Research progress of gut microbiota in hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer‐related death in the world. A number of challenges remain for the early detection and effective treatment of HCC. In recent years, microbiota have been proven to be associated with the development of HCC. Many studies have explored the pathogenesis, diagnostic marker, and therapeutic target potential of microbiota in hepatocellular carcinoma. Therefore, we aimed to introduce the research methods and achievements of gut microbiota in hepatocellular carcinoma and discuss the value of gut microbiota in the pathogenesis, diagnosis, and treatment of hepatocellular carcinoma.MethodsKeywords are used to search relevant articles which were mainly published from 2010 to 2021, and we further selected targeted articles and read the full text.ResultsGut microbiota involved in promoting the formation and development of hepatocellular carcinoma, and differential gut microbiota and microbial metabolites have the potential to be the biomarkers of hepatocellular carcinoma. Purposefully regulated gut microbiota can improve the prognosis of patients, which is expected to be used in hepatocellular carcinoma.ConclusionThe study of gut microbiota in hepatocellular carcinoma is definitely worthy of study. In‐depth and elaborate research design is crucial for the study of the mechanism of gut microbiota involved in hepatocellular carcinoma, which can provide new directions and targets for the diagnosis, treatment, and prognosis of hepatocellular carcinoma.     

Programmed cell death ligand 1 expression in a case of poorly differentiated lymphocyte‐rich hepatocellular carcinoma

Our pathological study of a case of poorly differentiated lymphocyte‐rich hepatocellular carcinoma suggested that immune checkpoint inhibitor may be an effective therapy. The histological type is an important factor in determining treatment choices.     

Dysfunction of miR‐802 in tumors

Recent studies have shown that miR‐802 is abnormally expressed in many tumors. miR‐802 is expressed at low levels in tissues and cells of gastric cancer, colorectal cancer, breast cancer, cervical cancer, epithelial ovarian cancer, tongue squamous cell carcinoma, oral squamous cell carcinoma, esophageal squamous cell carcinoma, laryngeal squamous cell carcinoma, and melanoma. In contrast, miR‐802 is overexpressed in hepatocellular carcinoma, bladder urothelial cancer, osteosarcoma, and cholesteatoma tissue cells. It should be noted that the results of studies on the expression of miR‐802 in pancreatic cancer, prostate cancer, and lung cancer are inconsistent. Current studies have found that miR‐802 can target and regulate genes in different tumors, and affect the regulation of the Wnt signaling pathway, EMT signaling pathway, PI3K/AKT signaling pathway, ERK signaling pathway, and Hedgehog signaling pathway. At the same time, miR‐802 is regulated by the endogenous competition of four ceRNAs, including circDONSON, IGFL2‐AS1, MIR155HG, and MIR4435‐2HG. This article reviews the abnormal expression of miR‐802 in a variety of tumors, expounds the mechanism by which miR‐802 affects tumor progression by regulating different target genes, and elaborates the network of miR‐802‐related ceRNAs. We also summarized the limitations of miR‐802 research and looked forward to the potential application of miR‐802 in the diagnosis and prognosis of tumors.     

CircRNA_0008194 functions as a ceRNA to promote invasion of hepatocellular carcinoma via inhibiting miR‐190a/AHNAK signaling pathway

BackgroundHepatitis B virus infection was identified as the main risk factor of hepatocellular carcinoma (HCC) in China, which induced a high morbidity and mortality. In recent years, circRNAs were reported involving in the oncogenesis and development of multiple malignant tumors.MethodBioinformatical analysis has been employed to predict the relevant circRNA with AHNAK. The loss of function and gain of function have been used by knocking‐down circRNA through the shRNA technology while overexpressing through lentivirus infection. Dual‐luciferase reporter assay was used to detect circRNA binding to miRNA and target genes. We further used immunoprecipitation technique to detect the binding ability between non‐coding RNAs.ResultsIn this study, according to the previous report, we mainly focused on AHNAK, which has been confirmed as an oncogene involving in the metastasis of HCC. Bioinformatics analysis showed that circ_0008194 could be spliced by AHNAK. In this study, the abnormal upregulated circ_0008194 in tumor tissues was detected. The positive correlation between circ_0008194 and AHNAK was also confirmed. Through knockdown and overexpression of circ_0008194, we conducted in vitro functional studies. We found circ_0008194 could induce the invasion of cells in vitro. Mechanically, circ_0008194 presented the binding ability with miR‐190a causing the suppression of miR‐190a expression, causing the competitive inhibition of AHNAK, resulting in the promotion of EMT.ConclusionOur results suggested that circ_0008194 may act as a sponge to adsorb miR‐190a, thereby promoting the expression of AHNAK and promoting the metastasis of liver cancer tumors.     

The clinical application of PIVKA‐II in hepatocellular carcinoma and chronic liver diseases: A multi‐center study in China

BackgroundDue to the absence of specific symptoms and low survival rate, efficient biomarkers for hepatocellular carcinoma (HCC) diagnosis are urgently required. The purpose of this study was to evaluate the diagnostic performance of protein induced by vitamin K absence or antagonist‐II (PIVKA‐II) and to determine the optimal cutoff values for HBV infection‐related HCC.MethodsWe conducted a cross‐sectional, multi‐center study in China to ascertain the cutoff value for HCC patients in the context of CHB‐ and HBV‐related cirrhosis. The receiver operating characteristic curve (ROC) and the area under the curve (AUC) were used to evaluate the diagnostic performance of PIVKA‐II.ResultsThis study enrolled 784 subjects and demonstrated that PIVKA‐II had a sensitivity of 84.08% and a specificity of 90.43% in diagnosis HCC from chronic liver diseases. PIVKA‐II at a cutoff of 37.5 mAU/mL yielded an AUC of 0.9737 (sensitivity 91.78% and specificity 96.30%) in discriminating HCC from chronic hepatitis B (CHB) patients. PIVKA‐II at a cutoff of 45 mAU/mL yielded an AUC of 0.9419 (sensitivity 77.46% and specificity 95.12%) in discriminating HCC‐ from HBV‐related cirrhosis patients. Furthermore, using a cutoff value of 40 mAU/mL for PIVKA‐II as an HCC marker, only 4.81% (15/312) was positive in chronic hepatitis and 12.80% (37/289) in cirrhosis patients, revealing the satisfactory specificity of PIVKA‐II in chronic liver disease of different etiologies.ConclusionOur data indicated that PIVKA‐II had satisfactory diagnostic efficiencies and could be used as a screening or surveillance biomarker in HCC high‐risk population.     

Ruled out of preeclampsia‐like syndrome due to COVID‐19: A case study

Coronavirus disease (COVID‐19) is an infectious disease. In this study, we report a 28‐year‐old pregnant woman who had a postpartum seizure with a background of HELLP syndrome and a proven COVID‐19 infection. Her child survived, and at 12‐week postpartum, all maternal COVID‐19–related symptoms vanished, and she was cured.     

Clinical Significance of Vimentin Expression and Her‐2 Status in Patients with Gastric Carcinoma

Objectives

To determine whether vimentin could be used as a marker of gastric carcinomas with more aggressive behavior. To detect the extent of Her‐2 status in gastric carcinoma and explore the correlation between vimentin expression and Her‐2 status.

Methods

Vimentin expression was detected in surgically resected gastric carcinoma tissue specimens from 143 patients by immunohistochemistry. The human epidermal growth factor receptor 2 (Her2) status was evaluated by fluorescence in situ hybridization (FISH). Correlations between vimentin expression, Her‐2 status and clinicopathological factors were evaluated using Kaplan‐Meier method and Cox multivariate survival models.

Results

Vimentin expression was significantly correlated with age, advanced stage, poorly differentiated type, venous invasion, hepatic metastasis, and recurrence (p < 0.05). Her‐2 gene was amplified in 16 (11.2%) out of the 143 gastric carcinoma tissue specimens. Her‐2 status was correlated with advanced cancer, poor differentiation, venous invasion, hepatic metastasis, and recurrence (p < 0.05). The result of multivariate analysis showed that vimentin expression and lymph node metastasis were independent prognostic factors.

Conclusions

Vimentin expression in epithelial cells of the surgically resected gastric adenocarcinoma tissue is an independent predictor of short survival, and Her‐2 status shows a valuable correlation with clinical parameters.     

The first reported case of Noonan syndrome complicated with hepatocellular carcinoma

Noonan syndrome is a genetic multisystem disorder and is associated with mutation of genes encoding the proteins in the RAS‐MAPK pathway. We reported the first case of Noonan syndrome complicated with hepatocellular carcinoma.     

Translation role of circRNAs in cancers

Circular RNAs (circRNAs) constitute a class of covalently closed RNA molecules. With the continuous advancement of high‐throughput sequencing technology and bioinformatics tools, many circRNAs have been identified in various human tissues and cell lines. Notably, recent studies have indicated that some circRNAs have translational functions. Internal ribosome entry sites and the N6‐methyladenosine modification mediate cap‐independent translation. This review describes these two translation mechanisms and verification methods at the molecular level. Databases (including ORF Finder, Pfam, BLASTp, CircRNADb, CircBase, CircPro, CircCode, IRESite, IRESbase) were used to analyze whether circRNAs have the structural characteristic of translation. CircRNA minigene reporter system containing green fluorescent protein (GFP) confirmed the translation potential of circRNAs. Also, we briefly summarize the roles of proteins/peptides encoded by circRNAs (circFBXW7, circFNDC3B, circLgr4, circPPP1R12A, circMAPK1, circβ‐catenin, circGprc5a, circ‐SHPRH, circPINTexon2, circAKT3) that have been verified thus far in human cancers (triple‐negative breast cancer, colon cancer, gastric cancer, hepatocellular carcinoma, bladder cancer, glioblastoma). Those findings suggest circRNAs have a great implication in translation of the human genome.     

A multi‐omics‐based investigation of the immunological and prognostic impact of necroptosis‐related genes in patients with hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is the most common histological subtype of liver cancer and the third leading cause of death from cancer globally. Recent studies suggested cell death is also a key regulator of tumour progression. The purpose of this study was to generate a new predictive signature for HCC patients based on a complete analysis of necroptosis‐associated genes.MethodsWe extracted the mRNA expression profiles of HCC patients from the TCGA and ICGC databases and their clinical data. In addition, we used the IMvigor210 cohort to validate our model molecule''s ability to predict the effect of immunotherapy. In the TCGA cohort, a seven‐gene risk‐prognostic model was constructed using univariate cox‐Lasoo regression. External validation was conducted using the ICGC cohort. The ssGSEA algorithm is used to determine the degree of immune function response. The CMAP databases are used for chemotherapy drug analysis and screening for drugs that reduce the expression of high‐risk genes. The cbioportal database was used to explore mutations in model genes.ResultsSurvival analysis shows shorter survival for high‐risk patients. Immune function analysis revealed significant differences in the activity of immune pathways between risk subgroups. Varied risk scores result in dramatically diverse immune infiltration and tumour growth, as well as significantly different chemotherapeutic sensitivity. In addition, Apigenin and LY‐294002 reduced the expression of high‐risk genes, while Arecoline had the opposite effect. In the immunotherapy IMvigor210 cohort, risk scores were significantly different between the objective responder and non‐responder groups. By comparing the models constructed with published literature, it is suggested that our model has better predictive power.ConclusionsWe created a new prognostic signature of necroptosis‐related genes that can be used as potential prognostic biomarkers to guide effective personalized therapy for hepatocellular carcinoma patients.     

Clinical value of serum AFP and PIVKA‐II for diagnosis,treatment and prognosis of hepatocellular carcinoma

BackgroundThe accuracy of alpha‐fetoprotein (AFP) as a diagnostic marker for hepatocellular carcinoma (HCC) is insufficient, and the application of abnormal prothrombin (PIVKA‐II) in HCC is still controversial.MethodsSerum AFP and PIVKA‐II levels were analyzed in 145 cases of HCC, 57 of benign liver disease, 55 of cholangiocarcinoma and gallbladder carcinoma, 112 of other gastrointestinal tumors with liver metastasis, and 101 healthy controls. Receiver operating characteristic curve and area under the curve were used to evaluate the diagnostic value of AFP and PIVKA‐II for HCC. The changes in serum AFP and PIVKA‐II levels before and after treatment in 47 HCC patients who underwent surgery and 77 who received interventional treatment were used to evaluate treatment efficacy and prognosis in HCC.ResultsThe concentrations of AFP and PIVKA‐II in the HCC group were significantly higher than those in other groups (p < 0.01). The diagnostic value of PIVKA‐II in HCC was better than that of AFP, and combined detection improved the diagnostic sensitivity and specificity. The levels of AFP and PIVKA‐II after liver cancer surgery were significantly lower than those before surgery. Elevated levels of PIVKA‐II before surgery predicted disease progression, and patients who remained positive for PIVKA‐II after surgery had worse prognosis than those who became negative after surgery.ConclusionsCombined detection of AFP and PIVKA‐II is superior to both tests alone. We found that higher serum level of PIVKA‐II indicates more severe HCC, with worse prognosis, while the level of AFP had no correlation with the prognosis.     

Hsa_circRNA_0001971 contributes to oral squamous cell carcinoma progression via miR‐186‐5p/Fibronectin type III domain containing 3B axis

BackgroundCircular RNAs (circRNAs) are closely associated with the progression of oral squamous cell carcinoma (OSCC). circRNA_0001971 has been proved to accelerate the OSCC development. Here, we aim to identify the new molecular mechanism of hsa_circRNA_0001971 (circRNA_0001971) in OSCC.MethodsThe levels of circRNA_0001971, miR‐186‐5p, and fibronectin type III domain containing 3B (FNDC3B) in tissues and cells were verified by qRT‐PCR or Western blotting. The interaction between circRNA_0001971, miR‐186‐5p, and FNDC3B was identified by bioinformatics analysis, luciferase assay, and RIP assay. The effect of circRNA_0001971/miR‐186‐5p/FNDC3B axis on OSCC cell proliferation, migration, and invasion by cell functional experiments including CCK8, wound healing, and transwell assays.ResultsOur study displayed that circRNA_0001971 and FNDC3B were elevated in OSCC, whereas miR‐186‐5p was declined in OSCC. Silencing circRNA_0001971 attenuated the malignancy of OSCC cells by suppressing proliferation, migration, and invasion. In OSCC cells, circRNA_0001971 sponged miR‐186‐5p to enhance FNDC3B. Due to the interaction between circRNA_0001971, miR‐186‐5p, and FNDC3B, FNDC3B overexpression relieved the negative function of silencing circRNA_0001971 in OSCC cells.ConclusionOverall, our study discovered that circRNA_0001971 was a tumor promoter in OSCC progression by targeting miR‐186‐5p/FNDC3B axis.     

Expression changes of serum LINC00941 and LINC00514 in HBV infection‐related liver diseases and their potential application values

BackgroundLong non‐coding RNAs (LncRNAs) are considered as potential diagnostic markers for a variety of tumors. Here, we aimed to explore the changes of LINC00941 and LINC00514 expression in hepatitis B virus (HBV) infection‐related liver disease and evaluate their application value in disease diagnosis.MethodsSerum levels of LINC00941 and LINC00514 were detected by qRT‐PCR. Potential diagnostic values were evaluated by receiver operating characteristic curve (ROC) analysis.ResultsSerum LINC00941 and LINC00514 levels were elevated in patients with chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) compared with controls. When distinguishing HCC from controls, serum LINC00941 and LINC00514 had diagnostic parameters of an AUC of 0.919 and 0.808, sensitivity of 85% and 90%, and specificity of 86.67% and 56.67%, which were higher than parameters for alpha fetal protein (AFP) (all p < 0.0001). When distinguishing HCC from LC, CHB, or LC from controls, the combined detection of LINC00941 or LINC00514 can significantly improve the accuracy of AFP test alone (all p < 0.05).ConclusionsLINC00941 and LINC00514 were increased in the serum of HBV infection‐associated liver diseases and might be independent markers for the detection of liver diseases.     

Hypertriglyceridemia‐induced pancreatitis after egg retrieval for in vitro fertilization and fenofibrate cessation

A 36‐year‐old woman with prior hypertriglyceridemia‐induced pancreatitis presented with a recurrence of pancreatitis after beginning in vitro fertilization (IVF). Her primary care physician had discontinued fenofibrate due to concerns for teratogenicity. This case illustrates the importance of fibrate therapy for high‐risk women undergoing IVF, despite limited evidence regarding its teratogenicity.     

LncRNA FGF14‐AS2 represses growth of prostate carcinoma cells via modulating miR‐96‐5p/AJAP1 axis

ObjectiveThis investigation devoted to lncRNA FGF14 antisense RNA 2 (FGF14‐AS2) in prostate carcinoma progression.MethodsThe levels of lncRNA FGF14‐AS2, miR‐96‐5p, and Adherens junction‐associated protein‐1 (AJAP1) in prostate carcinoma were tested by Western blot and qRT‐PCR. How these two genes interacted was confirmed by RNA immunoprecipitation and dualluciferase gene methods. The effect of FGF14‐AS2/miR‐96‐5p/AJAP1 axis in prostate carcinoma progression was determined by MTT, Transwell, and nude mice tumor model.ResultsFGF14‐AS2 was a downregulated lncRNA in prostate carcinoma tissue and cells. FGF14‐AS2 could restrain miR‐96‐5p expression while miR‐96‐5p hampered AJAP1. FGF14‐AS2 could effectively decrease the biological behaviors of prostate carcinoma cells, while knock‐down of FGF14‐AS2 triggered opposite results. Moreover, miR‐96‐5p mimic presented a cancer promoter role in prostate carcinoma cells. AJAP1 expression level could affect levels of proteins related to epithelial‐mesenchymal transition. In vivo experiment suggested that overexpressing FGF14‐AS2 could reverse the promotion of silenced AJAP1 on prostate carcinoma cell metastasis, thus to inhibit tumor growth.ConclusionlncRNA FGF14‐AS2 was a downregulated lncRNA in prostate carcinoma and influenced cell proliferation and metastasis. The influence relied on modulating miR‐96‐5p and its target gene AJAP1.     

Malignant transformation of tailgut cyst to squamous cell carcinoma,a rare case with poor outcome

Tailgut cyst, a type of retro‐rectal cyst, is a rare condition requiring evaluation for malignant transformation. We report a case of squamous cell carcinoma arising in the retro‐rectal cyst, in a 51‐year‐old female who underwent incomplete resection of the cyst and chemo‐radiotherapy, subsequently became locally recurred and metastatic.