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Ascitic fluid exosomal microRNAs from NASH-induced liver cirrhosis patients with and without HCC. The levels of ascitic fluid exosomal miRNA were measured by RT-qPCR. The values of the relative gene expression for target microRNA were normalised to miR-26a-5p and calculated using the 2-ΔΔCT method. The level of ascitic fluid exosomal miR-182, miR-301a, and miR-373 were upregulated in the HCC group compared to non-HCC group
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Introduction:
Recent studies have published the roles of exosomal miRNAs in the pathogenesis of various type of malignancies and can be developed as potential biomarkers for diagnostic, prognostic and therapeutic purposes. The aim of this study was to identify the expression level of selected miRNAs (miR-182, miR-301a, and miR-373) in exosomes of...
Contexts in source publication
Context 1
... expression levels of three ascitic fluid exosomal miRNA candidates between NASHinduced liver cirrhosis with or without HCC are demonstrated in FIG. 2. The level of ascitic fluid exosomal miR-182 were significantly increased in HCC group by 1.60 (±0.208) as compared to the control group (p = 0.042). On the other hand, the expression level for ascitic fluid exosomal miR-301a was also found to be significantly raised by 1.94 (±0.327) in HCC group as compared to control group (p=0.023). ...
Context 2
... expression levels of three ascitic fluid exosomal miRNA candidates between NASHinduced liver cirrhosis with or without HCC are demonstrated in FIG. 2. The level of ascitic fluid exosomal miR-182 were significantly increased in HCC group by 1.60 (±0.208) as compared to the control group (p = 0.042). On the other hand, the expression level for ascitic fluid exosomal miR-301a was also found to be significantly raised by 1.94 (±0.327) in HCC group as compared to control group (p=0.023). ...
Citations
... Non-coding transcripts exceeding 200 nucleotides are knowns as long non-coding RNAs (lncRNAs) [24]. Research has demonstrated that lncRNAs act as either oncogenes or tumor suppressors and play a role in the regulatory processes of cancer initiation and progression [25]. Along with modulating the proliferation and differentiation of cancer cells, lncRNAs also regulate the metabolic reprogramming of these cells and are implicated in cancer cell invasion and metastasis [26]. ...
Cuproptosis and N6-methyladenosine (m6A) have potential as prognostic predictors in cancer patients, but their roles in hepatocellular carcinoma (HCC) are unclear. This study aimed to screen a total of 375 HCC samples were retrieved from the TCGA database, and lncRNAs related to cuproptosis and m6A were obtained through correlation analysis. To construct a risk assessment model, univariate Cox regression analysis and LASSO Cox regression were employed. Analyze the regulatory effect of relevant risk assessment models on tumor mutation load (TMB) and immune microenvironment. A total of five lncRNAs (AC007405.3, AL031985.3, TMCC1-AS1, MIR210HG, TMEM220-AS1) with independent overall survival-related risk models were obtained by LASSO survival regression. TP53 and CTNNB1 were the three genes found to have the most mutations in high-risk group patients. The high-risk group with low TMB had the worst survival, whereas the low-risk group with high TMB had the best survival. KEGG pathway analysis revealed that the high-risk group was enriched with cell cycle, oocyte meiosis, cell senescence, and glycolysis/glucose production pathways. We constructed a reliable cuproptosis- and m6A-related lncRNA model for the prognosis of HCC. The model may provide new insights into managing HCC patients, but further research is needed to validate it.
... HCC, and the examination of EVs with the miRNAs-embedded panel showed higher accuracy in the diagnosis of HCC (Lin and Zhang, 2019;Yang J. et al., 2022). In addition, other numerous EVs miRNAs have been identified as potential early-diagnosed markers for HCC, including but not limited to , and the combinations of multiple miRNAs would present higher diagnostic utility (Qu et al., 2017;Wang et al., 2018b;Xue et al., 2018;Xue et al., 2019;Cho et al., 2020a;Li W. et al., 2020;Muhammad Yusuf et al., 2020;Sheng et al., 2020;Sun et al., 2021;Yang et al., 2021;Chen S. et al., 2022;Deng et al., 2022;Lin et al., 2022). These markers are expected to construct new liquid biopsy modalities in the near future. ...
Due to the lack of distinct early symptoms and specific biomarkers, most patients with hepatocellular carcinoma (HCC) are usually diagnosed at advanced stages, rendering the treatment ineffective and useless. Therefore, recognition of the malady at precancerous lesions and early stages is particularly important for improving patient outcomes. The interest in extracellular vesicles (EVs) has been growing in recent years with the accumulating knowledge of their multiple cargoes and related multipotent roles in the modulation of immune response and tumor progression. By virtue of the rapid advancement of high-throughput techniques, multiple omics, including genomics/transcriptomics, proteomics, and metabolomics/lipidomics, have been widely integrated to analyze the role of EVs. Comprehensive analysis of multi-omics data will provide useful insights for discovery of new biomarkers and identification of therapeutic targets. Here, we review the attainment of multi-omics analysis to the finding of the potential role of EVs in early diagnosis and the immunotherapy in HCC.
... Another recent study conducted by Muhammad Yusuf et al. showed the expression levels of selected miRNAs (miR-182, miR-301a, and miR-373) in exosomes of the serum and ascitic fluid in 52 patients with NASH-caused cirrhosis with or without associated HCC using quantitative real-time PCR (Table 1). Their preliminary data showed a significant increase in the expression levels of exosomal miR-182, miR-301a, and miR-373 in both serum and ascetic fluid, suggesting the possible roles of these miRNAs as circulating biomarkers for NASH-caused cirrhosis and associated HCC [66] (Table 1). Interestingly, Jampoka et al. found that decreased serum level of miR-29a (Table 1) in NASH patients are strongly negatively correlated with the disease of NASH [67]. ...
Nonalcoholic fatty liver disease (NAFLD)/metabolic associated fatty liver disease (MAFLD) is becoming a public health problem worldwide. Steatosis as the simple form and nonalcoholic steatohepatitis (NASH) as its progression form are commonly seen in liver biopsy specimens from patients with obesity, diabetes, hyperlipidemia, hypertension, and the use of certain drugs. Patients with NASH and advanced fibrosis were associated with increased risks of liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanisms regarding the progression from simple steatosis to NASH fibrosis remain incompletely understood. Because NASH-caused liver injury is a complex process and multiple cell types are involved, intercellular communication is likely mediated by extracellular vesicles. Exosomes are a type of small extracellular vesicles and contain various cellular molecules, including proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs). MiRNAs are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and may play an important role in the pathogenesis of NALFD/NASH. In this article, we review the articles about NASH and exosomal miRNAs published in the most recent English literature through PubMed search and discuss the most recent criteria for histological diagnosis, pathogenesis from steatosis to NASH, roles of exosomal miRNAs in NASH pathogenesis and progression, as well as their potential in future clinical diagnosis and treatment for patients with NASH.
... (2021) posited that plasma exosomal miR-16, miR-146a, miR-192, and miR-221 are promising diagnostic and prognostic markers for (Muhammad Yusuf et al., 2020) showed that levels of ascites-derived exosomal miR-182, miR-301a, and miR-373 were elevated in patients with liver cirrhosis, indicating that these miRNAs may have utility as biomarkers in patients with liver cirrhosis. Taken together, these studies demonstrate that nucleic acids and proteins carried by exosomes from different sources may aggravate or alleviate HF in certain conditions and have utility as biomarkers for predicting HF. ...
Exosomes are extracellular membrane-encapsulated vesicles that are released into the extracellular space or biological fluids by many cell types through exocytosis. As a newly identified form of intercellular signal communication, exosomes mediate various pathological and physiological processes by exchanging various active substances between cells. The incidence and mortality of liver diseases is increasing worldwide. Therefore, we reviewed recent studies evaluating the role of exosomes from various sources in the diagnosis and treatment of liver diseases.
... Although detection technologies of exosomes have been well-established, a critical clinical-related issue naturally arises regarding which exosomes (from which type of body fluid) are the best exosomes for predicting the efficacy of HCC immunotherapy. Following YUSUF's study, although both serum-derived and ascites-fluid-derived exosomal miRNA may be regarded as circulating biomarkers for HCC patients, the exact predictive values of them may be different [127], which indicates that exosomes from different body fluids may hold varying predictive value in HCC patients. Nakashiki et al., pointed out that blood exosomes may not be suitable for reflecting the liver state because they contain other systemically circulating exosomes. ...
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, having a significantly poor prognosis and no sufficiently efficient treatments. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided new therapeutic approaches for HCC patients. Nevertheless, most patients with HCC do not benefit from immunotherapy. Exosomes are biologically active lipid bilayer nano-sized vesicles ranging in size from 30 to 150 nm and can be secreted by almost any cell. In the HCC tumor microenvironment (TME), numerous cells are involved in tumor progression, and exosomes—derived from tumor cells and immune cells—exhibit unique composition profiles and act as intercellular communicators by transporting various substances. Showing the dual characteristics of tumor promotion and suppression, exosomes exert multiple functions in shaping tumor immune responses in the crosstalk between tumor cells and surrounding immune cells, mediating immunotherapy resistance by affecting the PD-1/PD-L1 axis or the anti-tumor function of immune cells in the TME. Targeting exosomes or the application of exosomes as therapies is involved in many aspects of HCC immunotherapies (e.g., ICIs, tumor vaccines, and adoptive cell therapy) and may substantially enhance their efficacy. In this review, we discuss the impact of exosomes on the HCC TME and comprehensively summarize the role of exosomes in immunotherapy resistance and therapeutic application. We also discuss the potential of exosomes as biomarkers for predicting the efficacy of immunotherapy to help clinicians in identifying HCC patients who are amenable to immunotherapies.
... When used together with AFP, the AUROC were 0.834 and 0.847, compared to 0.791 of AFP alone Glycopeptide Site-specific N-glycopeptides from serum haptoglobin showed better diagnostic accuracy for NASH-HCC than AFP [70,71] Cytokine (adipokine) Adiponectin had slightly better diagnostic ability (AUROC, 0.770) than AFP (AUROC, 0.763). When combined with age, sex, DCP and glypican-3, the AUROC increased to 0.948 [65] TERT promoter mutation (C228T) in serum cfDNA showed better diagnostic ability for early NAFLD-HCC than AFP and DCP Cell-free DNA Methylation biomarkers in cfDNA improved the diagnostic performance when combined with AFP [76,78] microRNA The expression levels of exosomal miR-182, miR-301a and miR-373 in both serum and ascetic fluid were higher in NASH-cirrhosis patients with HCC than in those without HCC [77] AFP thrombospondin-2 (TSP-2). Thus, serum TSP-2 testing may also be useful for NAFLD-HCC surveillance. ...
... For example, telomerase reverse transcriptase (TERT) promoter mutations, the most common form of HCC genetic alteration [73][74][75], can be analyzed using cell-free DNA (cfDNA). Akuta et al [76] reported that TERT C228T mutation could be detected in 63.9% of NAFLD-HCC patients by analyzing cfDNA [76]. Notably, it can be positive, even in patients with normal AFP and DCP levels. ...
... For example, telomerase reverse transcriptase (TERT) promoter mutations, the most common form of HCC genetic alteration [73][74][75], can be analyzed using cell-free DNA (cfDNA). Akuta et al [76] reported that TERT C228T mutation could be detected in 63.9% of NAFLD-HCC patients by analyzing cfDNA [76]. Notably, it can be positive, even in patients with normal AFP and DCP levels. ...
High rates of excessive calorie intake diets and sedentary lifestyles have led to a global increase in nonalcoholic fatty liver disease (NAFLD). As a result, this condition has recently become one of the leading causes of hepatocellular carcinoma (HCC). Furthermore, the incidence of NAFLD-associated HCC (NAFLD-HCC) is expected to increase in the near future. Advanced liver fibrosis is the most common risk factor for NAFLD-HCC. However, up to 50% of NAFLDHCC cases develop without underlying liver cirrhosis. Epidemiological studies have revealed many other risk factors for this condition; including diabetes, other metabolic traits, obesity, old age, male sex, Hispanic ethnicity, mild alcohol intake, and elevated liver enzymes. Specific gene variants, such as single-nucleotide polymorphisms of patatin-like phospholipase domain 3, transmembrane 6 superfamily member 2, and membrane-bound O-acyl-transferase domaincontaining 7, are also associated with an increased risk of HCC in patients with NAFLD. This clinical and genetic information should be interpreted together for accurate risk prediction. Alpha-fetoprotein (AFP) is the only biomarker currently recommended for HCC screening. However, it is not sufficiently sensitive in addressing this diagnostic challenge. The GALAD score can be calculated based on sex, age, lectin-bound AFP, AFP, and des-carboxyprothrombin and is reported to show better diagnostic performance for HCC. In addition, emerging studies on genetic and epigenetic biomarkers have also yielded promising diagnostic potential. However, further research is needed to establish an effective surveillance program for the early diagnosis of NAFLD-HCC.
... Exosomes from the urine of HCC patients were successfully extracted and it was found that LINC00161 was expressed in urine [38]. Furthermore, it has been found that the expression levels of ascitic fluid-derived exosomal miR-182, miR-301a, and miR-373 were significantly upregulated in liver cancer [39]. As bile is a fluid directly secreted by liver cells, bile-derived exosomes might be more organ-specific and sensitive. ...
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Since most patients with HCC are diagnosed at the intermediate or advanced stage and because HCC has a high incidence of metastasis and recurrence, it is one of the leading causes of cancer death. Exosomes are a subtype of extracellular vesicles and are typically 30–150 nm in diameter. Originating from endosomes, they can be secreted by almost all living cells. They are widely present in various body fluids and serve as an important medium for the interactions between cells. A series of studies have revealed that exosomes-mediated intercellular transfer of proteins, nucleic acids, and metabolites plays a crucial role in the initiation and progression of HCC, hypoxia and angiogenesis, chemotherapy sensitivity, and cell death mode and regulates the immune microenvironment. In this paper, we reviewed the recent researches on the multiple roles of tumor-associated exosomes in the progression of HCC. We laid particular focus on those researches that reveal how exosomes regulate the tumor immune microenvironment (TIME) and how exosomal cargos affect the progression of HCC. Besides, we emphasize some prospective directions to achieve a more accurate and complete analysis of the HCC immune microenvironment.
Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome caused by fat deposition in hepatocytes. Patients with nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD with severe fibrosis, are at high risk for liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanism of progression from simple fat deposition to NASH is complex, and previous reports have linked NAFLD to gut microbiota, bile acids, immunity, adipokines, oxidative stress, and genetic or epigenetic factors. NASH-related liver injury involves multiple cell types, and intercellular signaling is thought to be mediated by extracellular vesicles. MicroRNAs (miRNAs) are short, noncoding RNAs that play important roles as post-transcriptional regulators of gene expression and have been implicated in the pathogenesis of various diseases. Recently, many reports have implicated microRNAs in the pathogenesis of NALFD/NASH, suggesting that exosomal miRNAs are potential non-invasive and sensitive biomarkers and that the microRNAs involved in the mechanism of the progression of NASH may be potential therapeutic target molecules. We are interested in which miRNAs are involved in the pathogenesis of NASH and which are potential target molecules for therapy. We summarize targeted miRNAs associated with the etiology and progression of NASH and discuss each miRNA in terms of its pathophysiology, potential therapeutic applications, and efficacy as a NASH biomarker.
Every year, thousands of liver cancer (LC) cases go undiagnosed. Despite the advances in LC diagnosis, treatment, and management, many patients continued to have rapid disease recurrence with poor outcomes. At present, physicians extensively rely on tissue tumor biopsy, which is invasive. Therefore, better noninvasive tools are urgently required to fight against such diseases. Human body fluids are a rich reservoir of potential biomarkers that are easily accessible and less invasive. But these body fluid proteins are complex and have a dynamic range of abundances, making it challenging to evaluate them efficiently. Thus, the study review and discuss a systematic analysis of LC human body fluid biomarkers and their clinical significance.
Background:
Liver cancer is the fourth most significant cause of cancer-related death. Lack of early diagnosis strategy and a scarcity of efficient therapy constitute the main reasons for its lethality. Exosomes, which contain various bioactive molecules, are characterized by high biocompatibility, low immunogenicity, and high transport efficiency. As a result, exosomes have become a research hotspot and present significant potential for cancer diagnosis biomarkers, biotherapeutics, therapy targets, drug carriers and therapeutic agents.
Aim:
To explore the potential of exosomes in the diagnosis and treatment of liver cancer.
Methods:
We conducted a systematic literature search via PubMed and Web of Science. The following keywords were used: "exosomal biomarkers", "exosomal therapy", "exosomal therapy", and "liver cancer" or "HCC". The duplicate data were deleted by EndNote software. Literature search focused on full-texts and references of each article were carefully checked. One author (Xiao-Cui Wei) screened the literature that met the following inclusion criteria: (1) Detection of exosomes or their contents in clinical samples (body fluid or tissue); or (2) Exosomes served as drug carriers or therapeutic factors. Two authors (Xiao-Cui Wei and Li-Juan Liu) independently reviewed all retained literature and analyzed the information.
Results:
A total of 1295 studies were identified using the systematic literature search. Of these, 835 duplicate studies were removed. A further 402 irrelevant studies were excluded due to being irrelevant, including other diseases, review articles, the literature containing neither clinical samples nor animal experiments, exosome-independent studies, methods for detecting exosomes, or articles in Chinese. Finally, 58 published papers were retained and analyzed in the study. It showed a list of potential exosomal biomarkers that were upregulated in the blood samples of patients with liver cancer. Those downregulated in exosomes might serve as possible biotherapeutics. Some exosomes derived from cells in vitro were used for cytology or animal experiments to explore the mechanism of these exosome contents in disease. These contents might serve as potential targets for liver cancer. Additionally, we also discussed that exosomes serve as drug carriers or therapeutic factors.
Conclusion:
Exosomes might serve as potential biomarkers or therapeutic biotargets in liver cancer and have the potential to act as drug carriers and self-treatment factors for liver cancer patients.
