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Because most previous data on proton therapy for hepatocellular carcinoma (HCC) were retrospectively collected from inoperable or previously treated cases, our aim was to evaluate the outcome of image-guided proton therapy (IGPT) for operable or radiofrequency ablation–treatable primary HCC.
Our purpose was to evaluate the accuracy of LI-RADS Treatment Response Algorithm (LR-TRA) for assessing the viability of hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT), using explant pathology as the gold standard.
To develop a comprehensive framework to simulate the response to immune checkpoint inhibitors (ICIs) in combination with radiation therapy (RT) and to apply the framework for investigating ICI-RT combination regimen in patients with hepatocellular carcinoma (HCC).
Highlights: • ST-OMVs is a promising antitumor monotherapy or as an adjuvant to chemotherapies. • ST-OMVs downregulated Ki-67 and upregulated CD49b immune-expression. • ST-OMVs downregulated angiogenesis by inhibiting VEGF gene expression. • ST-OMVs increased tumor cells apoptosis and autophagy (increased caspase-3and Beclin1). Nano-sized Gram-negative bacterial outer membrane vesicles possess unique structural and immunostimulatory effects that could be exploited to regress tumors by alerting the host immune system and reversing the immunosuppressive tumor microenvironment. The current study was conducted to investigate the antitumor activity of the outer membrane vesicles (ST-OMVs) of Salmonella Typhimurium ATCC 14028, in vitro in human colorectal carcinoma (HTC116), breast cancer (MCF-7), and hepatocellular carcinoma (HepG2) cell lines and in vivo in Ehrlich solid carcinoma-bearing mice model either as a mono-immunotherapy or as an adjuvant to a commonly used conventional chemotherapy. In addition, we investigated the safety of ST-OMVs. Adult Swiss albino female mice with transplanted Ehrlich solid carcinoma were treated with either ST-OMVs, paclitaxel or a combination of both. Tumor volume, growth inhibition rate, quantitative RT-PCR of Bax and VEGF genes expression, histopathology and immune-expression of caspase-3, Beclin-1, CD49b and Ki-67 were all analyzed. Our results showed that ST-OMVs significantly decreased tumor volume, significantly increased tumor growth inhibition rate, up-regulated the immunohistochemical expression of caspase-3, Beclin-1, and CD49b (enhanced recruitment of NK cells). Furthermore, ST-OMVs down-regulated the expression of Ki-67, increased Bax gene expression and decreased VEGF gene expression as detected by qRT-PCR analysis. Histologically, ST-OMVs promoted apoptosis, decreased tumor invasion and mitotic activities. Moreover, ST-OMVs showed a remarkable cytotoxic activity in various investigated in vitro cancer cell lines. Our findings demonstrate potential antitumor activity of ST-OMVs that might be used as a promising safe antitumor immunotherapy or an adjuvant to conventional chemotherapeutic drugs, resolving some of their problems.
Highlights: • DAZAP1 effectively promotes HCC progression. • DAZAP1 negatively regulates ferroptosis in HCC cells. • DAZAP1 interacts with SLC7A11 mRNA, and positively regulates its stability. RNA-binding proteins (RBPs) closely regulate the whole lifecycle of most RNA molecules, from the very early stage of transcription to RNA decay. Dysregulation of RBPs significantly affects the fate of cancer-related transcripts. Therefore, it is imperative to fully understand the complicated RBP-RNA regulatory networks in malignant diseases and to explore novel therapeutic targets. The RBP DAZAP1 (deleted in azoospermia-associated protein 1), originally identified as an important protein in spermatogenesis, had rarely been studied in the context of carcinogenesis. The role of DAZAP1 in hepatocellular carcinoma (HCC) was unveiled in this study. The relative expression of DAZAP1 was significantly upregulated in HCC and was positively associated with several key malignant characteristics and poor postoperative survival in patients. DAZAP1 knockdown by small interfering RNA markedly inhibited HCC cell proliferation, migration and invasion. Furthermore, DAZAP1 significantly reduced cellular sensitivity to sorafenib (SF), which had been proven to be an inducer of ferroptosis by targeting the system Xc{sup −} (composed of a light chain, xCT/SLC7A11, and a heavy chain, 4F2 heavy chain). At the mechanistic level, DAZAP1 was identified as a potent inhibitor of ferroptosis and an efficient binding partner of SLC7A11 mRNA. Further study revealed that DAZAP1 interacted with the 3′UTR (untranslated region) of SLC7A11 mRNA and positively regulated its stability. In our work, we clarified novel functions of DAZAP1 and preliminarily revealed its underlying mechanism in ferroptosis, which may be conducive to the exploration of biomarkers and therapeutic targets in HCC patients.
Highlights: • Low USP46 level is correlated with poor prognosis in HCC. • USP46 suppresses the proliferation and metastasis of HCC. • USP46 suppress the progression of HCC by inhibiting the expression of YAP1. • MST1 mediates the regulation of USP46 on YAP1. • USP46 stabilized MST1 protein through inhibiting its ubiquitination and degradation. The deubiquitinating enzyme USP46 (ubiquitin-specific protease 46) is implicated in various cancers. However, its role and regulatory mechanism in HCC (hepatocellular carcinoma) are still unknown. In this study, we showed that USP46 is downregulated in HCC tissues and that low USP46 levels are associated with poor prognosis in HCC patients. In functional experiments, overexpression of USP46 impaired proliferation and metastasis of HCC cells, whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo. Furthermore, we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1. Ectopic expression of YAP1 rescued the inhibition of cell proliferation and metastasis caused by USP46 overexpression. Mechanistically, USP46 promotes the degradation of YAP1 by increasing expression of MST1, and the increase in MST1 protein antagonizes YAP1 to suppress HCC progression. Finally, we demonstrated that USP46 stabilizes the MST1 protein by directly binding to it and decreasing its ubiquitination. Taken together, our results demonstrated that USP46 may be a novel tumor suppressor in HCC. Moreover, USP46 acts as a deubiquitinating enzyme of MST1 to potentiate MST1 kinase activity to suppress tumor growth and metastasis, indicating that USP46 activation may represent a potential treatment strategy for HCC.
Aberrant activation of Hedgehog-Gli1 signaling and accumulation of Gli1 in hepatocellular carcinoma (HCC) are frequently observed. However, the mechanisms leading to the overactivation of this signaling pathway are not fully understood. In this study, we show that the short isoform of PHD finger protein 19 (PHF19) interacts with β-TrCP, the E3 ligase of Gli1, and that knocking down PHF19 promotes the ubiquitination of Gli1. In a biological function study, PHF19 was found to promote the growth of HCC cells both in liquid culture and in soft agar. Moreover, knocking out PHF19 in a HCC mouse model (Myc{sup F/F}) using the hydrodynamic method inhibited tumorigenesis and improved survival. Taken together, these results demonstrate that PHF19 promotes the growth of HCC cells by activating the Hedgehog signaling pathway.
Highlights: • BRD9 is up-regulated in HCC and correlated with poor prognosis. • BRD9 promotes the proliferation, cell cycle progression, and inhibited apoptosis of HCC cells. • BRD9 promotes HCC progression by activating the Wnt/β-catenin signaling pathway. • The roles of BRD9 in the above functions and pathways in HCC are supported by bioinformatics analysis. Epigenetic dysregulation participates in the initiation and progression of hepatocellular carcinoma (HCC). Bromodomain-containing protein 9 (BRD9) can identify acetylated lysine residues, contributing to several cancers. The function and molecular mechanism of BRD9 in HCC remain poorly understood.
Highlights: • PFKP levels were higher in HCC as compared to normal hepatic tissues. • Silencing PFKP decreased HCC proliferation and stemness markers' levels. • Overexpression of PFKP enhances HCC proliferation and stemness markers' levels. • PFKP might be a potential therapeutic target for HCC treatment. Glycolysis reprogramming is deeply involved in the progression of hepatocellular carcinoma (HCC), in which HCC cells with stemness traits play important roles as well. Thus, whether platelet isoform of phosphofructokinase 1 (PFKP), a rate-limiting enzyme in glycolysis, contributes to the maintenance of stemness of HCC cells is worth investigation.
Highlights: • AC104958.2 is a novel lncRNA identified to be upregulated in HCC tissues and associated with MVI. • Knockout of AC104958.2 inhibited cell proliferation, invasion, migration and EMT. • AC104958.2 interacted with PCBP2. • PCBP2 was upregulated in HCC and enhanced the RNA stability of AC104958.2. Long non-coding RNAs (lncRNAs) were reported to be involved in tumorigenesis and progression of hepatocellular carcinoma (HCC). Microvascular invasion (MVI) is an independent predictor for early recurrence and overall survival in postoperative patients with HCC. However, the mechanisms how lncRNAs affect HCC and MVI remain elusive. By RNA sequencing (RNA-seq) in a series of 65 HCC samples and 30 paired adjacent non-tumor liver tissue, we identified a novel lncRNA AC104958.2 that was significantly upregulated in HCC tissues and associated with MVI. Overexpression of AC104958.2 obviously elevated cell viability, metastasis, invasion and epithelial-mesenchymal transition (EMT), while knockout of AC104958.2 mediated by CRISPR/Cas9 technique showed the opposite effects. In addition, the interaction between AC104958.2 and Poly (rC) binding protein 2 (PCBP2) was identified by RNA pull down and mass spectrometry (MS), which was further validated by RNA immunoprecipitation (RIP). PCBP2 was also upregulated in HCC and associated with MVI. High expression of both AC104958.2 and PCBP2 was correlated with tumor size, TNM stage and MVI in HCC. Overexpression of PCBP2 greatly increased the cell viability, metastasis, invasion and EMT. Moreover, actinomycin D assay showed that overexpression of PCBP2 enhanced the RNA stability of AC104958.2. In conclusion, our study showed that a novel lncRNA AC104958.2 exerted oncogenic roles in HCC and might be a promising biomarker and therapeutic target.
Angiogenesis has been certified to account for tumor pathobiology. Circular RNAs (circRNAs) have been demonstrated to be involved in angiogenesis-related diseases, including hepatocellular carcinoma (HCC). Nevertheless, the regulatory roles of most circRNAs remain obscure. This study aims to uncover the function of hsa{sub c}irc{sub 0}004018 on angiogenesis in HCC. Firstly, quantitative real-time RT-PCR (RT-qPCR) analyzed that circ{sub 0}004018 was definitely down-regulated in HCC. Western blot analysis was conducted to detect the protein level of fused protein in sarcoma (FUS) and TIMP metallopeptidase inhibitor 2 (TIMP2). Functional assays were carried out to assess the impacts of circ{sub 0}004018 on HCC. From the experimental results, we found that overexpression of circ{sub 0}004018 significantly inhibited angiogenesis in HCC. The regulatory mechanism of circ{sub 0}004018 in HCC was determined by chromatin immunoprecipitation (ChIP), luciferase reporter assays and RNA immunoprecipitation (RIP) assay. Therefore, we proved that estrogen receptor 1 (ESR1) mediated circ{sub 0}004018 regulated TIMP2 by recruiting FUS. A series of rescue assays verified that circ{sub 0}004018 participated in angiogenesis in HCC via modulating TIMP2. In summary, this paper disclosed that ESR1 activated circ{sub 0}004018 inhibited angiogenesis in HCC via binding to FUS and stabilizing TIMP2 expression.
Highlights: • High Tiam1 expression in HCC is related to the poor prognosis after surgery. • Tiam1 promotes invadopodia formation in HCC cells. • Tiam1-mediated invadopodia formation is regulated by the PI3K/Akt pathway. • PIP2 is an important factor in Tiam1-mediated invadopodia formation. At present, there are still many poorly understood aspects of the mechanisms underlying hepatocellular carcinoma (HCC) invasion and metastasis. Invadopodia are important structures for cancer cell invasion and metastasis. We determined that high T-lymphoma invasion and metastasis 1 (Tiam1) expression is associated with HCC invasion and metastasis and poor patient prognosis after surgery. Gain- and loss-of-function studies confirmed that Tiam1 promotes invadopodia formation in HCC by activating Rac1. A series of biochemical experiments confirmed that this effect is regulated by the PI3K/Akt signaling pathway. We also confirmed that PIP2 facilitates this effect. In summary, these findings reveal that Tiam1 plays an important role in invadopodia formation in HCC.
Highlights: • The expression of HNRNPU is upregulated in hepatocellular carcinoma. • HNRNPU knockdown significantly inhibits HCC cell proliferation. • HNRNPU knockdown induces cell cycle arrest. • HNRNPU regulates CDK2 transcription by directly binding to the CDK2 gene locus. The nuclear matrix-associated protein Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU), also known as SAF-A, is known to maintain active chromatin structure in mouse hepatocytes. However, the functional roles and molecular mechanisms of HNRNPU in the development of hepatocellular carcinoma (HCC) remain largely unknown. Herein, we found that HNRNPU was upregulated in HCC, and the proliferation of HCC cells was inhibited in vitro and in vivo upon HNRNPU knockdown. Moreover, the upregulation of HNRNPU was correlated with poor prognosis in HCC. Mechanistically, HNRNPU bound to the CDK2 gene locus, a key factor in cell cycle regulation, where it was enriched with H3K27 acetylation (H3K27ac), H3K9 acetylation (H3K9ac), and H3K4 mono-methylation (H3K4me1). Furthermore, HNRNPU knockdown reduced the levels of H3K27ac and H3K9ac at the binding site, where the levels of H3K27 tri-methylation (H3K27me3) were increased, eventually leading to the downregulation of CDK2. Collectively, our results provide a new mechanism whereby HNRNPU promotes HCC development by enhancing the transcription of CDK2.
Highlights: • iRFA treatment inhibited cisplatin-induced pyroptosis of HCC cells. • Heat shock protein 70 was involved in the suppression of NLRP3 activation. • iRFA treatment decreased the cisplatin sensitivity of HCC through regulating HSP70. Radiofrequency ablation (RFA) is a common minimally invasive treatment for hepatocellular carcinoma (HCC). Incomplete RFA (iRFA) due to the sub-lethal heat shock challenge of some cell populations leads to the generation of transformed survivor cells with enhanced chemoresistance. However, the underlying mechanism of iRFA on HCCs chemoresistance remains unknown. In the present study, we investigated the effect of iRFA on HCCs sensitivity to cisplatin. Cells treated with the sub-lethal heat shock challenge were used to mimic iRFA treatment in vitro. An orthotopic implantation HCC model was established and also performed iRFA treatment. Flow cytometry, transwell assay, and cell counting kit-8 assay were used to determine the effect of iRFA treatment on cisplatin-induced HCC cell apoptosis, invasion, and cell viability. ELISA and Western blot were used to detect the effect of iRFA treatment on cisplatin-induced HCC cell pyroptosis. We found that iRFA treatment increased the HCC cell proliferation and invasion ability, and inhibited cisplatin-induced pyroptosis. Further experiments showed that iRFA treatment induced upregulation of HSP70, which inhibited the cisplatin-induced NLRP3 inflammasome activation, leading to inhibition of pyroptosis. HSP70 knockdown or NLRP3 overexpression could reverse the effect of iRFA treatment in vitro. In vivo, HSP70 knockdown reversed the chemosensitivity of HCC to cisplatin, which was decreased by iRFA. In conclusion, we demonstrated that iRFA induced drug resistance by HSP70-mediated inhibition of cell pyroptosis in HCC.