Downregulated liver-elevated long intergenic noncoding RNA (LINC02428) is a tumor suppressor that blocks KDM5B/IGF2BP1 positive feedback loop in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses worldwide. Many studies have reported that long noncoding RNAs (lncRNAs) are related to the progression and prognosis of HCC. However, the functions of downregulated liver-elevated (LE) lncRNAs in HCC remain elusive. Here we report the roles and mechanisms of downregulated LE LINC02428 in HCC. Downregulated LE lncRNAs played significant roles in HCC genesis and development. LINC02428 was upregulated in liver tissues compared with other normal tissues and showed low expression in HCC. The low expression of LINC02428 was attributed to poor HCC prognosis. Overexpressed LINC02428 suppressed the proliferation and metastasis of HCC in vitro and in vivo. LINC02428 was predominantly located in the cytoplasm and bound to insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) to prevent it from binding to lysine demethylase 5B (KDM5B) mRNA, which decreased the stability of KDM5B mRNA. KDM5B was found to preferentially bind to the promoter region of IGF2BP1 to upregulate its transcription. Therefore, LINC02428 interrupts the KDM5B/IGF2BP1 positive feedback loops to inhibit HCC progression. The KDM5B/IGF2BP1 positive feedback loop is involved in tumorigenesis and progression of HCC.

Multifunctional Nanoplatform Based on Sunitinib for Synergistic Phototherapy and Molecular Targeted Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a tumor that poses a serious threat to human health, with an extremely low five-year survival rate due to its difficulty in early diagnosis and insensitivity to radiotherapy and chemotherapy. To improve the therapeutic efficiency of HCC, we developed a novel multifunctional nanoplatform (SCF NPs) with an amphiphilic polymer (Ce6-PEG2000-FA) and a multitarget tyrosine kinase inhibitor sunitinib. SCF NPs showed superior therapeutical efficiency for HCC due to the synergetic effect of molecular targeted therapy and phototherapy. The Ce6-PEG2000-FA not only serves as a nanocarrier with excellent biocompatibility but also can act as a therapeutic reagent for photothermal therapy (PTT) and photodynamic therapy (PDT). Furthermore, the folic acid group of Ce6-PEG2000-FA enhanced the active targeting performance of SCF NPs. As a multitargeted tyrosine kinase inhibitor, sunitinib in SCF NPs can play a role in molecular targeted therapies, including tumor growth inhibition and anti-angiogenesis. In vivo experiments, SCF NPs showed multimode imaging capabilities, which can be used for tumorous diagnosis and intraoperative navigation. Meanwhile, SCF NPs showed outstanding synergetic tumor inhibition ability. Tumors of SCF NPs group with laser radiation were eradicated without any recrudescence after 14 days of treatment. Such theranostic nanoparticles offer a novel therapeutic tactic for HCC.

Risk factors and predictive nomograms for early death of patients with pancreatic cancer liver metastasis: A large cohort study based on the SEER database and Chinese population.

Background: The liver is the most common organ for distant metastasis of pancreatic cancer, and patients with pancreatic cancer liver metastases (PCLM) often die in a short period of time. As such, the establishment of an effective nomogram to predict the probability of early death (survival time ≤3 months) in PCLM patients is of considerable significance. Methods: Patients diagnosed with PCLM in the Surveillance, Epidemiology, and End Result (SEER) database between 2010 and 2015 were included for model construction and internal validation. A data set was obtained from the Chinese population for external validation. Risk factors that contributed to all-cause and cancer-specific early death were determined by means of univariable and multivariable logistic regression. The accuracy of the nomogram was verified by means of receiver operating characteristic (ROC) curves, and the true consistency of the model was assessed by calibration curves. The clinical applicability of the model was evaluated by means of decision curve analysis (DCA). Results: A total of 12,955 patients were included in the present study, of whom 7,219 (55.7%) experienced early death and 6,973 (53.8%) patients died of PCLM. Through multivariable logistic regression analysis, 11 risk factors associated with all-cause early death and 12 risk factors associated with cancer-specific early death were identified. The area under the curves (AUCs) for all-cause and cancer-specific early death were 0.806 (95% CI: 0.785- 0.827) and 0.808 (95% CI: 0.787- 0.829), respectively. Internal validation showed that the C-indexes of all-cause and cancer-specific early death after bootstrapping (5,000 re-samplings) were 0.805 (95% CI: 0.784-0.826) and 0.807 (95% CI: 0.786-0.828), respectively. As revealed by the calibration curves, the constructed nomograms exhibited good consistency. The decision curve analysis (DCA) indicated the nomograms had significant clinical applicability. Conclusion: In the present study, reliable nomograms were developed for predicting the early death probability in patients with PCLM. Such tools can help clinicians identify high-risk patients and develop individualized treatment plans as early as possible.

RAB6B is a potential prognostic marker and correlated with the remolding of tumor immune microenvironment in hepatocellular carcinoma.

Backgrounds: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the second leading cause of death among all cancers. The Ras-associated binding (Rab) proteins constitute the largest family of the Ras superfamily of small GTPases, which mainly mediate membrane trafficking processes. RAB6B is a member of Rab GTPases, and it has been found to be dysregulated in various tumors. However, the clinical significance, correlations with immune cells, and stroma infiltration of RAB6B in HCC remain unclear. Methods: RAB6B mRNA and protein expression in HCC were examined using the TIMER, HCCDB, UALCAN, and HPA databases. The genetic alterations of RAB6B were analyzed by cBioPortal and COSMIC databases. The correlations between RAB6B and tumor-infiltrating immune cells and cancer-associated fibroblasts were explored by using TIMER, TISIDB, and GEPIA databases. Co-expression networks of RAB6B were investigated based on LinkedOmics. Drug sensitivity was analyzed through the GDSC and CTRP databases. RAB6B was knocked down with siRNA in HCC cell lines. EdU assay was performed to detect the cell proliferation ability, flow cytometry was used to compare the differences in the ability of apoptosis, and MTT was used to evaluate the drug sensitivity in vitro. Results: RAB6B mRNA and protein expression were upregulated in the HCC tissues. Kaplan-Meier and Cox regression analyses suggested that highly expressed RAB6B was an independent prognostic factor for poor survival in HCC patients. Moreover, we found that RAB6B expression was positively correlated with the infiltration of immune cells in HCC, including some immunosuppressive cells, chemokines, and receptors, meanwhile RAB6B expression was associated with CD8+T cells exhaustion, resulting in an immunosuppressive microenvironment. Additionally, functional enrichment analysis indicated that RAB6B may be involved in ECM remodeling in the TME, and RAB6B expression was positively associated with CAFs infiltration. Furthermore, RAB6B presented a positive association with sensitivity to GDSC and CTRP drugs. RAB6B knockdown inhibited the cell proliferation and promoted apoptosis and sensitivity to cisplatin of HCC cells in vitro. Conclusion: Our study revealed that RAB6B is a potential biomarker for poor prognosis in HCC patients and correlates with the formation of the immunosuppressive microenvironment in HCC.

Risk factors and predictive nomograms for early death of patients with advanced hepatocellular carcinoma: a large retrospective study based on the SEER database.

BACKGROUND: Hepatocellular carcinoma (HCC) is a kind of tumor with high invasiveness, and patients with advanced HCC have a higher risk of early death. The aim of the present study was to identify the risk factors of early death in patients with advanced HCC and establish predictive nomograms. METHODS: Death that occurred within 3 months of initial diagnosis is defined as early death. Patients diagnosed with stage IV HCC between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results database for model establishment and verification. Univariable and multivariable logistic regression analyses were used to identify the risk factors. Predictive nomograms were constructed and an internal validation was performed. Decision curve analysis (DCA) was used to verify the true clinical application value of the models. RESULTS: Of 6603 patients (57% age > 60, 81% male, 70% white, 46% married), 21% and 79% had stage IVA and IVB, respectively. On the multivariable analyses, risk factors for early deaths in patients with stage IVA were age, tumor size, histological grade, alpha-fetoprotein (AFP), fibrosis score, tumor stage (T stage), surgery, radiotherapy, and chemotherapy, and that in stage IVB were age, histological grade, AFP, T stage, node stage (N stage), bone metastasis, lung metastasis, surgery, radiotherapy, and chemotherapy. The areas under the curves (AUCs) were 0.830 (95% CI 0.809-0.851) and 0.789 (95% CI 0.768-0.810) in stage IVA and IVB, respectively. Nomograms comprising risk factors with the concordance indexes (C-indexes) were 0.820 (95% CI 0.799-0.841) in stage IVA and 0.785 (95% CI 0.764-0.0.806) in stage IVB for internal validation (Bootstrapping, 1000re-samplings). The calibration plots of the nomograms show that the predicted early death was consistent with the actual value. The results of the DCA analysis show that the nomograms had a good clinical application. CONCLUSION: The nomograms can be beneficial for clinicians in identifying the risk factors for early death of patients with advanced HCC and predicting the probability of early death, so as to allow for individualized treatment plans to be accurately selected.

RAB42 is a Potential Biomarker that Correlates With Immune Infiltration in Hepatocellular Carcinoma.

Backgrounds: Hepatocellular carcinoma (HCC) is a malignant cancer with high mortality. Previous studies have reported that RAB42 is associated with prognosis and progression in glioma. However, the role of RAB42 in HCC is still unknown. Therefore, we aimed to elucidate the value of RAB42 in the predicting prognosis of HCC, and its relationship with immune cells infiltration. Methods: UALCAN, HCCDB, and MethSurv databases were used to examine the expression and methylation levels of RAB42 in HCC and normal samples. cBioPortal and MethSurv were used to identify genetic alterations and DNA methylation of RAB42, and their effect on prognosis. The correlations between RAB42 and the immune cells and cancer-associated fibroblasts infiltration were analyzed by TIMER, TISIDB, and GEPIA database. The LinkedOmics database was used to analyze the enriched pathways associated with genes co-expressed with RAB42. EdU assay was used to evaluate the proliferation ability of liver cancer cells, and transwell assay was used to detect the invasion and migration ability of liver cancer cells. Results: The expression levels of RAB42 were increased in HCC tissues than that in normal tissues. Highly expressed RAB42 was significantly correlated with several clinical parameters of HCC patients. Moreover, increased RAB42 expression clearly predicted poor prognosis in HCC. Furthermore, multivariate Cox regression analysis showed that RAB42 was an independent prognostic factor in HCC. The RAB42 genetic alteration rate was 5%. RAB42 DNA methylation in HCC tissues was lower than that in normal tissues. Among the 7 DNA methylation CpG sites, two were related to the prognosis of HCC. The results of gene set enrichment analysis (GSEA) showed that RAB42 was associated with various immune cells and cancer-associated fibroblasts infiltration in HCC. Meanwhile, we found RAB42 methylation was strongly correlated with immune infiltration levels, immunomodulators, and chemokines. Experiments in vitro indicated that knockdown of RAB42 inhibited the proliferation, invasion, and migration of liver cancer cells. Conclusions: Our study highlights the clinical importance of RAB42 in HCC and explores the effect of RAB42 on immune infiltration in the tumor microenvironment, and RAB42 may act as a pro-oncogene that promotes HCC progression.

Emerging treatment modalities for systemic therapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has long been a major global clinical problem as one of the most common malignant tumours with a high rate of recurrence and mortality. Although potentially curative therapies are available for the early and intermediate stages, the treatment of patients with advanced HCC remains to be resolved. Fortunately, the past few years have shown the emergence of successful systemic therapies to treat HCC. At the molecular level, HCC is a heterogeneous disease, and current research on the molecular characteristics of HCC has revealed numerous therapeutic targets. Targeted agents based on signalling molecules have been successfully supported in clinical trials, and molecular targeted therapy has already become a milestone for disease management in patients with HCC. Immunotherapy, a viable approach for the treatment of HCC, recognizes the antigens expressed by the tumour and treats the tumour using the immune system of the host, making it both selective and specific. In addition, the pipeline for HCC is evolving towards combination therapies with promising clinical outcomes. More drugs designed to focus on specific pathways and immune checkpoints are being developed in the clinic. It has been demonstrated that some drugs can improve the prognosis of patients with HCC in first- or second-line settings, and these drugs have been approved by the Food and Drug Administration or are nearing approval. This review describes targeting pathways and systemic treatment strategies in HCC and summarizes effective targeted and immune-based drugs for patients with HCC and the problems encountered.

pH-Responsive Pluronic F127-Lenvatinib-Encapsulated Halogenated Boron-Dipyrromethene Nanoparticles for Combined Photodynamic Therapy and Chemotherapy of Liver Cancer.

Combination therapy such as photodynamic therapy (PDT)-enhanced chemotherapy is regarded as a promising strategy for cancer treatment. Boron-dipyrromethene (BODIPY), as close relatives of porphyrins, was widely used in PDT. However, poor water solubility, rapid metabolism by the body and lack of targeting limits its clinical application. Lenvatinib, as the first-line drug for molecular-targeted therapy of liver cancer, restricted its clinical application for its side effects. Herein, to achieve the synergy between PDT and chemotherapy, we synthesized two halogenated BODIPY, BDPBr2 and BDPCl2, which were prepared into self-assembly nanoparticles with lenvatinib, and were encapsulated with Pluronic F127 through the nanoprecipitation method, namely, LBPNPs (LBBr2 NPs and LBCl2 NPs). The fluorescence quantum yields of LBPNPs were 0.73 and 0.71, respectively. The calculated loading rates of lenvatinib for LBBr2 NPs and LBCl2 NPs were 11.8 and 10.2%, respectively. LBPNPs can be hydrolyzed under weakly acidic conditions (pH 5.0) to generate reactive oxygen species (ROS), and the release rate of lenvatinib reached 88.5 and 82.4%. Additionally, LBPNPs can be effectively taken up by Hep3B and Huh7 liver cancer cells, releasing halogenated BODIPY and lenvatinib in the acidic environment of tumor cells to enhance the targeting performance of chemotherapeutics. Compared with free lenvatinib and separate halogenated BODIPY, LBPNPs can inhibit tumor growth more effectively through pH-responsive chemo/photodynamic synergistic therapy and significantly promote the cascade of caspase apoptotic protease. This study shows that LBPNPs can be a promising nanotheranostic agent for synergetic chemo/photodynamic liver cancer therapy.

Integrated Analysis of Immunity- and Ferroptosis-Related Biomarker Signatures to Improve the Prognosis Prediction of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses around the world. Ferroptosis is a new form of cell death, and some studies have found that it is related to cancer immunotherapy. The aim of our research was to find immunity- and ferroptosis-related biomarkers to improve the treatment and prognosis of HCC by bioinformatics analysis. METHODS: First, we obtained the original RNA sequencing (RNA-seq) expression data and corresponding clinical data of HCC from The Cancer Genome Atlas (TGCA) database and performed differential analysis. Second, we used immunity- and ferroptosis-related differentially expressed genes (DEGs) to perform a computational difference algorithm and Cox regression analysis. Third, we explored the potential molecular mechanisms and properties of immunity- and ferroptosis-related DEGs by computational biology and performed a new prognostic index based on immunity- and ferroptosis-related DEGs by multivariable Cox analysis. Finally, we used HCC data from International Cancer Genome Consortium (ICGC) data to perform validation. RESULTS: We obtained 31 immunity (p < 0.001)- and 14 ferroptosis (p < 0.05)-related DEGs correlated with overall survival (OS) in the univariate Cox regression analysis. Then, we screened five immunity- and two ferroptosis-related DEGs (HSPA4, ISG20L2, NRAS, IL17D, NDRG1, ACSL4, and G6PD) to establish a predictive model by multivariate Cox regression analysis. Receiver operating characteristic (ROC) and Kaplan-Meier (K-M) analyses demonstrated a good performance of the seven-biomarker signature. Functional enrichment analysis including Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the seven-biomarker signature was mainly associated with HCC-related biological processes such as nuclear division and the cell cycle, and the immune status was different between the two risk groups. CONCLUSION: Our results suggest that this specific seven-biomarker signature may be clinically useful in the prediction of HCC prognoses beyond conventional clinicopathological factors. Moreover, it also brings us new insights into the molecular mechanisms of HCC.