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Exosome-transferred long non-coding RNA ASMTL-AS1 contributes to malignant phenotypes in residual hepatocellular carcinoma after insufficient radiofrequency ablation.

ABSTRACT: OBJECTIVES:Long non-coding RNAs (lncRNAs) are emerging RNA regulators in cancer progression, including in hepatocellular carcinoma (HCC). Recently, insufficient radiofrequency ablation (RFA) has been reported to lead to recurrence and metastasis of residual HCC tumours. Herein, we aimed to the role of ASMTL-AS1 in residual HCC after insufficient RFA. MATERIALS AND METHODS:In vitro insufficient RFA model was simulated in Huh7 cells and subsequently named Huh7-H cells. In vitro and in vivo assays were conducted to investigate ASMTL-AS1 function in HCC. RESULTS:LncRNA ASMTL-AS1 low expressed in normal human liver was found to be highly expressed in HCC tissues and further increased in tumours after insufficient RFA. ASMTL-AS1 expression was related to stage, metastasis and prognosis in HCC. Huh7-H possessed higher ASMTL-AS1 level and more aggressive than Huh7 cells. ASMTL-AS1 contributed to the malignancy of HCC cells both in vitro and in vivo. Mechanistically, ASMTL-AS1 was trans-activated by MYC and promoted NLK expression to activate YAP signalling via sequestering miR-342-3p in HCC. Interestingly, ASMTL-AS1 could be wrapped by exosomes and then convey malignancy through NLK/YAP axis between cells even in residual HCC after insufficient RFA. CONCLUSIONS:Exosomal ASMTL-AS1 aggravates the malignancy in residual HCC after insufficient RFA via miR-342-3p/NLK/YAP signalling, opening a new road for the treatment of HCC and the prevention of recurrence or metastasis of residual HCC after insufficient RFA.

SUBMITTER: Ma D

PROVIDER: S-EPMC7507479 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Exosome-transferred long non-coding RNA ASMTL-AS1 contributes to malignant phenotypes in residual hepatocellular carcinoma after insufficient radiofrequency ablation.

Ma Dening D Gao Xinyi X Liu Zhuo Z Lu Xingang X Ju Haixing H Zhang Ning N

Cell proliferation 20200728 9

<h4>Objectives</h4>Long non-coding RNAs (lncRNAs) are emerging RNA regulators in cancer progression, including in hepatocellular carcinoma (HCC). Recently, insufficient radiofrequency ablation (RFA) has been reported to lead to recurrence and metastasis of residual HCC tumours. Herein, we aimed to the role of ASMTL-AS1 in residual HCC after insufficient RFA.<h4>Materials and methods</h4>In vitro insufficient RFA model was simulated in Huh7 cells and subsequently named Huh7-H cells. In vitro and ...[more]

PMID: 32722884

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Project description:BackgroundThe mechanism regarding rapid progression of residual hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA) has been preliminarily discussed. However, most studies have mainly focused on RFA-induced changes in the tumor cells. The present study was designed to determine whether tumor-associated endothelial cells (TAECs) could contribute to the invasiveness of HCC after insufficient RFA.MethodsTAECs were isolated from fresh HCC tissue and characterized. Morphological changes were observed in TAECs after heat treatment for 10 min. TAEC proliferation, migration and tube formation after heat treatment for 10 min at 37°C (control group), and 42 and 47°C (insufficient RFA groups) were examined. The differences in TAECs interactions with HepG2-GFP or HCCLM3-GFP cells among the two insufficient RFA groups and control group were evaluated. The expression of E-selectin, ICAM-1 and VCAM-1 in TAECs was measured. The effects of TAECs on the invasiveness of HepG2-GFP or HCCLM3-GFP cells after insufficient RFA were analyzed. The IL-6, IL-8, MCP-1 and GRO-α concentrations in conditioned medium from TAECs were measured after insufficient RFA. The associated signaling pathways of Akt, ERK1/2, STAT3 and NF-κB were analyzed in TAECs after insufficient RFA.ResultsTAECs expressed the EC-specific markers and took up complexes of Dil-Ac-LDL. Relative to the control group, the proliferation of TAECs was significantly inhibited and their migration and tube formation were significantly enhanced in the insufficient RFA groups. Significantly more HepG2-GFP or HCCLM3-GFP cells adhered to TACEs in these groups than in the control group (all P<0.001), via up-regulated expression of E-selectin, ICAM-1 and VCAM-1. TAECs promoted the invasiveness of HepG2-GFP or HCCLM3-GFP cells after insufficient RFA via the up-regulation of IL-6, IL-8, MCP-1 and GRO-α in conditioned medium (all P<0.05). Insufficient RFA enhanced the activities of Akt, ERK1/2 and NF-κB signaling pathways and inhibited STAT3 signaling pathways.ConclusionsInsufficient RFA enhanced TAEC migration and tube formation, and this may play a key role in the rapid growth of residual HCC. Increased expression of metastasis-related molecules in TAECs after insufficient RFA may be a potential mechanism for the metastasis of residual HCC.

Project description:Residual lesions and undetectable metastasis after insufficient radiofrequency ablation (iRFA) are associated with earlier new metastases and poor survival in cancer patients, for induced aggressive tumor phenotype and immunosuppression. Programmed cell death protein 1(PD-1) blockade has been reported to enhance the radiofrequency ablation-elicited antitumor immunity, but its ability to eliminate incompletely ablated residual lesions has been questioned. Here, we report a combined treatment modality post iRFA based on integrating an oxygen self-enriching nanodrug PFH-Ce6 liposome@O2 nanodroplets (PCL@O2)-augmented noninvasive sonodynamic therapy (SDT) with PD-1 blockade. PCL@O2 containing Ce6 as the sonosensitizer and PFH as O2 reservoir, was synthesized as an augmented SDT nanoplatform and showed increased ROS generation to raise effective apoptosis of tumor cells, which also exposed more calreticulin to induce stronger immunogenic cell death (ICD). Combining with PD-1 blockade post iRFA, this optimized SDT induced a better anti-tumor response in MC38 tumor bearing mouse model, which not only arrested residual primary tumor progression, but also inhibited the growth of distant tumor, therefore prolonging the survival. Profiling of immune populations within the tumor draining lymph nodes and tumors further revealed that combination therapy effectively induced ICD, and promoted the maturation of dendritic cells, tumor infiltration of T cells, as well as activation of cytotoxic T lymphocytes. While iRFA alone could result in an increase of regulatory T cells (Tregs) in the residual tumors, SDT plus PD-1 blockade post iRFA reduced the number of Tregs in both primary and distant tumors. Moreover, the combined treatment could significantly initiate long-term immune memory, manifesting as elevated levels of CD8+ and CD4+ central memory cells. Therefore, this study establishes the preclinical proof of concept to apply oxygen self-enriching SDT to augment cancer immunotherapy after iRFA.

Dataset Information

Exosome-transferred long non-coding RNA ASMTL-AS1 contributes to malignant phenotypes in residual hepatocellular carcinoma after insufficient radiofrequency ablation.

Publications

Exosome-transferred long non-coding RNA ASMTL-AS1 contributes to malignant phenotypes in residual hepatocellular carcinoma after insufficient radiofrequency ablation.

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