Hepatocellular carcinoma (HCC) remains one of the most common malignant neoplasms. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a key role in the lipid remodelling and is correlated with various neoplasms. Nonetheless, the biological functions and molecular mechanisms of LPCAT1 underlying HCC remain obscure.

Ovarian carcinoma is caused by multiple factors, but its etiology associated with microbes and infection is unknown. Using 16S rRNA high-throughput sequencing methods, the diversity and composition of the microbiota from ovarian cancer tissues (25 samples) and normal distal fallopian tube tissues (25 samples) were analyzed. High-throughput sequencing showed that the diversity and richness indexes were significantly decreased in ovarian cancer tissues compared to tissues from normal distal fallopian tubes. The ratio of the two phyla for Proteobacteria/Firmicutes was notably increased in ovarian cancer, which revealed that microbial composition change might be associated with the process of ovarian cancer development. In addition, transcriptome-sequencing (RNA-seq) analyses suggested that the transcriptional profiles were statistically different between ovarian carcinoma and normal distal fallopian tubes. Moreover, a set of genes including 84 different inflammation-associated or immune-associated genes, which had been named as the human antibacterial-response genes were also modulated expression. Therefore, we hypothesize that the microbial composition change, as a novel risk factor, may be involving the initiation and progression of ovarian cancer via influencing and regulating the local immune microenvironment of fallopian tubes except for regular pathways.

Although miR-132 has been studied in various human tumors, few studies have investigated the role of miR-132 in hepatocellular carcinoma (HCC). The present study aimed to evaluate the associations between miR-132 and clinicopathological parameters, including recurrence, in patients with HCC. Reverse transcription-quantitative polymerase chain reaction analysis was used to detect the expression levels of miR-132 in 95 cases of HCC and their corresponding non-cancerous liver tissues. Th e associations between miR-132 expression levels and clinicopathological characteristics, including recurrence, were investigated in patients with HCC. miR-132 expression levels were significantly reduced in HCC tissues, as compared with adjacent non-cancerous tissues (1.9245±0.7564 vs. 2.7326±1.1475; P<0.001). The area under curve (AUC) of receiver operating characteristic (ROC) used to distinguish cancerous and non-cancerous tissues was 0.711 for miR-132 expression (95% confidence interval, 0.637-0.785; P<0.001) and the optimal cut-off value was 2.25. Expression levels of miR-132 were significantly reduced in the distant metastasis (P=0.031), advanced clinical TNM stage (P=0.022), hepatitis B virus-positive (P<0.001), NM23-expressed (P=0.034), high Ki-67 labeling index (LI; P=0.005) and tumor infiltration or no capsule groups (P=0.026). Spearman correlation analysis demonstrated that miR-132 was significantly correlated with hepatitis B virus infection (r=-0.351; P<0.001), NM23 (r=-0.220; P=0.032), Ki-67 LI (r=-0.264; P=0.010) and tumor capsule (r=-0.207; P=0.044). Kaplan-Meier analysis with the log-rank test indicated an approximate difference of 8 months, although miR-132 may exhibit inferior values for the prediction of recurrence in HCC patients (50.95 vs. 58.68 months; P=0.512). Therefore, the findings of the present study indicated that miR-132 is downregulated in HCC and may serve as a tumor suppressor in its progression.

HPV integration usually occurs in HPV-related cancer, and is the main cause of cancer. But the carcinogenic mechanism of HPV integration is unclear. The study aims to provide a theoretical basis for understanding the pathogenesis of cervical adenocarcinoma (AC) and cervical squamous carcinoma (SCC).

The current study aimed to evaluate the synergistic efficacy of lenvatinib and FOLFOX (infusional fluorouracil (FU), folinic acid, and oxaliplatin) in hepatocellular carcinoma (HCC) using patient-derived xenograft (PDX) and PDX-derived organotypic spheroid (XDOTS) models in vivo and in vitro.

Sorafenib is the first molecular-targeted drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its treatment efficiency decreases after a short period of time because of the development of drug resistance. This study investigates the role of key genes in regulating sorafenib-resistance and elucidates the mechanism of drug resistance in hepatocellular carcinoma.

Predicting the prognosis of hepatocellular carcinoma (HCC) is a major medical challenge and of guiding significance for treatment. This study explored the actual relevance of RNA expression in predicting HCC prognosis. Cox's multiple regression was used to establish a risk score staging classification and to predict the HCC patients' prognosis on the basis of data in the Cancer Genome Atlas (TCGA). We screened seven gene biomarkers related to the prognosis of HCC from the perspective of oxidative stress, including Alpha-Enolase 1(ENO1), N-myc downstream-regulated gene 1 (NDRG1), nucleophosmin (NPM1), metallothionein-3, H2A histone family member X, Thioredoxin reductase 1 (TXNRD1) and interleukin 33 (IL-33). Among them we measured the expression of ENO1, NGDP1, NPM1, TXNRD1 and IL-33 to investigate the reliability of the multi-index prediction. The first four markers' expressions increased successively in the paracellular tissues, the hepatocellular carcinoma samples (from patients with better prognosis) and the hepatocellular carcinoma samples (from patients with poor prognosis), while IL-33 showed the opposite trend. The seven genes increased the sensitivity and specificity of the predictive model, resulting in a significant increase in overall confidence. Compared with the patients with higher-risk scores, the survival rates with lower-risk scores are significantly increased. Risk score is more accurate in predicting the prognosis HCC patients than other clinical factors. In conclusion, we use the Cox regression model to identify seven oxidative stress-related genes, investigate the reliability of the multi-index prediction, and develop a risk staging model for predicting the prognosis of HCC patients and guiding precise treatment strategy.

Pulmonary Sarcomatoid Carcinoma (PSC) constitutes a heterogeneous group of non-small-cell lung carcinomas (NSCLCs) with a poor prognosis. In this study, a group of 7 patients with PSC was studied. Microscope analysis of all 7 cases revealed a pleomorphic carcinoma subtype. Moreover, 5 cases (71.4%) were composed entirely of malignant sarcomatoid-like elements, and 2 cases (28.6%) were composed of malignant sarcomatoid-like elements and at least 10% adenocarcinoma-like elements. Immunohistochemically, the PSC components of all 7 cases were positive for vimentin and cytokeratins, including cytokeratin (CK) and cytokeratin 7 (CK7). Next-Generation Sequencing (NGS) was performed, and a total of 136 putative somatic variants and one gene fusion were identified, of which 16 variants were considered hot spot mutations, including the genes EGFR, EML4-ALK, MET, BRAF, PIK3CA, and TP53. Of these hot spot mutations, one sample expressing an EML4-ALK fusion was further confirmed by Ventana IHC, and one sample containing an EGFR exon 19 deletion was also confirmed. The NGS results imply that TP53 mutations occur often in PSCs and that EML4-ALK fusion events and EGFR exon deletions also occur in these rare tumors. Molecular targeted therapy may be a useful treatment strategy for these rare lung tumors.

Ferroptosis is a new type of cell death that has been recognized in recent years and is different from apoptosis, autophagy, and necrosis. It is mainly due to cellular iron homeostasis and lipid peroxidation of iron metabolism caused by large accumulation. There is a close correlation between ferroptosis and hepatocellular carcinoma (HCC). This study shows that the expression of the long noncoding RNA HEPFAL was reduced in HCC tissues. We found that lncRNA HEPFAL can promote ferroptosis by reducing the expression of solute carrier family 7 member 11 (SLC7A11) and increasing the levels of lipid reactive oxygen species (ROS) and iron (two surrogate markers of ferroptosis). In addition, we found that lncRNA HEPFAL increases the sensitivity of erastin-induced ferroptosis, which may be related to mTORC1, and lncRNA HEPFAL can promote the ubiquitination of SLC7A11 and reduce the stability of the SLC7A11 protein, resulting in decreased expression. Understanding these mechanisms indicates that lncRNAs related to ferroptosis are essential for the occurrence and treatment of HCC.

Despite the advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfactory due to postsurgical recurrence and treatment resistance. Therefore, it is important to reveal the mechanisms underlying HCC and identify potential therapeutic targets against HCC, which could facilitate the development of novel therapies. Based on 12 HCC samples and 12 paired paracancerous normal tissues, we identified differentially expressed mRNAs and lncRNAs using the "limma" package in R software. Moreover, we used the weighted gene coexpression network analysis (WGCNA) to analyze the expression data and screened hub genes. Furthermore, we performed pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. In addition, the relative abundance of a given gene set was estimated by single-sample Gene Set Enrichment Analysis. We identified 687 differentially expressed mRNAs and 260 differentially expressed lncRNAs. A total of 6 modules were revealed by WGCNA, and MT1M and MT1E genes from the red module were identified as hub genes. Moreover, pathway analysis revealed the top 10 enriched KEGG pathways of upregulated or downregulated genes. Additionally, we also found that CD58 might act as an immune checkpoint gene in HCC via PD1/CTLA4 pathways and regulate the levels of tumor-infiltrating immune cells in HCC tissues, which might be an immunotherapeutic target in HCC. Our research identified key functional modules and immunomodulatory regulators for HCC, which might offer novel diagnostic biomarkers and/or therapeutic targets for cancer immunotherapy.

Oral, gut, and tumor microbiota have been implicated as important regulators in the carcinogenesis and progression of gastrointestinal malignancies. However, few studies focused on the existence and association of resident microbes within different body regions. Herein, we aim to reveal the durability of the oral-gut-tumor microbiome and its diagnostic performance in hepatocellular carcinoma (HCC). Our study included two cohorts: a retrospective discovery cohort of 364 HBV-HCC patients and 160 controls with oral or fecal samples, a prospective validation cohort of 91 cases, and 124 controls for matching samples, as well as 48 HBV, and 39 HBV-cirrhosis patients for gut microbial patterns examined by 16S rRNA gene sequencing. With the random forest analysis, 10 oral and 9 gut genera that could distinguish HCC from controls in the retrospective cohort were validated among the prospective matching participants, with area under the curve (AUC) values of 0.7971 and 0.8084, respectively. When influential taxa were merged, the AUC of the consistent classifier increased to 0.9405. The performance continued to improve to 0.9811 when combined with serum levels of alpha-fetoprotein (AFP). Specifically, microbial biomarkers represented by Streptococcus displayed a constantly increasing trend during the disease transition. Furthermore, the presence of several dominant microbiota species was confirmed in hepatic tumor and non-tumor tissues with fluorescence in situ hybridization (FISH) and 5 R 16S rRNA gene sequencing. Overall, our findings based on the oral-gut-tumor microbiota provide a reliable approach for the early detection of HCC.

The WD-repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1-6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune-competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A-DDB1-ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFα locus by blocking autophagic degradation of p65, elevates intratumoral myeloid-derived suppressor cell (MDSC) number, and reduces CD8+ T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFα blockade. TNFα recruits NF-κB to activate the transcription of WDR6, establishing a WDR6-TNFα loop. Clinically, the WDR6/UVRAG/NF-κB pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR-like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti-PD-L1 against HCC with WDR6 dysregulation.

BACKGROUND Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic protein cloned from activated macrophages in human and rat allografts. AIF-1 has been identified as a modulator of inflammatory response, and recently published studies have shown its increased expression in carcinogenesis. However, there are still limited data on the potential functional role of AIF-1 in hepatocellular carcinoma (HCC). MATERIAL AND METHODS We evaluated the expression of AIF-1 in 104 cases of paired HCC and adjacent non-cancerous liver tissues using immunohistochemistry, Western blotting, and qPCR analysis, and sought to determine whether its expression was correlated with clinicopathological features. In vitro assays, including cell proliferation and migration assays, were used to study the effects of AIF-1 knockdown in L02 human hepatocyte, and Huh7 and SMMC7721 liver cancer cell lines. RESULTS Expression of AIF-1 was increased in HCC compared to adjacent normal liver tissues and was positively correlated with median tumor size (p=0.046), number of tumor deposits (p=0.009), the Barcelona Clinic Liver Cancer (BCLC) stage (p=0.004), and portal vein tumor thrombus (PVTT) (p<0.001). Huh7 and SMMC7721 human HCC cells demonstrated upregulated AIF-1 expression compared to normal hepatocytes. Small interfering RNA (siRNA)-mediated silencing of AIF-1 expression resulted in a reduction in cell proliferation and migration in human HCC cells. CONCLUSIONS These findings suggest AIF-1 may have roles as a diagnostic or prognostic biomarker and a promising therapeutic target in HCC.

Previously, we found that the expression of microRNA-146a (miR-146a) was downregulated in hepatocellular carcinoma (HCC) formalin-fixed paraffin-embedded (FFPE) tissues compared to the adjacent noncancerous hepatic tissues. In the current study, we have explored the in vitro effect of miR-146a on the malignant phenotypes of HCC cells. MiR-146a mimic could suppress cell growth and increase cellular apoptosis in HCC cell lines HepG2, HepB3, and SNU449, as assessed by spectrophotometry, fluorimetry, and fluorescence microscopy, respectively. Furthermore, western blot showed that miR-146a mimic downregulated EGFR, ERK1/2, and stat5 signalings. These effects were less potent compared to that of a siRNA targeting EGFR, a known target gene of miR-146a. Moreover, miR-146a mimic could enhance the cell growth inhibition and apoptosis induction impact of various EGFR targeting agents. The most potent combination was miR-146a mimic with cetuximab, presenting a synergistic effect. In conclusion, miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC.

Ferroptosis is a newly identified cell death mechanism and potential biomarker for hepatocellular carcinoma (HCC) therapy; however, its clinical relevance and underlying mechanism remain unclear. In this study, transcriptome and methylome data from 374 HCC cases were investigated for 41 ferroptosis-related genes to identify ferroptosis activity-associated subtypes. These subtypes were further investigated for associations with clinical and pathological variables, gene mutation landscapes, deregulated pathways and tumour microenvironmental immunity. A gene expression signature and predictive model were developed and validated using an additional 232 HCC cases from another independent cohort. Two distinct ferroptosis phenotypes (Ferroptosis-H and Ferroptosis-L) were identified according to ferroptosis gene expression and methylation in the patients with HCC. Patients with the Ferroptosis-H had worse overall and disease-specific survival, and the molecular subtypes were significantly associated with different clinical characteristics, mRNA expression patterns, tumour mutation profiles and microenvironmental immune status. Furthermore, a 15-gene ferroptosis-related prognostic model (FPM) for HCC was developed and validated which demonstrated accurate risk stratification ability. A nomogram included the FPM risk score, ECOG PS and hepatitis B status was developed for eventual clinical translation. Our results suggest that HCC subtypes defined by ferroptosis gene expression and methylation may be used to stratify patients for clinical decision-making.

Alternative splicing (AS) is crucial a mechanism by which the complexity of mammalian and viral proteom increased overwhelmingly. There lacks systematic and comprehensive analysis of the prognostic significance of AS profiling landscape for uteri corpus endometrial carcinoma (UCEC). In this study, univariate and multivariate Cox regression analyses were conducted to identify candidate survival-associated AS events curated from SpliceSeq for the construction of prognostic index (PI) models. A correlation network between splicing factor-related AS events and significant survival-associated AS events were constructed using Cytoscape 3.5. As consequence, 28281 AS events from 8137 genes were detected from 506 UCEC patients, including 2630 survival-associated AS events. Kaplan Meier survival analysis revealed that six of the seven PI models (AD, AP, AT, ME, RI and ALL) exhibited good performance in stratifying the prognosis of low risk and high risk group (P<0.05). Among the six PI models, PI-AT performed best with an area under curves (AUC) value of 0.758 from time-dependent receiver operating characteristic. Correlation network implicated potential regulatory mechanism of AS events in UCEC. PI models based on survival-associated AS events for UCEC in this study showed preferable prognosis-predicting ability and may be promising prognostic indicators for UCEC patients.Summary: This is the first study to systematically investigate the prognostic value of AS in UCEC. Findings in the presents study supported the clinical potential of AS for UCEC and shed light on the potential AS-associated molecular basis of UCEC.

Drug resistance is the leading cause of chemotherapy failure in the treatment of ovarian cancer. So far, little is known about the mechanism of chemoresistance in ovarian cancer. In this study, we explored the mechanism that HSP27 was involved in cisplatin resistance of ovarian cancer both in vitro and clinically. HSP27 protein was found to be upregulated and expressed in cisplatin-resistant ovarian cancer cell line C13*, and HSP27 siRNA transfection reversed the chemoresistance of C13*. We found that HSP27 exerted its chemoresistant role by inhibiting p21 transferring from the nucleus to the plasma through the activation of phosphorylated-Akt pathway. These findings have implications for clinical trials aimed at a potential therapeutic target for ovarian tumors that are refractory to conventional treatment.

The clinical significance of microRNA (miR)‑136‑5p in hepatocellular carcinoma (HCC) has not been verified. Therefore, in the current study, the authors aimed to explore miR‑136‑5p expression and its clinical significance in HCC, as well as to investigate its potential target genes function. The authors detected the levels of miR‑136‑5p in 101 pairs of HCC and para‑cancer tissues via reverse transcription‑quantitative polymerase chain reaction. Gene Expression Omnibus database and the Cancer Genome Atlas (TCGA) database were used to further verify the clinical significance of miR‑136‑5p expression in HCC. The target genes prediction analysis of miR‑136‑5p, natural language processing (NLP) analysis of HCC in PubMed and gene functional enrichment analysis were conducted. The miR‑136‑5p level was markedly downregulated in HCC tissue, compared to para‑non‑tumor tissue. MiR‑136‑5p expression decreased in HCC patients with metastasis (P=0.004), advance TNM stage (P<0.001), portal vein tumor embolus (P=0.007) and vaso‑invasion (P=0.003), compared with those HCC patients with non‑metastasis, early TNM stage, non‑portal vein tumor embolus and non‑vaso‑invasion, respectively. In the TCGA database, downregulated miR‑136‑5p was also observed in HCC tissue compared to normal liver tissue (P<0.001). There were 178 genes obtained from the overlap between predicted targets and NLP analysis. GO and KEGG pathway analyses revealed some significant pathways related to cancers. Downregulation of miR‑136‑5p may be responsible for the carcinogenesis and aggressiveness of HCC. miR‑136‑5p may act as an anti‑carcinoma miRNA, which is essential for HCC progression through the regulation of various signaling pathways. Thus, miR‑136‑5p interaction may provide a novel strategy for HCC treatment.

Kidney renal papillary cell carcinoma (KIRP) accounts for 10%-15% of renal cell carcinoma (RCC), patients with KIRP tend to have a poor prognosis, and there was a lack of effective prognostic indicators for this type of cancer. Currently, owing to the availability of The Cancer Genome Atlas (TCGA), long non-coding RNAs (LncRNAs) have been discovered to indicate a prognostic value in some tumors. In that regard, we analyzed lncRNA-sequencing data of KIRP in TCGA, and among 780 differentially-expressed lncRNAs, we selected 37 lncRNAs which were able to assist the prognosis. In addition, by using the multivariate cox regression analysis, the prognosis index (PI) that consisted of 7 lncRNAs (including AFAP1-AS1, GAS6-AS1, RP11-1C8.7, RP11-21L19.1, RP11-503C24.1, RP11-536I6.2, and RP11-63A11.1) could predict the progression and outcomes of KIRP with accuracy. More importantly, the PI was considered an independent indicator for prognostication of KIRP. Moreover, having categorized patients with KIRP into cohorts of high risk and low risk, according to the PI, we found that the key genes and pathways varied in these two groups. Overall, these LncRNAs, especially the PI, may be conceived as biomarkers and helpful for determining the different pathological stages for KIRP patients. However, their biological functions need to be further confirmed.

Cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) has been reported in cancers but its role and potential molecular mechanism in hepatocellular carcinoma (HCC) is unclear. Therefore, we aimed to investigate the clinical value and molecular mechanism of CELSR3 in HCC using an in vitro experiment, a meta-analysis and bioinformatics. The in vitro experiment determined the promoting effect of CELSR3 in the proliferation, invasion, and migration of HCC cells. CELSR3 knockout causes S-phage arrest in HCC cells. CELSR3 can also inhibit the apoptosis of HCC cells. The expression of the CELSR3 gene and protein was significantly elevated in HCC. Elevated CELSR3 was correlated to the bigger tumor size, higher pathological stage, and the worse overall survival of HCC. Methylation analysis revealed that the hypomethylation of CELSR3 regulated by DNMT1, DNMT3A, and DNMT3B may be the underlying mechanism of upregulated CELSR3. Biological enrichment analysis uncovered that the cell cycle, DNA replication, and PI3K-Akt signaling pathways were important pathways regulated by CELSR3 and its co-expressed genes in HCC. Taken together, upregulated CELSR3 is an important regulator in the progression and prognosis of HCC. The hypomethylation of CELSR3 and its regulation in the cell cycle may be the potential molecular mechanism in HCC.