Strategy For Treatment Of Hepatocellular Carcinoma Research Articles

Glycopolymers Mediate Suicide Gene Therapy in ASGPR-Expressing Hepatocellular Carcinoma Cells in Tandem with Docetaxel.

Cationic glycopolymers stand out as gene delivery nanosystems due to their inherent biocompatibility and high binding affinity to the asialoglycoprotein receptor (ASGPR), a target receptor overexpressed in hepatocellular carcinoma (HCC) cells. However, their synthesis procedure remains laborious and complex, with problems of solubilization and the need for protection/deprotection steps. Here, a mini-library of well-defined poly(2-aminoethyl methacrylate hydrochloride-co-poly(2-lactobionamidoethyl methacrylate) (PAMA-co-PLAMA) glycopolymers was synthesized by activators regenerated by electron transfer (ARGET) ATRP to develop an efficient gene delivery nanosystem. The glycoplexes generated had suitable physicochemical properties and showed high ASGPR specificity and high transfection efficiency. Moreover, the HSV-TK/GCV suicide gene therapy strategy, mediated by PAMA144-co-PLAMA19-based nanocarriers, resulted in high antitumor activity in 2D and 3D culture models of HCC, which was significantly enhanced by the combination with small amounts of docetaxel. Overall, our results demonstrated the potential of primary-amine polymethacrylate-containing-glycopolymers as HCC-targeted suicide gene delivery nanosystems and highlight the importance of combined strategies for HCC treatment.

Therapeutic options in hepatocellular carcinoma: a comprehensive review.

Hepatocellular carcinoma (HCC) is a chronic liver disease that is highly fatal if not detected and treated early. The incidence and death rate of HCC have been increasing in recent decades despite the measures taken for preventive screening and effective diagnostic and treatment strategies. The pathophysiology of HCC is multifactorial and highly complex owing to its molecular and immune heterogeneity, and thus the gap in knowledge still precludes making choices between viable therapeutic options and also the development of effective regimens. The treatment of HCC demands multidisciplinary approaches and primarily depends on tumor stage, hepatic functional reserve, and response to treatment by patients. Although curative treatments are limited but critical in the early stages of cancer, there are numerous palliative treatments available for patients with intermediate and advanced-stage HCC. In recent times, the use of combination therapy has succeeded over the use of monotherapy in the treatment of HCC by achieving effective tumor suppression, increasing survival rate, decreasing toxicity, and also aiding in overcoming drug resistance. This work focuses on reviewing the current and emerging treatment strategies for HCC.

Preoperative Immunotherapy in Hepatocellular Carcinoma: Current State of the Art.

Hepatocellular carcinoma (HCC) is a malignancy that requires multidisciplinary evaluation to develop individualized and tailored treatment concepts. While liver resection and transplantation represent the mainstay of curative treatment in patients with early-stage HCC, disease recurrence remains an important burden. Immune checkpoint inhibitors (ICI) have become standard of care in the palliative setting, achieving promising response rates with overall good tolerability. Accordingly, ICIs are being evaluated in (neo)adjuvant concepts in order to improve survival. Nevertheless, neoadjuvant therapies are not recommended by current guidelines as they have not been proven to improve the outcome in large Phase III trials yet. Especially in the context of liver transplantation (LT), perioperative ICI usage is in need of a particularly critical risk-benefit assessment, as the immunotherapy may significantly increase the risk of rejection. In this review, we summarize available data on ICI-based perioperative treatment strategies in HCC. We discuss current drawbacks and challenges of this treatment concept and specifically highlight the risk of allograft rejection when ICI are given in patients (subsequently) considered for liver transplantation.

FNBP4 is a Potential Biomarker Associated with Cuproptosis and Promotes Tumor Progression in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors that lacks an efficient therapeutic approach because of its elusive molecular mechanisms. This study aimed to investigate the biological function and potential mechanism of formin-binding protein 4 (FNBP4) in HCC. FNBP4 expression in tissues and cells were detected by quantitative real-time PCR (qRT‒PCR), Western blot, and immunohistochemistry (IHC). The Kaplan-Meier method was used to explore the correlation between the FNBP4 expression and clinical survival. MTT, EdU incorporation, colony formation, and Transwell assays were performed to evaluate the function of FNBP4 in cell proliferation and migration in vitro. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to explore the potential mechanism of FNBP4. The prognostic risk signature and nomogram were constructed to demonstrate the prognostic value of FNBP4. We found that FNBP4 was upregulated in patients with HCC and associated with poor overall survival (OS). Furthermore, knockdown of FNBP4 inhibited the proliferation and migration in HCC cells. Then, we performed a KEGG pathway analysis of the coexpressed genes associated with FNBP4 and found that FNBP4 may be associated with tumor-related signaling pathways and cuproptosis. We verified that FNBP4 could cause cell cycle progression and inactivation of the hippo signaling pathway. A prognostic risk signature containing three FNBP4-related differentially expressed cuproptosis regulators (DECRs) was established and can be used as an independent risk factor to evaluate the prognosis of patients with HCC. In addition, a nomogram including a risk score and clinicopathological factors was used to predict patient survival probabilities. FNBP4, as a potential biomarker associated with cuproptosis, promotes HCC cell proliferation and metastasis. We provide a new potential strategy for HCC treatment by targeting FNBP4.

Combining γ-GT, PIVKA-II, and AFP to predict long-term prognosis in patients with hepatocellular carcinoma after hepatectomy.

Hepatocellular carcinoma (HCC) is one of the top five contributors to the cancer burden in China, with a poor prognosis and heavy disability-adjusted life year burden. The criteria used for HCC prognosis are complicated and therefore restricted in routine clinical practice. Multiple factors influence HCC malignancy and progression. In this study, we retrospectively evaluated 173 patients with HCC who underwent curative resection for 9 years to evaluate the correlation of a combination of γ-glutamyl transferase (γ-GT), protein induced by vitamin K absence or antagonist-II (PIVKA-II), and α-fetoprotein (AFP) with the long-term survival of patients with HCC. Multivariate analysis revealed that the γ-GT level was an independent prognostic factor for recurrence. The prediction rate of early recurrence with γ-GT, PIVKA-II, and AFP levels individually was 63.5%, 79.4%, and 39.7%, respectively, whereas the prediction rate of early recurrence was 95.2% with the combination of γ-GT, PIVKA-II, and AFP levels as a composite indicator. Our long-term retrospective study revealed that γ-GT, PIVKA-II, and AFP can aid in predicting long-term prognosis of HCC recurrence. The combination of γ-GT, PIVKA-II, and AFP can further aid in identifying patients with early recurrence. Together, γ-GT, PIVKA-II, and AFP may a be used to develop a new prediction method to improve the prognosis of patients with HCC, and our results indicate the requirement of more active HCC treatment strategies.

Combining local regional therapy and systemic therapy: Expected changes in the treatment landscape of recurrent hepatocellular carcinoma.

Improvements in early screening, new diagnostic techniques, and surgical treatment have led to continuous downward trends in hepatocellular carcinoma (HCC) morbidity and mortality rates. However, high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC. The clinical characteristics and prognosis of recurrent HCC are heterogeneous, and guidelines on treatment strategies for recurrent HCC are lacking. Therapies such as surgical resection, radiofrequency ablation, and transhepatic arterial chemoembolization are effective for tumors confined to the liver, and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis. With the deepening of the understanding of the immune microenvironment of HCC, blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC. In addition, improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment. Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC. This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment, demonstrates the basis for combining local treatment and systemic treatment, and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.

Immunotherapy or targeted therapy as the first-line strategies for unresectable hepatocellular carcinoma: A network meta-analysis and cost-effectiveness analysis.

The existence of many phase III randomized controlled trials (RCTs) of first-line treatment for unresectable hepatocellular carcinoma (HCC) puzzle doctors and patients in choosing the most effective treatment strategies. We aimed to assess the efficacy, safety, and cost-effectiveness of immunotherapy or targeted therapy as the first-line strategy for unresectable HCC. The included clinical trials were retrieved from PubMed, Embase, the Cochrane library, and Web of Science databases, in which immunotherapy or targeted therapy was regarded as the first-line treatment for unresectable HCC, published in English between January 1, 2010, and September 20, 2022. We conducted a network meta-analysis (NMA) and cost-effectiveness analysis (CEA) from the Chinese payer's perspective. Overall survival (OS), progression-free survival (PFS), the ranks of different treatments using P-score, and adverse events (AEs) were evaluated by NMA. Total costs, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-benefit ratio (ICER) were estimated from 15-year Markov models developed by CEA. We identified 2,825 records, including 11,796 patients, from 15 RCTs. The NMA revealed that sintilimab plus a bevacizumab biosimilar (HR, 0.57; 95% CI, 0.43 to 0.75; P = 0.96) and camrelizumab plus rivoceranib (HR, 0.56; 95% CI, 0.41 to 0.66; P = 0.94) could lead to great improvements in OS and PFS compared with sorafenib-related survival. The CEA indicated that tislelizumab increased by 0.220 QALYs (0.312 LYs) and decreased by $1,938 compared with sorafenib, which yielded ICERs of -$8,809/QALY (-$2,612/LY). Sensitivity analysis showed that the model was stable. Sintilimab plus a bevacizumab biosimilar and camrelizumab plus rivoceranib significantly prolonged OS and PFS, respectively. Further considering the pharmacoeconomics factors, tislelizumab is the most cost-effective first-line treatment strategy for unresectable HCC in China.

O-GlcNAcylation of SPOP promotes carcinogenesis in hepatocellular carcinoma.

Aberrantly elevated O-GlcNAcylation level is commonly observed in human cancer patients, and has been proposed as a potential therapeutic target. Speckle-type POZ protein (SPOP), an important substrate adaptor of cullin3-RING ubiquitin ligase, plays a key role in the initiation and development of various cancers. However, the regulatory mechanisms governing SPOP and its function during hepatocellular carcinoma (HCC) progression remain unclear. Here, we show that, in HCC, SPOP is highly O-GlcNAcylated by O-GlcNAc transferase (OGT) at Ser96. In normal liver cells, the SPOP protein mainly localizes in the cytoplasm and mediates the ubiquitination of the oncoprotein neurite outgrowth inhibitor-B (Nogo-B) (also known as reticulon 4 B) by recognizing its N-terminal SPOP-binding consensus (SBC) motifs. However, O-GlcNAcylation of SPOP at Ser96 increases the nuclear positioning of SPOP in hepatoma cells, alleviating the ubiquitination of the Nogo-B protein, thereby promoting HCC progression in vitro and in vivo. In addition, ablation of O-GlcNAcylation by an S96A mutation increased the cytoplasmic localization of SPOP, thereby inhibiting the Nogo-B/c-FLIP cascade and HCC progression. Our findings reveal a novel post-translational modification of SPOP and identify a novel SPOP substrate, Nogo-B, in HCC. Intervention with the hyper O-GlcNAcylation of SPOP may provide a novel strategy for HCC treatment.

Allosteric regulation of the lid domain of PCK2 as a novel strategy for modulating mitochondrial dynamics.

Aberrant PCK2 overexpression has been linked to an unfavorable prognosis and shorter survival, particularly in hepatocellular carcinoma (HCC). Thus, the inactivation of PCK2 provides a promising strategy for HCC treatment. In this study, we used a chemical genetic strategy to identify a natural-derived small-molecule cucurbitacin B (CuB) as a selective PCK2 inhibitor. CuB covalently bound to PCK2 at a unique Cys63 site, blocking the Ω-loop lid domain formation via a previously undisclosed allosteric mechanism. Additionally, targeted lipidomics analysis also revealed that CuB destroyed mitochondrial membrane integrity, leading to the disruption of mitochondrial fusion-fission dynamics. Taken together, this study highlights the discovery of a small-molecule CuB, which reprograms lipid metabolism for controlling mitochondrial dynamics via targeting PCK2 in cancer cells.

Multifunctional gene delivery vectors containing different liver-targeting fragments for specifically transfecting hepatocellular carcinoma (HCC) cells.

Gene therapy is a promising strategy for HCC treatment, but it commonly faces the problem of low specificity in gene transfection. In this study, we designed and synthesized a series of peptide-based gene delivery vectors (H-01 to H-18) containing varied HCC cell-targeting fragments for specifically binding different receptors highly expressed on HCC cell membranes. The physicochemical properties of peptide vectors or peptide/DNA complexes were characterized, and the gene delivery abilities of peptide vectors were evaluated in HepG2 cell lines. The results showed that peptide vectors H-02 and H-09, which contained targeted fragments for ACE2 and c-Met receptors, respectively, could specifically transfect HCC cells in a highly -efficient manner in vitro. Furthermore, the liver-targeting function in vivo of Cy5.5 labeled H-02 (H-17) and H-09 (H-18) was investigated by fluorescence imaging.

ACE2 negatively regulates the Warburg effect and suppresses hepatocellular carcinoma progression via reducing ROS-HIF1α activity.

Aerobic glycolysis has pleiotropic roles in the pathogenesis of hepatocellular carcinoma (HCC). Emerging studies revealed key promoters of aerobic glycolysis, however, little is known about its negative regulators in HCC. In this study, an integrative analysis identifies a repertoire of differentially expressed genes (DNASE1L3, SLC22A1, ACE2, CES3, CCL14, GYS2, ADH4, and CFHR3) that are inversely associated with the glycolytic phenotype in HCC. ACE2, a member of the rennin-angiotensin system, is revealed to be downregulated in HCC and predicts a poor prognosis. ACE2 overexpression significantly inhibits the glycolytic flux as evidenced by reduced glucose uptake, lactate release, extracellular acidification rate, and the expression of glycolytic genes. Opposite results are noticed in loss-of-function studies. Mechanistically, ACE2 metabolizes Ang II to Ang-(1-7), which activates Mas receptor and leads to the phosphorylation of Src homology 2-containing inositol phosphatase 2 (SHP-2). SHP2 activation further blocks reactive oxygen species (ROS)-HIF1α signaling. Addition of Ang-(1-7) or the antioxidant N-acetylcysteine compromises in vivo additive tumor growth and aerobic glycolysis induced by ACE2 knockdown. Moreover, growth advantages afforded by ACE2 knockdown are largely glycolysis-dependent. In clinical settings, a close link between ACE2 expression and HIF1α or the phosphorated level of SHP2 is found. Overexpression of ACE2 significantly retards tumor growth in patient-derived xenograft model. Collectively, our findings suggest that ACE2 is a negative glycolytic regulator, and targeting the ACE2/Ang-(1-7)/Mas receptor/ROS/HIF1α axis may be a promising therapeutic strategy for HCC treatment.

Characteristics and treatment strategies for hepatocellular carcinoma caused by nonalcoholic fatty liver disease

In recent years, nonalcoholic fatty liver disease (NAFLD) incidence has rapidly increased, and it is gradually becoming a major contributor to liver cirrhosis and hepatocellular cancer (HCC). The degree of liver fibrosis, diabetes mellitus (DM), obesity, age, and gender are the main risk factors for nonalcoholic steatohepatitis (NASH) progression to HCC. Patients with NASH-related HCC are predominantly male, and almost all of them have at least one metabolic disorder (obesity, DM, dyslipidemia, hypertension, etc.). Most HCCs manifest as solitary tumor nodules and a significant number of NASH-related HCCs are non- cirrhotic. Case fatality rates are similar across patients with cirrhotic and noncirrhotic HCC, despite the fact that patients with noncirrhotic HCC tend to be older, have a single macronodular tumor, and have lower incidence of type 2 diabetes and liver transplantation. Controlling the risk factors for NASH might thereby minimize the likelihood of developing HCC. The BCLC staging system should be used as a guide to treat patients with NASH-related HCC. The long-term outcomes of NAFLD-related HCC treatment are similar to those for other HCCs of different etiologies. However, patients combined with metabolic syndrome are at high perioperative risk, so apporpriate preoperative preparation, especially cardiac examination, is essential to avoid this risk.

CircTNPO3 promotes hepatocellular carcinoma progression by sponging miR-199b-5p and regulating STRN expression.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor, which seriously threatens human health. CircTNPO3 was up-regulated in HCC tissues. However, the regulatory mechanism of circTNPO3 in HCC was still unclear. We aimed to investigate the circTNPO3 function in the development of HCC. qRT-PCR and Western blot examined gene and protein levels. CCK8, EdU, flow cytometry, and Transwell assays were used to detect cell viability, proliferation, apoptosis, and invasion abilities. Dual-luciferase reporter and RIP assays determined the relationship between circTNPO3, miR-199b-5p, and striatin (STRN). The effect of CircTNPO3 on HCC progress was investigated in vivo. CircTNPO3 and STRN were significantly increased, while miR-199b-5p was repressed in HCC tissues or cells. Afterward, miR-199b-5p was negatively correlated with STRN. circTNPO3 was positively correlated with STRN. Knockdown of circTNPO3 inhibited cell viability, proliferation, invasion, and promoted apoptosis, while circTNPO3 overexpression had the opposite results. Furthermore, miR-199b-5p inhibition could eliminate the regulatory effect of sh-circTNPO3 on the proliferation and apoptosis in HCC cells. CircTNPO3 positively regulated STRN expression by targeting miR-199b-5p. MiR-199b-5p suppressed HCC progression by inhibiting STRN expression. Tumor formation in nude mice showed that knockdown of circTNPO3 significantly inhibited tumor growth and suppressed ki-67 levels. CircTNPO3 promoted HCC progression through regulating STRN expression by sponging miR-199b-5p, which provided a strategy for HCC treatment.

Nanomedicine‐boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

Traditional treatments for advanced hepatocellular carcinoma (HCC), such as surgical resection, transplantation, radiofrequency ablation, and chemotherapy are unsatisfactory, and therefore the exploration of powerful therapeutic strategies is urgently needed. Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects. Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC. Encouragingly, in 2022, icaritin soft capsules were approved by the National Medical Products Administration (NMPA) of China for the immunotherapy of advanced HCC. However, the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency. Recently, functionalized drug delivery systems including stimuli-responsive nanocarriers, cell membrane-coated nanocarriers, and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs, including the low bioavailability and limited delivery efficiency as well as side effects. Taken together, the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC. Herein, we compared the different preparation methods for icaritin, interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC, and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritin-based nanomedicines for advanced HCC immunotherapy. Finally, the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed.

PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells

Programmed death receptor-1 (PD-1) blockade have achieved some efficacy but only in a fraction of patients with hepatocellular carcinoma (HCC). Programmed cell death 1 ligand 1 (PD-L1) binds to its receptor PD1 on T cells to dampen antigen-tumor immune responses. However, the mechanisms underlying PD-L1 regulation are not fully elucidated. Herein, we identify that tumoral Prdm1 overexpression inhibits cell growth in immune-deficient mouse models. Further, tumoral Prdm1 overexpression upregulates PD-L1 levels, dampening anti-tumor immunity in vivo, and neutralizes the anti-tumor efficacy of Prdm1 overexpression in immune-competent mouse models. Mechanistically, PRDM1 enhances USP22 transcription, thus reducing SPI1 protein degradation through deubiquitination, which enhances PD-L1 transcription. Functionally, PD-1 mAb treatment reinforces the efficacy of Prdm1-overexpressing HCC immune-competent mouse models. Collectively, we demonstrate that the PRDM1-USP22-SPI1 axis regulates PD-L1 levels, resulting in infiltrated CD8+ T cell exhaustion. Furthermore, PRDM1 overexpression combined with PD-(L)1 mAb treatment provides a therapeutic strategy for HCC treatment.

A novel inhibitor of PGK1 suppresses the aerobic glycolysis and proliferation of hepatocellular carcinoma

Phosphoglycerate kinase 1(PGK1) is an important enzyme in the metabolic glycolysis pathway. Nowadays, PGK1 is an appealing therapeutic target for multiple cancers. However, no effective inhibitor of PGK1 has been reported. In this study, we demonstrate that Ilicicolin H a 5-(4-hydroxyphenyl)-pyridone with a decalin ring system and a non-ATP-competitive inhibitor of PGK1, inhibits the proliferation and promotes apoptosis of Hepatocellular carcinoma (HCC). Many cancer cells display enhanced glycolysis which is critical for tumor development. Here we identified that Ilicicolin H can target PGK1 in vitro to inhibit the lactate production and glucose uptake of HCC cells. These findings suggest that the PGK1 inhibitor- Ilicicolin H is a promising anticancer agent and may provide a better therapeutic strategy for HCC treatment in the future.

Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation and progression are favored by different etiological risk factors including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, non-/and alcoholic fatty liver disease (N/AFLD), and tobacco smoking. In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, etc.), and dysregulation of key signaling pathways (Wnt/β-catenin, JAK/STAT, etc.) strongly contribute to the development of HCC. The multitude and complexity of different pathomechanisms also reflect the difficulties in tailored medical therapy of HCC. Treatment options for HCC are strictly dependent on tumor staging and liver function, which are structured by the updated Barcelona Clinic Liver Cancer classification system. Surgical resection, local ablative techniques, and liver transplantation are valid and curative therapeutic options for early tumor stages. For multifocal and metastatic diseases, systemic therapy is recommended. While Sorafenib had been the standalone HCC first-line therapy for decades, recent developments had led to the approval of new treatment options as first-line as well as second-line treatment. Anti-PD-L1 directed combination therapies either with anti-VEGF directed agents or with anti-CTLA-4 active substances have been implemented as the new treatment standard in the first-line setting. However, data from clinical trials indicate different responses on specific therapeutic regimens depending on the underlying pathogenesis of hepatocellular cancer. Therefore, histopathological examinations have been re-emphasized by current international clinical guidelines in addition to the standardized radiological diagnosis using contrast-enhanced cross-sectional imaging. In this review, we emphasize the current knowledge on molecular pathogenesis of hepatocellular carcinoma. On this occasion, the treatment sequences for early and advanced tumor stages according to the recently updated Barcelona Clinic Liver Cancer classification system and the current algorithm of systemic therapy (first-, second-, and third-line treatment) are summarized. Furthermore, we discuss novel precautional and pre-therapeutic approaches including therapeutic vaccination, adoptive cell transfer, locoregional therapy enhancement, and non-coding RNA-based therapy as promising treatment options. These novel treatments may prolong overall survival rates in regard with quality of life and liver function as mainstay of HCC therapy.

Combined Loco-Regional and Systemic Treatment Strategies for Hepatocellular Carcinoma: From Basics to New Developments.

Recent advances in systemic therapeutic options have led to improved survival in patients with advanced hepatocellular carcinoma. In order to optimize patient outcomes across different disease stages, attempts are being made at exploiting combinations of loco-regional treatments and systemic therapeutic regimens. The possibilities of a beneficial synergistic effect are strongly supported by biological evidence of changes in tumor microenvironment and systemic immunity. With the advent of newer interventional technologies and newer biological and immunological drugs, these possibilities keep on gaining interest and expectations, yet many questions remain unanswered as to how to best manipulate and combine the two therapeutic approaches.This review aims at providing a general overview of biological foundations, preliminary clinical applications, critical issues and future directions of this constantly growing field.

Micronome Revealed miR-205-5p as Key Regulator of VEGFA During Cancer Related Angiogenesis in Hepatocellular Carcinoma.

The high ratio of global mortality rate to incidence rate and steep increase in incidence of liver cancer warrants need for advancement of innovative cancer treatment and therapy for hepatocellular carcinoma (HCC). miRNAs are fascinating prospects as treatments in the form of miRNA mimics or therapeutic targets because of their capacity to target various mRNAs that are changed in diseased states. Micronome is a tool to find signature miRNA for any disease and there is hardly any study on micronome in HCC. The aim of the present study was to identify the genes involved in tumor growth and angiogenesis in HCC patients and determine the signature miRNA by constructing a micronome. Herein, we performed a comprehensive analysis on dysregulated genes obtained from liver cancer gene databases. Only experimentally validated miRNA of angiogenesis genes were included in the study. Micronome was constructed using Cytoscape software and search tools for the retrieval of interacting genes (STRING) database. Dysregulated genes of HCC were integrated with miRNAs for identification of signature miRNA involved and identify genes (acting as positive or negative regulator) to elucidate the potential regulatory pathway or signaling. The study clearly reflects that hsa-mir-205-5p is the signature miRNA for positively regulating angiogenesis in HCC through VEGFA. These regulatory genes and signature miRNAs may be useful to understand the unique angiogenesis process of HCC and quick development of novel/better and cost effective molecular-targeted treatment strategies in HCC as the responsible regulatory molecules can be pinpointed with limited resources with use of bioinformatics.

CAFs-derived SCUBE1 promotes malignancy and stemness through the Shh/Gli1 pathway in hepatocellular carcinoma

BackgroundThe tumour microenvironment and cirrhotic liver are excellent sources of cancer-associated fibroblasts (CAFs), which participate in carcinogenesis. Thus, it is important to clarify the crosstalk between CAFs and HCC cells and the related mechanism in regulating carcinogenesis.MethodsHuman hepatocellular carcinoma (HCC) tissues and matched adjacent normal tissues were obtained from HCC patients. Immunohistochemistry, Western blotting (WB) and RT–qPCR were performed to detect the expression of SCUBE1. The roles of SCUBE1 in inducing stemness features in HCC cells were explored and investigated in vitro and in vivo. Student’s t tests or Mann–Whitney U tests were used to compare continuous variables, while chi-square tests or Fisher’s exact tests were used to compare categorical variables between two groups.ResultsSCUBE1 was confirmed to be highly expressed in CAFs in HCC and had a strong connection with stemness and a poor prognosis. In addition, CAFs were found to secrete SCUBE1 to enhance the malignancy of HCC cells and increase the proportion of CD133-positive cells. Silencing SCUBE1 expression had the opposite effect. The Shh pathway was activated by SCUBE1 stimulation. Inhibition of cyclopamine partially reversed the stimulating effect of SCUBE1 both in vivo and in vitro. Moreover, based on the RT–qPCR, ELISA and WB results, a high SCUBE1 expression level was found in HCC tissue and serum.ConclusionThis study revealed that CAFs-derived SCUBE1 can enhance the malignancy and stemness of HCC cells through the Shh pathway. This study aims to provide new perspectives for future HCC studies and provide new strategies for HCC treatment.