), the main glia cells of the PNS, augment cancer metastasis in contact-dependent or contact-independent manner in various malignancies. In the present study, we aimed to determine whether interplay between pancreatic cancer cells and SCs via paracrine signaling contributes to cancer progression. Methods: Immunofluorescence analysis was performed to reveal the distribution of SCs in PDAC tissues and to determine the prognostic value and clinicopathological relevance of the level of intra‑tumoral SC markers for patients diagnosed with PDAC. Transwell assays and wound healing assays were carried out to investigate the influence of SC conditioned medium (SCM), SC co‑culture, or co-cultured CM on the migratory and invasive abilities of pancreatic cancer cells. The mechanism of SCs induced cancer cells migration and invasion was confirmed using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assays (ELISAs), western blotting, immunofluorescence, immunohistochemistry, siRNA-mediated gene interference, and an in vivo mouse model. Results: Immunofluorescence analysis of tissue samples revealed that there were two different types of SCs distributed in the tumor microenvironment, the presence of which correlated with several clinicopathological characteristics and overall survival for patients with PDAC. Although SCM had no impact on the motility and invasiveness of tumor cells, both co-cultivation with SCs and co‑cultured CM enhanced pancreatic cancer cell migration and invasion. Mechanistically, SC‑derived Interleukin 6 (IL6), which was induced by co-culture with pancreatic cancer cells, augmented cancer cell migration and invasion by activating STAT3 signaling in cancer cells, while IL6 neutralization or STAT3 downregulation abrogated these effects. Furthermore, Interleukin 1β (IL1β), secreted by tumor cells, activated the nuclear actor (NF)-kappa B pathway in SCs, resulting in increased cytokines production, including IL6, while inhibiting the IL1β-IL1R1 axis led to inactivation of NF-kappa B signaling and downregulated cytokines expression in SCs. Interfering with tumor-neuroglia crosstalk impeded cancer cell dissemination in vivo. Conclusion: Schwann cells were extensively distributed in the PDAC tumor microenvironment and high level of intra-tumoral SC markers could serve as an independent prognostic factor for poor survival of patients with PDAC. The tumor-neuroglia interaction is indispensable for SCs to acquire a tumor-facilitating phenotype. Targeting the tumor-neuroglia interplay might be a promising strategy to treat PDAC.

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Pigment epithelium-derived factor promotes tumor metastasis through an interaction with laminin receptor in hepatocellular carcinomas.

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