Liver Cancer Progression Research Articles

Oncofetal TRIM71 drives liver cancer carcinogenesis through remodeling CEBPA-mediated serine/glycine metabolism.

Rationale: Tumor cells remodel transcriptome to construct an ecosystem with stemness features, which maintains tumor growth and highly malignant characteristics. However, the core regulatory factors involved in this process still need to be further discovered. Methods: Single cell RNA-sequncing (scRNA-seq) and bulk RNA-sequencing profiles derived from fetal liver, normal liver, liver tumors, and their adjacent samples were collected to analyze the ecosystem of liver cancer. Mouse models were established to identify molecular functions of oncofetal-related oncogenes using hydrodynamic tail vein injection. Results: We found that liver cancer rebuilt oncofetal ecosystem to maintain malignant features. Interestingly, we identified a group of RNA-binding proteins (RBPs) that were highly overexpressed with oncofetal features. Among them, TRIM71 was specifically expressed in liver cancers and was associated with poor outcomes. TRIM71 drove the carcinogenesis of hepatocellular carcinoma (HCC), and knockdown of TRIM71 significantly abolished liver cancer cell proliferation. Mechanistically, TRIM71 formed a protein complex with IGF2BP1, bound to and stabilized the mRNA of CEBPA in an m6A-dependent manner, enhance the serine/glycine metabolic pathway, and ultimately promoted liver cancer progression. Furthermore, we identified that all-trans-retinoic acid (ATRA) combined with e1A binding protein p300 (EP300) inhibitor A-485 repressed TRIM71, attenuated glycine/serine metabolism, and inhibited liver cancer cell proliferation with high TRIM71 levels. Conclusions: We demonstrated the oncofetal status in liver cancer and highlighted the crucial role of TRIM71 and provided potential therapeutic strategies and liver cancer-specific biomarker for liver cancer patients.

Landscape of m6A RNA methylation regulators in liver cancer and its therapeutic implications.

Liver cancer remains as the third leading cause of cancer-related death globally as of 2020. Despite the significant progress made in the field of liver cancer treatment, there is still a lack of effective therapies in patients with advanced cancer and the molecular mechanisms underlying liver cancer progression remain largely elusive. N6-methyladenosine (m6A) modification, as the most prevalent and abundant internal RNA modification in eukaryotic RNAs, plays an essential role in regulating RNA metabolism including RNA splicing, stability, translation, degradation. To date, there is mounting evidence showing that m6A dysregulation is closely associated with the onset and development of many tumors including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and hepatoblastoma (HB). In this review, we summarize the last research progress regarding the functions of m6A-related regulators in liver cancer and its underlying mechanisms. Additionally, we also discuss the therapeutic applications of m6A-based inhibitors in liver cancer treatment.

ST8SIA6-AS1, a novel lncRNA star in liver cancer.

Liver cancer is one of the most lethal gastrointestinal malignancies. Emerging evidence has underscored the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis, with ST8SIA6-AS1 identified as a novel oncogenic lncRNA contributing to liver cancer progression. ST8SIA6-AS1 is consistently upregulated in hepatic cancer tissues and is strongly associated with unfavorable prognosis. Moreover, it demonstrates high diagnostic efficacy in detecting HCC. ST8SIA6-AS1 is involved in various cellular processes including proliferation, migration, and invasion, primarily through its function as a competing endogenous RNA (ceRNA), thereby facilitating hepatocarcinogenesis and disease advancement. This review provides a detailed examination of the molecular functions and regulatory mechanisms of ST8SIA6-AS1 in hepatocellular carcinoma (HCC) and highlights its potential as a promising biomarker for liver cancer, aiming to propel the development of innovative therapeutic strategies for HCC management.

Effect of Diosmin on The Expression of Epithelial-Mesenchymal Transition Signaling Molecules in Ndea-Induced Hepato-Cellular Carcinoma in Experimental Rats

Hepatocellular carcinoma (HCC) is a primary liver cancer, distinct from other cancers originating in other organs. Previous study demonstrated that diosmin exhibits anticancer effects by influencing the expression of apoptotic signaling molecules in NDEA-induced hepatocellular carcinoma in rats. However, its impact on the epithelial-mesenchymal transition (EMT) signaling pathway, crucial in liver cancer progression, remains unknown. The research aimed to investigate diosmin’s effects on EMT signaling molecule expression in NDEA-induced hepatocellular carcinoma in rats. In this experiment, adult male albino rats were categorized into three groups: a control group, NDEA-induced hepatocellular carcinogenic rats and rats with HCC treated with diosmin orally for 28 days. Liver function markers (AST and ALT) were done by biochemical analysis while mNRA expression analysis of EMT-signaling molecules ( E-cadherin and vimentin) were analyzed by Real Time-RT-PCR analysis. One-Way-ANOVA was used for the statistical analysis and significance was considered at p<0.05. Diosmin treatment resulted in a significant decrease in liver function markers compared to the control group (p<0.05). Moreover, diosmin administration led to a notable reduction in mRNA levels of EMT signaling molecules, specifically E-cadherin and vimentin, indicating its potential chemopreventive role against liver cancer. Findings of the present study concludes that diosmin, an alkaloid, may merge as a promising candidate for hepatocellular carcinoma treatment based on its demonstrated efficacy in this experimental model. Keywords: Novel method, Hepatocellular carcinoma, EMT signaling, diosmin, wistar rats, liver function, innovative technique.

Actual issues of secondary prevention of liver cancer in Kazakhstan

Liver cancer is characterized by high mortality and low survival rates in most countries of the world. According to the WHO data, more than 1.3 million people with liver cancer die annually in the world and according to the data of the 9th volume of "Cancer on five continents" - the highest standardized incidence rates are in Korea - 44.9 per 100 thousand population as well as in Thailand, Japan, China. Low rates were in Algeria, India, Belgium and the Netherlands. In Russia 61.5% of patients die of liver cancer progression in the first year after diagnosis [1,2].<br /> Information on the global burden of cancer in 2018 showed that the specific weight of liver cancer in the structure of malignant neoplasms (MN) is 8.2%, and in 2020 - 8.3% [3].  <br /> The worldwide peculiarity of liver cancer is its late diagnosis. Several evidence-based treatment options for liver cancer are currently available: liver transplantation for hepatocellular liver cancer (HCC) (according to the Milan criteria), radiofrequency ablation as a radical treatment option (RFA), chemoembolization for intrahepatic cholangiocarcinoma (TACE), and the administration of Sorafenib as systemic therapy [4].<br /> Current approaches for the treatment of early-stage primary liver cancer are represented by hepatic RFA, and the efficacy of this approach depends on the subjective attentiveness and visual acuity of the clinician. The latest technique used in liver RFA is the hyperspectral imaging which utilize objective assessment [2].<br /> Ultrasound is usually used to detect liver lesions, but the detection rate is low for many reasons, such as clinician skills and technical capabilities. Modern approaches of diagnostic capabilities, such as contrast-enhanced ultrasound integrated imaging (CEUS) and comprehensive ultrasound imaging - contrast-enhanced CT (CECT) or contrast-enhanced MRI (CEMRI) for visualization of focal liver lesions (FLL) - increase the confidence of the interventional physician so it should be recommended for use as a routine procedure [5-6].<br /> The ratio of morbidity and mortality in many countries reaches 91.6%, which represents the third most important cause of cancer deaths [7-9].

Role of hepatitis B virus non-structural protein HBx on HBV replication, interferon signaling, and hepatocarcinogenesis.

Hepatitis B, a global health concern caused by the hepatitis B virus (HBV), infects nearly 2 billion individuals worldwide, as reported by the World Health Organization (WHO). HBV, a hepatotropic DNA virus, predominantly targets and replicates within hepatocytes. Those carrying the virus are at increased risk of liver cirrhosis and hepatocellular carcinoma, resulting in nearly 900,000 fatalities annually. The HBV X protein (HBx), encoded by the virus's open reading frame x, plays a key role in its virulence. This protein is integral to viral replication, immune modulation, and liver cancer progression. Despite its significance, the precise molecular mechanisms underlying HBx remain elusive. This review investigates the HBx protein's roles in HBV replication, interferon signaling regulation, and hepatocellular carcinoma progression. By understanding the complex interactions between the virus and its host mediated by HBx, we aim to establish a solid foundation for future research and the development of HBx-targeted therapeutics.

Hsa_circ_0002980 prevents proliferation, migration, invasion, and epithelial-mesenchymal transition of liver cancer cells through microRNA-1303/cell adhesion molecule 2 axis.

Liver cancer (LC) is a rare malignancy. Circular RNA (circRNA) dysregulation is associated with LC metastasis. hsa_circ_0002980 was found to be unexpectedly downregulated in LC tissues; however, its specific function remains unclear. hsa_circ_0002980 expression was confirmed using RT-qPCR. The effects of circ_0002980 on the proliferation, metastasis, and EMT-related proteins of LC cells were assessed using clone formation, flow cytometry, Transwell assays, and Western blotting. The relationship between circ_0002980 and miR-1303 or miR-1303 and CADM2 was analyzed using a dual-luciferase reporter assay. Thereafter, the influence of these three genes on LC cell progression was determined through rescue experiments. hsa_circ_0002980 expression was lower in LC. circ_0002980 overexpression inhibited the proliferation, migration, invasion, and EMT of LC cells. In addition, circ_0002980 specifically binds to miR-1303, and the accelerated effect of miR-1303 overexpression on LC progression was partially reversed by circ_0002980. Moreover, miR-1303 can also target CADM2, and CADM2-mediated prevention can also be attenuated by miR-1303 overexpression. In LC cells, circ_0002980 upregulation prevents cell proliferation, metastasis, and EMT by affecting the miR-1303/CADM2 axis. Therefore, this axis may be a novel therapeutic target in LC.

Protein O-GlcNAcylation: The sweet hub in liver metabolic flexibility from a (patho)physiological perspective.

O-GlcNAcylation is a dynamic, reversible and atypical O-glycosylation that regulates various cellular physiological processes via conformation, stabilisation, localisation, chaperone interaction or activity of target proteins. The O-GlcNAcylation cycle is precisely controlled by collaboration between O-GlcNAc transferase and O-GlcNAcase. Uridine-diphosphate-N-acetylglucosamine, the sole donor of O-GlcNAcylation produced by the hexosamine biosynthesis pathway, is controlled by the input of glucose, glutamine, acetyl coenzyme A and uridine triphosphate, making it a sensor of the fluctuation of molecules, making O-GlcNAcylation a pivotal nutrient sensor for the metabolism of carbohydrates, amino acids, lipids and nucleotides. O-GlcNAcylation, particularly prevalent in liver, is the core hub for controlling systemic glucose homeostasis due to its nutritional sensitivity and precise spatiotemporal regulation of insulin signal transduction. The pathology of various liver diseases has highlighted hepatic metabolic disorder and dysfunction, and abnormal O-GlcNAcylation also plays a specific pathological role in these processes. Therefore, this review describes the unique features of O-GlcNAcylation and its dynamic homeostasis maintenance. Additionally, it explains the underlying nutritional sensitivity of O-GlcNAcylation and discusses its mechanism of spatiotemporal modulation of insulin signal transduction and liver metabolic homeostasis during the fasting and feeding cycle. This review emphasises the pathophysiological implications of O-GlcNAcylation in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and hepatic fibrosis, and focuses on the adverse effects of hyper O-GlcNAcylation on liver cancer progression and metabolic reprogramming.

Construction and validation of a novel lysosomal signature for hepatocellular carcinoma prognosis, diagnosis, and therapeutic decision-making

Lysosomes is a well-recognized oncogenic driver and chemoresistance across variable cancer types, and has been associated with tumor invasiveness, metastasis, and poor prognosis. However, the significance of lysosomes in hepatocellular carcinoma (HCC) is not well understood. Lysosomes-related genes (LRGs) were downloaded from Genome Enrichment Analysis (GSEA) databases. Lysosome-related risk score (LRRS), including eight LRGs, was constructed via expression difference analysis (DEGs), univariate and LASSO-penalized Cox regression algorithm based on the TCGA cohort, while the ICGC cohort was obtained for signature validation. Based on GSE149614 Single-cell RNA sequencing data, model gene expression and liver tumor niche were further analyzed. Moreover, the functional enrichments, tumor microenvironment (TME), and genomic variation landscape between LRRSlow/LRRShigh subgroup were systematically investigated. A total of 15 Lysosomes-related differentially expressed genes (DELRGs) in HCC were detected, and then 10 prognosis DELRGs were screened out. Finally, the 8 optimal DELRGs (CLN3, GBA, CTSA, BSG, APLN, SORT1, ANXA2, and LAPTM4B) were selected to construct the LRRS prognosis signature of HCC. LRRS was considered as an independent prognostic factor and was associated with advanced clinicopathological features. LRRS also proved to be a potential marker for HCC diagnosis, especially for early-stage HCC. Then, a nomogram integrating the LRRS and clinical parameters was set up displaying great prognostic predictive performance. Moreover, patients with high LRRS showed higher tumor stemness, higher heterogeneity, and higher genomic alteration status than those in the low LRRS group and enriched in metabolism-related pathways, suggesting its underlying role in the progression and development of liver cancer. Meanwhile, the LRRS can affect the proportion of immunosuppressive cell infiltration, making it a vital immunosuppressive factor in the tumor microenvironment. Additionally, HCC patients with low LRRS were more sensitive to immunotherapy, while patients in the high LRRS group responded better to chemotherapy. Upon single-cell RNA sequencing, CLN3, GBA, and LAPTM4B were found to be specially expressed in hepatocytes, where they promoted cell progression. Finally, RT-qPCR and external datasets confirmed the mRNA expression levels of model genes. This study provided a direct links between LRRS signature and clinical characteristics, tumor microenvironment, and clinical drug-response, highlighting the critical role of lysosome in the development and treatment resistance of liver cancer, providing valuable insights into the prognosis prediction and treatment response of HCC, thereby providing valuable insights into prognostic prediction, early diagnosis, and therapeutic response of HCC.

CHMP3 promotes the progression of hepatocellular carcinoma by inhibiting caspase‑1‑dependent pyroptosis.

Charged multivesicular body protein3 (CHMP3) is an elemental constituent of the endosomal sorting complex required for transport (ESCRT)III, whose function as a tumor susceptibility gene in the development of liver cancer remains unclear. CHMP3 was found to be associated with pyroptosis by bioinformatics analysis of data from patients with hepatocellular carcinoma (HCC) in The Cancer Genome Atlas database. It was aimed to explore the role and potential mechanisms of CHMP3 in the development of liver cancer. The expression of CHMP3 at the tissue level was examined using immunohistochemistry and western blot analysis. Subsequently, HepG2 and Huh‑7cells were transfected with small interfering RNA and overexpression plasmids to change CHMP3 expression. The proliferative capacity of cells was examined using colony formation and Cell Counting Kit‑8 assays. Wound healing and Transwell assays were used to examine the migratory and invasive abilities of the cells. Transmission electron microscopy was used to observe changes in cell morphology. Western blotting was used to examine the expression of caspase‑1 signaling pathway related proteins, a classic pathway of pyroptosis. In addition, a xenograft tumor model was used to examine the tumorigenic ability of CHMP3 invivo. The results demonstrated that CHMP3 expression was upregulated in HCC and was associated with poor prognosis. Knockdown or overexpression of CHMP3 inhibited or promoted the proliferation, migration and invasion of liver cancer cells. Knockdown of Huh‑7 showed changes in cell membrane integrity as well as cytoplasmic leakage. Furthermore, knockdown of CHMP3 may activate the caspase‑1 pyroptosis signaling pathway which in turn inhibits the progression of liver cancer, and this effect can be reversed by the caspase‑1 inhibitor AYC. In conclusion, CHMP3 may affect the development of liver cancer through the caspase‑1‑mediated pyroptosis pathway.

Revealing the role of necroptosis microenvironment: FCGBP + tumor-associated macrophages drive primary liver cancer differentiation towards cHCC-CCA or iCCA.

Previous research has demonstrated that the conversion of hepatocellular carcinoma (HCC) to intrahepatic cholangiocarcinoma (iCCA) can be stimulated by manipulating the tumor microenvironment linked with necroptosis. However, the specific cells regulating the necroptosis microenvironment have not yet been identified. Additionally, further inquiry into the mechanism of how the tumor microenvironment regulates necroptosis and its impact on primary liver cancer(PLC) progression may be beneficial for precision therapy. We recruited a single-cell RNA sequencing dataset (scRNA-seq) with 34 samples from 4 HCC patients and 3 iCCA patients, and a Spatial Transcriptomic (ST) dataset including one each of HCC, iCCA, and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Quality control, dimensionality reduction and clustering were based on Seurat software (v4.2.2) process and batch effects were removed by harmony (v0.1.1) software. The pseudotime analysis (also known as cell trajectory) in the single cell dataset was performed by monocle2 software (v2.24.0). Calculation of necroptosis fraction was performed by AUCell (v1.16.0) software. Switch gene analysis was performed by geneSwitches(v0.1.0) software. Dimensionality reduction, clustering, and spatial image in ST dataset were performed by Seurat (v4.0.2). Tumor cell identification, tumor subtype characterization, and cell type deconvolution in spot were performed by SpaCET (v1.0.0) software. Immunofluorescence and immunohistochemistry experiments were used to prove our conclusions. Analysis of intercellular communication was performed using CellChat software (v1.4.0). ScRNA-seq analysis of HCC and iCCA revealed that necroptosis predominantly occurred in the myeloid cell subset, particularly in FCGBP + SPP1 + tumor-associated macrophages (TAMs), which had the highest likelihood of undergoing necroptosis. The existence of macrophages undergoing necroptosis cell death was further confirmed by immunofluorescence.Regions of HCC with poor differentiation, cHCC-CCA with more cholangiocarcinoma features, and the tumor region of iCCA shared spatial colocalization with FCGBP + macrophages, as confirmed by spatial transcriptomics, immunohistochemistry and immunofluorescence. Pseudotime analysis showed that premalignant cells could progress into two directions, one towards HCC and the other towards iCCA and cHCC-CCA. Immunofluorescence and immunohistochemistry experiments demonstrated that the number of macrophages undergoing necroptosis in cHCC-CCA was higher than in iCCA and HCC, the number of macrophages undergoing necroptosis in cHCC-CCA with cholangiocarcinoma features was more than in cHCC-CCA with hepatocellular carcinoma features. Further investigation showed that myeloid cells with the highest necroptosis score were derived from the HCC_4 case, which had a severe inflammatory background on pathological histology and was likely to progress towards iCCA and cHCC-CCA. Switchgene analysis indicated that S100A6 may play a significant role in the progression of premalignant cells towards iCCA and cHCC-CCA. Immunohistochemistry confirmed the expression of S100A6 in PLC, the more severe inflammatory background of the tumor area, the more cholangiocellular carcinoma features of the tumor area, S100A6 expression was higher. The emergence of necroptosis microenvironment was found to be significantly associated with FCGBP + SPP1 + TAMs in PLC. In the presence of necroptosis microenvironment, premalignant cells appeared to transform into iCCA or cHCC-CCA. In contrast, without a necroptosis microenvironment, premalignant cells tended to develop into HCC, exhibiting amplified stemness-related genes (SRGs) and heightened malignancy.

Targeting the mechano-microenvironment and liver cancer stem cells: a promising therapeutic strategy for liver cancer.

Over the past 2 decades, cancer stem cells (CSCs) have been identified as the root cause of cancer occurrence, progression, chemoradioresistance, recurrence, and metastasis. Targeting CSCs is a novel therapeutic strategy for cancer management and treatment. Liver cancer (LC) is a malignant disease that can endanger human health. Studies are increasingly suggesting that changes in the liver mechanical microenvironment are a primary driver triggering the occurrence and development of liver cancer. In this review, we summarize current understanding of the roles of the liver mechano-microenvironment and liver cancer stem cells (LCSCs) in liver cancer progression. We also discuss the relationship between the mechanical heterogeneity of liver cancer tissues and LCSC recruitment and metastasis. Finally, we highlight potential mechanosensitive molecules in LCSCs and mechanotherapy in liver cancer. Understanding the roles and regulatory mechanisms of the mechano-microenvironment and LCSCs may provide fundamental insights into liver cancer progression and aid in further development of novel therapeutic strategies.

LASS2 enhances p53 protein stability and nuclear import to suppress liver cancer progression through interaction with MDM2/MDMX

LASS2 functions as a tumor suppressor in hepatocellular carcinoma (HCC), the most common type of primary liver cancer, but the underlying mechanism of its action remains largely unknown. Moreover, details on its role and the downstream mechanisms in Cholangiocarcinoma (CCA) and hepatoblastoma (HB), are rarely reported. Herein, LASS2 overexpression was found to significantly inhibit proliferation, migration, invasion and induce apoptosis in hepatoma cells with wild-type (HB cell line HepG2) and mutated p53 (HCC cell line HCCLM3 and CCA cell line HuCCT1). Gene set enrichment analysis determined the enrichment of the differentially expressed genes caused by LASS2 in the p53 signaling pathway. Moreover, the low expression of LASS2 in HCC and CCA tumor tissues was correlated with the advanced tumor-node-metastasis (TNM) stage, and the protein expression of LASS2 positively correlated with acetylated p53 (Lys373) protein levels. At least to some extent, LASS2 exerts its tumor-suppressive effects in a p53-dependent manner, in which LASS2 interacts with MDM2/MDMX and causes dual inhibition to disrupt p53 degradation by MDM2/MDMX. In addition, LASS2 induces p53 phosphorylation at ser15 and acetylation at lys373 to promote translocation from cytoplasm to nucleus. These findings provide new insights into the LASS2-induced tumor suppression mechanism in liver cancer and suggest LASS2 could serve as a potential therapeutic target for liver cancer.

Cucurbitacin B suppresses hepatocellular carcinoma progression through inducing DNA damage-dependent cell cycle arrest

BackgroundThe mortality rate of liver cancer ranks third in the world, and hepatocellular carcinoma (HCC) is a malignant tumor of the digestive tract. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae spp., is the main active component of Chinese patent medicine the Cucurbitacin Tablet, which has been widely used in the treatment of various malignant tumors in clinics, especially HCC. PurposeThis study explored the role and mechanism of CuB in the suppression of liver cancer progression. MethodsCell Counting Kit-8 (CCK-8) and colony formation assays were used to detect the inhibitory function of CuB in Huh7, Hep3B, and Hepa1/6 hepatoma cells. Calcein-AM/propidium iodide (PI) staining and lactate dehydrogenase (LDH) measurement assays were performed to determine cell death. Mitochondrial membrane potential (Δψm) was measured, and flow cytometry was performed to evaluate cell apoptosis and cell cycle. Several techniques, such as proteomics, Western blotting (WB), and ribonucleic acid (RNA) interference, were utilized to explore the potential mechanism. The animal experiment was performed to verify the results of in vitro experiments. ResultsCuB significantly inhibited the growth of Huh7, Hep3B, and Hepa1/6 cells and triggered the cell cycle arrest in G2/M phage without leading to cell death, especially apoptosis. Knockdown of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), a target of CuB, did not reverse CuB elicited cell cycle arrest. CuB enhanced phosphorylated ataxia telangiectasia mutated (p-ATM) and phosphorylated H2A histone family member X (γ-H2AX) levels. Moreover, CuB increased p53 and p21 levels and decreased cyclin-dependent kinase 1 (CDK1) expression, accompanied by improving phosphorylated checkpoint kinase 1 (p-CHK1) level and suppressing cell division cycle 25C (CDC25C) protein level. Interestingly, these phenomena were partly abolished by a deoxyribonucleic acid (DNA) protector methylproamine (MPA). Animal studies showed that CuB also significantly suppressed tumor growth in BALB/c mice bearing Hepa1/6 cells. In tumor tissues, CuB reduced the expression levels of proliferating cell nuclear antigen (PCNA) and γ-H2AX but did not change the terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) level. ConclusionThis study demonstrated for the first time that CuB could effectively impede HCC progression by inducing DNA damage-dependent cell cycle arrest without directly triggering cell death, such as necrosis and apoptosis. The effect was achieved through ataxia telangiectasia mutated (ATM)-dependent p53-p21-CDK1 and checkpoint kinase 1 (CHK1)-CDC25C signaling pathways. These findings indicate that CuB may be used as an anti-HCC drug, when the current findings are confirmed by independent studies and after many more clinical phase 1, 2, 3, and 4 testings have been done.

TGF-β/SMAD canonical pathway induces the expression of transcriptional cofactor TAZ in liver cancer cells

The TGF-β and Hippo pathways are critical for liver size control, regeneration, and cancer progression. The transcriptional cofactor TAZ, also named WWTR1, is a downstream effector of Hippo pathway and plays a key role in the maintenance of liver physiological functions. However, the up-regulation of TAZ expression has been associated with liver cancer progression. Recent evidence shows crosstalk of TGF-β and Hippo pathways, since TGF-β modulates TAZ expression through different mechanisms in a cellular context-dependent manner but supposedly independent of SMADs. Here, we evaluate the molecular interplay between TGF-β pathway and TAZ expression and observe that TGF-β induces TAZ expression through SMAD canonical pathway in liver cancer HepG2 cells. Therefore, TAZ cofactor is a primary target of TGF-β/SMAD-signaling, one of the pathways altered in liver cancer.

MYC in liver cancer: mechanisms and targeted therapy opportunities.

MYC, a major oncogenic transcription factor, regulates target genes involved in various pathways such as cell proliferation, metabolism and immune evasion, playing a critical role in the tumor initiation and development in multiple types of cancer. In liver cancer, MYC and its signaling pathways undergo significant changes, exerting a profound impact on liver cancer progression, including tumor proliferation, metastasis, dedifferentiation, metabolism, immune microenvironment, and resistance to comprehensive therapies. This makes MYC an appealing target, despite it being previously considered an undruggable protein. In this review, we discuss the role and mechanisms of MYC in liver physiology, chronic liver diseases, hepatocarcinogenesis, and liver cancer progression, providing a theoretical basis for targeting MYC as an ideal therapeutic target for liver cancer. We also summarize and prospect the strategies for targeting MYC, including direct and indirect approaches to abolish the oncogenic function of MYC in liver cancer.

Crosstalk between autophagy inhibitor and salidroside-induced apoptosis: A novel strategy for autophagy-based treatment of hepatocellular cancer

Autophagy regulates many cell function related to cancer, including cell proliferation, invasion and apoptosis. Therefore, we investigated the potential value of crosstalk between autophagy and apoptosis. The present study demonstrated that seven autophagy related genes were screened from the biological network of salidroside (Sal) acting on liver cancer. The GO analysis showed that these genes were mainly involved in apoptosis and autophagy. The KEGG analysis showed that these genes regulated the process of liver cancer through Th17 cell differentiation, PI3K-Akt signaling pathway and other pathways. Moreover, seven genes were positively correlated with tumor purity, number of B cells, number of CD4+ T cells, number of CD8+ T cells, number of macrophages, number of dendritic cells and number of neutrophils. The overall survival time of liver cancer patients in the high expression group of BIRC5, HSP90AB1 and MTOR was lower than that in the low expression group (P < 0.05), while the overall survival time of the liver cancer patients in the high expression group of DLC1 and FOXO1 was higher than that in the low expression group (P < 0.05). In the pan-cancer analysis, we also found that BIRC5, HSP90AB1, MTOR, and ITGA6 were highly expressed in various cancers, while DLC1, FOXO1, and FOS were low expressed in various cancers. In the molecule docking analysis, we found that FOS, HSP90AB1, and MTOR had the best binding ability. Notably, in the vitro validation experiments, Sal was confirmed to induce autophagy and apoptosis, inhibite invasion and metastasis of liver cancer cells through the PI3K/Akt/mTOR signaling pathway. Meanwhile, inhibition of autophagy by chloroquine diphosphate (CQ) promoted Sal-induced mitochondrial apoptosis via corresponding cell and animal experiments. We speculated that Sal-induced autophagy might be a protective mechanism, inhibition of autophagy could further promote the progression of liver cancer. It may provide important insight into the molecular mechanism of crosstalk between autophagy and apoptosis, and provide a new theoretical basis of Sal combined with autophagy inhibitors as a adjuvant chemotherapeutic strategy for human liver cancer.

RBM12 regulates the progression of hepatocellular cancer via miR-497–5p/CPNE1 Axis

BackgroundHepatocellular Carcinoma (HCC), also called hepatocellular cancer, has emerged as a highly prevalent malignancy globally. By binding to specific RNA via one or more spherical RNA Domains (RBDs) or RNA Motifs (RBMs), RNA Binding Proteins (RBPs) can affect RNA modification, splicing, localization, translation, and stability. MethodsThis paper builds on previous research by further investigating the impact of RBM12 on LC progression. In order to determine the effect of RBM12 expression on the prognosis of patients with hepatocellular cancer, we first investigated its expression in liver cancer cells (LCC) and tissues. The effect of RBM12 on the malignant biological behavior of LCC was subsequently detected using cytological experiments. To explore the upstream mechanism affecting RBM12, we predicted the miRNA targeting RBM12. According to the database, miR-497–5p was the best candidate gene. The double Luciferase reporter gene experiment was executed to validate the bounding of miR-497–5p with RBM12. ResultsAccording to the cytological experiments, a high RBM12 expression promoted the propagation, migration, and invasion of LCC and impeded liver cancer cell apoptosis. By secreting TGF-β1, RBM12 could induce the EMT process. The miR-497–5p expression is suppressed in hepatocellular cancer. As shown by the CCK8, plate cloning, Transwell, EDU, and other experiments, miR-497–5p suppressed RBM12 expression and tumor growth. The double Luciferase reporter gene system was utilized to verify the combination of miR-497–5p and RBM12. The CPNE1 is a downstream gene regulated by RBM12. A high CPNE1 expression was exhibited in LCC and tissues. The CPNE1 is essential in the process where RBM12 promotes the incidence and progression of liver cancer. ConclusionsBy elucidating the exact molecular mechanism through which RBM12 promotes the initiation and progression of LC, thus, the current investigation provides some reference for the clinical management of LC.

CircUSP10 promotes liver cancer progression by regulating miR-211-5p/TCF12/EMT signaling pathway

There is no precise diagnosis or prognosis for liver cancer (LC) using a single biomarker. Circular RNAs (circRNAs) contribute to the pathogenesis of different cancers, but their role in LC is not entirely understood. In this study, circUSP10, an aberrantly expressed circRNA in LC, was screened using the Gene Expression Omnibus database, and its tissue-specific expression was verified using qRT-PCR. In vitro, functional assays and nude mouse tumorigenesis models were used to investigate circUSP10 role in LC. RNA immunoprecipitation and dual-luciferase reporter assays were performed to study the mechanistic relationship between circUSP10, miR-211-5p, and transcription factor 12 (TCF12). We found that circUSP10 expression was upregulated in LC tissues and cells. CircUSP10 expression was linked to tumor size and tumor node metastasis stage and negatively correlated with LC prognosis. In vitro assays confirmed circUSP10-mediated proliferation, migration, and invasion of LC cells and their association with the epithelial-mesenchymal transition (EMT) pathway. Mechanistically, circUSP10 adsorbed miR-211-5p, which regulated TCF12 and promoted tumorigenesis via the EMT signaling pathway. Therefore, our results suggest that circUSP10 may promote LC progression by modulating the miR-211-5p/TCF12/EMT signaling cascade and may serve as a potential biomarker for LC diagnosis and prognosis.

Coculturing liver cancer cells and monocytes in spheroids conditions monocytes to adopt tumor-associated macrophage phenotypes that favor tumor growth via cholesterol metabolism.

Tumor-infiltrating immune cells and their crosstalk with cancer cells in the tumor microenvironment (TME) play a crucial role in shaping tumor progression and response to therapy. We utilized 3-dimensional liver cancer spheroids incorporating human primary monocytes to investigate the crosstalk between tumor-associated macrophages (TAMs) and Hepatocellular carcinoma (HCC) cells, HepG2 and PLC/PRF/5. Using multiplexed gene expression panels, the critical pathways involved in shaping primary human monocytes to adopt TAMs phenotypes were identified. The specific inhibitor for an identified pathway was used to explore its involvement in polarization of TAMs. In the cocultured spheroids comprising the human HCC cell lines, the infiltrating monocytes resembled protumor M2-like macrophage phenotypes. Gene expression panels of the infiltrating monocytes demonstrated that the upregulated genes were enriched in the cholesterol metabolism pathway. Cholesterol metabolism-related genes were upregulated together with the nuclear receptors, PPARG and LXR. When lysosomal acid lipase (LAL), the key enzyme necessary for the hydrolysis of lipoprotein, was inhibited, infiltrating monocytes in 3-dimensional spheroid coculture showed significantly decreased M2 marker and lipid uptake receptor expression as well as increased cellular lipid content, which indicated that cholesterol metabolism was important for conditioning the TAMs. Moreover, LAL inhibition reduced the spheroid growth and invasiveness of HCC cell lines. Small interfering RNA-mediated LAL silencing in monocytes yielded similar results upon spheroid coculture. These data indicated that liver cancer cells and infiltrating monocytes participate in crosstalk via cholesterol metabolism to condition monocytes toward TAMs, which favors tumor growth and survival, thereby promoting liver cancer progression.