Abstract
PurposeRadiofrequency ablation (RFA) therapy has proven to be effective and feasible for early-stage hepatocellular carcinoma (HCC); however, rapid progression of residual tumor cells after RFA has been confirmed, but the molecular mechanisms of this phenomenon are poorly understood. This study evaluated the effect of the lipid raft proteins known as flotillins on the invasive and metastatic potential of residual HCC.MethodsThe human HCC cell line HCCLM3 was used to establish insufficient RFA models in vivo and in vitro. Changes in cellular morphology, soft agar colony formation, motility, metastasis, and epithelial–mesenchymal transition (EMT) markers after insufficient RFA intervention in vitro and in vivo were detected by real-time PCR, western blotting, immunohistochemistry and transwell assays.ResultsThe results showed that flotillin-1 and flotillin-2 expression were upregulated in HCCLM3 cells following 45 °C heat treatment and in residual HCCLM3 xenografts cells after insufficient RFA. Knocking down flotillin-1 or flotillin-2 in HCCLM3 cells by shRNA significantly lowered insufficient RFA-induced tumor growth, EMT changes, and metastasis in vitro and in vivo. Furthermore, mechanism studies indicated that flotillins altered the EMT status and metastatic potential of heat-treated HCCLM3 cells by activating the Akt/Wnt/β-catenin signaling pathway.ConclusionsOur findings present new evidence that flotillins play a key role in the aggressive behaviors of residual cancer cells after insufficient RFA and provide new insights into the regulatory mechanism of Wnt/β-catenin signaling.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths worldwide (Siegel et al 2015)
Western blot results showed that FLOT1 and FLOT2 were significantly upregulated in heat-treated cells compared with the control group, especially at 45 °C for HCCLM3 cells
FLOT1 and FLOT2 expression were similar in heat-treated and control HepG2 cells (Fig. 1). Consistent with these in vitro results, western blot (Fig. 2a), RT-qPCR (Fig. 2b) and immunohistochemistry (Fig. 2c, d) results demonstrated that both FLOT1 and FLOT2 were significantly upregulated in insufficient Radiofrequency ablation (RFA)-treated HCCLM3 tumors compared with controls
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths worldwide (Siegel et al 2015). A variety of therapies such as surgical resection, liver transplantation, interventional treatment, and systemic therapies are employed, HCC patients have low 5-year survival rates and high recurrence rates due to invasion and metastasis (Au and Frenette 2015; Forner et al 2012; Schlachterman et al 2015). A better understanding of the molecular mechanisms that regulate HCC invasion and metastasis is essential for developing novel prognostic and of therapeutic strategies for HCC. Journal of Cancer Research and Clinical Oncology (2019) 145:895–907 et al 2018). Local recurrences after RFA show more invasive growth and vascular invasion, and less differentiation compared with tumors from patients without RFA. The underlying mechanisms behind this phenomenon were still less unknown
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