Cancer-related Signaling Pathways Research Articles

Targeted exome-based predictors of patterns of progression of colorectal liver metastasis after percutaneous thermal ablation.

Percutaneous thermal ablation is a curative-intent locoregional therapy (LRT) for selected patients with unresectable colorectal liver metastasis (CLM). Several factors have been identified that contribute to local tumour control after ablation. However, factors contributing to disease progression outside the ablation zone after ablation are poorly understood. In this retrospective study, using next-generation sequencing, we identified genetic biomarkers associated with different patterns of progression following thermal ablation of CLM. A total of 191 ablation naïve patients between January 2011 and March 2020 were included in the analysis, and 101 had genomic profiling available. Alterations in the TGFβ pathway were associated with increased risk of development of new intrahepatic tumours (hazard ratio [HR], 2.75, 95% confidence interval [95% CI] 1.39-5.45, P = 0.004); and alterations in the Wnt pathway were associated with increased probability of receiving salvage LRT for any intrahepatic progression (HR, 5.8, 95% CI 1.94-19.5, P = 0.003). Our findings indicate that genomic alterations in cancer-related signalling pathways can predict different progression patterns and the likelihood of receiving salvage LRT following percutaneous thermal ablation of CLM.

Recent advances on the structural modification of parthenolide and its derivatives as anticancer agents

Parthenolide (PTL) is a sesquiterpene lactone derived from medicinal plant feverfew (Tanacetum parthenium). Recent studies have demonstrated that it has multiple pharmacological activities, especially in the treatment of various hematological and solid cancers. The superior anticancer activity of PTL suggests that it has the potential to be a first-line drug. However, due to the limited physical and chemical properties, as well as bioavailability, structural modification strategies are strongly recommended to improve the anticancer activity. This review describes representative PTL derivatives obtained by different modification strategies, which are reported to exert antiproliferative activities superior to the parent compound PTL. Furthermore, we also summarize their basic mechanisms on cancer-related signaling pathways, so as to explain the potential and characteristics of PTL and its derivatives in cancer therapy.

Knockdown of TTC9 inhibits the proliferation, migration and invasion, but induces the apoptosis of lung adenocarcinoma cells

Lung adenocarcinoma (LUAD) is one of the most commonly diagnosed subtypes of lung cancer, and one of the deadliest cancers. Tetratricopeptide repeat domain 9A (TTC9) is upregulated and has played an oncogenic role in some malignant tumors. However, the expression and role of TTC9 has not yet been elucidated in LUAD. Here, we investigated the expression profiles, biological functions and potential molecular mechanism of the TTC9 gene in LUAD. TTC9 expression was significantly overexpressed in LUAD tissues compared with that in normal lung tissues. TTC9 expression was closely correlated with gender, lymph node metastasis, and survival status in the TCGA-LUAD cohort. Subsequent cellular function assays demonstrated that knockdown of TTC9 promoted PC9 cell apoptosis and inhibited cell proliferation, migration and invasion, leading to cell cycle arrest in G2 phase. Moreover, inhibition of TTC9 suppressed the tumorigenicity of PC9 cells in nude mice. TTC9 might serve as oncogene in LUAD through cancer-related signaling pathways including p38 MAPK pathway. The expression of TTC9 gene might be modulated by DNA copy number variant and DNA methylation. TTC9 was significantly associated with tumor immune infiltration patterns. Accordingly, TTC9 may be a novel therapeutic target for the treatment of LUAD.

The Critical Gene Screening to Prevent Chromophobe Cell Renal Carcinoma Metastasis through TCGA and WGCNA.

Common chromophobe renal cell carcinoma (chRCC) has a good prognosis when cured by surgery. However, clinical practice shows that a small number of patients with chRCC will produce metastasis, and the prognosis after metastasis is poor. In this regard, we try to find potential biological targets to prevent CRCC metastasis. In this experiment, we analyzed the clinical traits and gene expression data of chRCC samples which were provided by the TCGA database by the WGCNA method. On this basis, we selected MEtan, a module with a significant positive correlation with the M phase of chRCC, for subsequent analysis. The MEtan module genes in the biological process of chRCC were mainly related to steroid metabolic process, cholesterol metabolic process and STEM cell differentiation. KEGG analysis showed that these genes were mainly enriched in cancer-related signaling pathways, such as Neuroactive Ligand−receptor interaction, cAMP signaling pathway, and Wnt signaling pathway. Subsequently, we mapped the PPI interaction network and screened the key gene beta-arrestin 2 (ARRB2). Expression analysis showed that there was a significantly increased expression of ARRB2 in chRCC patients in comparison to the normal group. Expression survival analysis indicated that ARRB2 was inversely associated with overall survival. We firmly believe that the key genes identified in this study would be able to provide new clues and research basis for the treatment of chRCC.

Constructed the ceRNA network and predicted a FEZF1-AS1/miR-92b-3p/ZIC5 axis in colon cancer.

The purpose of this study was to identify the role of FEZF1-AS1 in colon cancer and predicted the underlying mechanism. We extracted sequencing data of colon cancer patients from The Cancer Genome Atlas database, identified the differential expression of long noncoding RNA, microRNA, and messenger RNA, constructed a competitive endogenous RNA network, and then analyzed prognosis. Then, we used the enrichment analysis databases for functional analysis. Finally, we studied the FEZF1-AS1/miR-92b-3p/ZIC5 axis. We detected the expression of FEZF1-AS1, miR-92b-3p, and ZIC5 via quantitative reverse transcription-PCR, transfected colon cancer cell RKO with lentivirus and conducted FEZF1-AS1 knockdown, and performed cancer-related functional assays. It indicated that many RNA in the competitive endogenous RNA network, such as ZIC5, were predicted to be related to overall survival of colon cancer patients, and enrichment analysis showed cancer-related signaling pathways, such as PI3K/AKT signaling pathway. The expression of FEZF1-AS1 and ZIC5 was significantly higher and that of miR-92b-3p was lower in the colon cancer than in the normal colon tissues. FEZF1-AS1 promoted the migration, proliferation, as well as invasion of RKO. According to the prediction, FEZF1-AS1 and ZIC5 might competitively bind to miR-92b-3p, leading to the weakening of the inhibitory impact of miR-92b-3p on ZIC5 and increasing expression of ZIC5, thus further activating the PI3K/AKT signaling pathway, which led to the occurrence and development of colon cancer. The study suggested that FEZF1-AS1 might be an effective diagnosis biomarker for colon cancer.

Synthesis and Inhibitory Activity of Machaeridiol-Based Novel Anti-MRSA and Anti-VRE Compounds and Their Profiling for Cancer-Related Signaling Pathways.

Three unique 5,6-seco-hexahydrodibenzopyrans (seco-HHDBP) machaeridiols A–C, reported previously from Machaerium Pers., have displayed potent activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, and E. faecalis (VRE). In order to enrich the pipeline of natural product-derived antimicrobial compounds, a series of novel machaeridiol-based analogs (1–17) were prepared by coupling stemofuran, pinosylvin, and resveratrol legends with monoterpene units R-(−)-α-phellandrene, (−)-p-mentha-2,8-diene-1-ol, and geraniol, and their inhibitory activities were profiled against MRSA ATCC 1708, VRE ATCC 700221, and cancer signaling pathways. Compounds 5 and 11 showed strong in vitro activities with MIC values of 2.5 μg/mL and 1.25 μg/mL against MRSA, respectively, and 2.50 μg/mL against VRE, while geranyl analog 14 was found to be moderately active (MIC 5 μg/mL). The reduction of the double bonds of the monoterpene unit of compound 5 resulted in 17, which had the same antibacterial potency (MIC 1.25 μg/mL and 2.50 μg/mL) as its parent, 5. Furthermore, a combination study between seco-HHDBP 17 and HHDBP machaeriol C displayed a synergistic effect with a fractional inhibitory concentrations (FIC) value of 0.5 against MRSA, showing a four-fold decrease in the MIC values of both 17 and machaeriol C, while no such effect was observed between vancomycin and 17. Compounds 11 and 17 were further tested in vivo against nosocomial MRSA at a single intranasal dose of 30 mg/kg in a murine model, and both compounds were not efficacious under these conditions. Finally, compounds 1–17 were profiled against a panel of luciferase genes that assessed the activity of complex cancer-related signaling pathways (i.e., transcription factors) using T98G glioblastoma multiforme cells. Among the compounds tested, the geranyl-substituted analog 14 exhibited strong inhibition against several signaling pathways, notably Smad, Myc, and Notch, with IC50 values of 2.17 μM, 1.86 μM, and 2.15 μM, respectively. In contrast, the anti-MRSA actives 5 and 17 were found to be inactive (IC50 > 20 μM) across the panel of these cancer-signaling pathways.

Fibroblast activation protein-based theranostics in pancreatic cancer.

Fibroblast activation protein-α (FAP) is a type II transmembrane serine protease that has specific endopeptidase activity. Given its well-established selective expression in the activated stromal fibroblasts of epithelial cancers, although not in quiescent fibroblasts, FAP has received substantial research attention as a diagnostic marker and therapeutic target. Pancreatic cancer is characterized by an abundant fibrotic or desmoplastic stroma, leading to rapid progression, therapeutic resistance, and poor clinical outcomes. Numerous studies have revealed that the abundant expression of FAP in cancer cells, circulating tumor cells, stromal cells, and cancer-associated fibroblasts (CAFs) of pancreatic adenocarcinoma is implicated in diverse cancer-related signaling pathways, contributing to cancer progression, invasion, migration, metastasis, immunosuppression, and resistance to treatment. In this article, we aim to systematically review the recent advances in research on FAP in pancreatic adenocarcinoma, including its utility as a diagnostic marker, therapeutic potential, and correlation with prognosis. We also describe the functional role of FAP-overexpressing stromal cells, particulary CAFs, in tumor immuno- and metabolic microenvironments, and summarize the mechanisms underlying the contribution of FAP-overexpressing CAFs in pancreatic cancer progression and treatment resistance. Furthermore, we discuss whether targeting FAP-overexpressing CAFs could represent a potential therapeutic strategy and describe the development of FAP-targeted probes for diagnostic imaging. Finally, we assess the emerging basic and clinical studies regarding the bench-to-bedside translation of FAP in pancreatic cancer.

Effects of writers, erasers and readers within miRNA-related m6A modification in cancers.

As one of the most abundant post-transcriptional mRNA modifications, N6-methyladenosine (m6A) has attracted extensive attention from scientists. Emerging evidence indicates that m6A modification plays a significant role in cancer-related signalling pathways. Existing research demonstrates that m6A modifications were also identified in miRNAs and contribute to cancer-related signalling pathways. A literature retrieval has been performed to collect m6A-miRNA-related original articles published in recent years. Later, a systematic analysis has been conducted to abstract and classify the relationships between m6A modification and miRNAs, and their contributions to tumorigenesis and cancer development. Accumulating literature provides important insights into multiple relationships between m6A modifications and miRNAs. Mechanically, m6A writer and eraser alter pri-miRNAs m6A levels, and m6A readers could dually modulate pri-miRNAs processing and pri-miRNAs degradation. It is also been demonstrated that miRNAs impair m6A regulators' translation to influence m6A medication function in return. Aberrant expressions of m6A regulators and miRNAs could dysregulate proliferative, apoptosis, cell adhesion-related, and malignant transformation signalling pathways, and contribute to tumour occurrence and development. This review summarizes the interrelationship between m6A modification and miRNAs; highlights the combined effects of each type of m6A regulator and miRNAs in cancers. These findings enhance our understanding of m6A-miRNAs' multiple interactions and significant modulatory role in tumorigenesis and progression.

A 9-gene prognostic signature for kidney renal clear cell carcinoma overall survival based on co-expression and regression analyses.

This research attempted to screen potential signatures associated with KIRC progression and overall survival by weighted gene co-expression network analysis (WGCNA) and Cox regression. The KIRC-associated mRNA expression and clinical data were accessed from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were screened by differential analysis. A co-expression network was constructed by "WGCNA". Based on WGCNA module, GO and KEGG analyses were performed. Protein-protein interaction (PPI) network was constructed. Prognostic signatures were screened by Lasso-Cox regression. Prognostic model was evaluated by Receiver Operating Characteristic (ROC) and Kaplan-Meier (K-M) curves. Multivariate Cox and nomogram were introduced to examine whether risk score could be an independent marker. qRT-PCR was introduced to determine expression of 9 hub genes in KIRC clinical tumor tissues and adjacent tissues, respectively. Genes in the green module were highly associated with clinical status, and green module genes were significantly enriched in mitotic nuclear division, cell cycle, and p53 signaling pathway. Twenty-six candidates were subsequently screened out from the green module. Next, a 9-gene prognostic model (DLGAP5, NUF2, TOP2A, RRM2, HJURP, PLK1, AURKB, KIF18A, CCNB2) was constructed. The predicting ability of the model was optimal. Some cancer-related signaling pathways were differently activated between two risk score groups. Additionally, under-expression of some signature genes (AURKB, CCNB2, PLK1, RRM2, TOP2A) was associated with better survival rate for KIRC patients. Meanwhile, all 9 hub genes were substantially overexpressed in KIRC patients. A KIRC prognostic signature was screened in this study, contributing valuable findings to KIRC biomarker development.

Inhibition of cannabinoid receptor type 1 sensitizes triple-negative breast cancer cells to ferroptosis via regulating fatty acid metabolism

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that displays highly aggressive with poor prognosis. Owing to the limited targets and drugs for TNBC clinical therapy, it is necessary to investigate the factors regulating cancer progression and develop novel therapies for cancer treatment. Ferroptosis, a nonapoptotic form of programmed cell death characterized by accumulation of iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various cancer-related signaling pathways. Recently, considerable progress has been made in demonstrating the critical role of lipid metabolism in regulating ferroptosis, indicating potential combinational therapeutic strategies for cancer treatment. In this study, by drug combination screen of lipid metabolism compounds with ferroptosis inducers in decreasing TNBC cell viability, we found potent synergy of the CB1 antagonist rimonabant with erastin/(1 S, 3 R)-RSL3 (RSL3) in inhibiting TNBC cell growth both in vitro and in vivo via promoting the levels of lipid peroxides, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and cytosolic reactive oxygen species (ROS) production, enhancing intracellular glutathione (GSH) depletion and inducing G1 cell cycle arrest. We identified that inhibition of CB1 promoted the effect of erastin/RSL3 on inducing ferroptosis and enhanced their inhibitory effect on tumor growth. Using RNA-Seq, fatty acid analyses and functional assays, we found that CB1 regulated stearoyl-CoA desaturase 1 (SCD1)- and fatty acyl desaturase 2 (FADS2)-dependent fatty acid metabolism via phosphatidylinositol 3 kinase (PI3K)-AKT and mitogen-activated protein kinase (MAPK) signaling pathways to modulate ferroptosis sensitivity in TNBC cells. These data demonstrate that dual targeting of CB1 and ferroptosis could be a promising therapeutic strategy for TNBC.

Investigation of cell signalings and therapeutic targets in PTPRK-RSPO3 fusion-positive colorectal cancer.

Colorectal cancer (CRC) is one of the most deadly and common diseases in the world, accounting for over 881,000 casualties in 2018. The PTPRK-RSPO3 (P:R) fusion is a structural variation in CRC and well known for its ability to activate WNT signaling and tumorigenesis. However, till now, therapeutic targets and actionable drugs are limited in this subtype of cancer. The purpose of this study is to identify key genes and cancer-related pathways specific for P:R fusion-positive CRC. In addition, we also inferred the actionable drugs in bioinformatics analysis using the Cancer Genome Atlas (TCGA) data. 2,505 genes were altered in RNA expression specific for P:R fusion-positive CRC. By pathway analysis based on the altered genes, ten major cancer-related signaling pathways (Apoptosis, Direct p53, EGFR, ErbB, JAK-STAT, tyrosine kinases, Pathways in Cancer, SCF-KIT, VEGFR, and WNT-related Pathway) were significantly altered in P:R fusion-positive CRC. Among these pathways, the most altered cancer genes (ALK, ACSL3, AXIN, MYC, TP53, GNAQ, ACVR2A, and FAS) specific for P:R fusion and involved in multiple cancer pathways were considered to have a key role in P:R fusion-positive CRC. Based on the drug-target network analysis, crizotinib, alectinib, lorlatinib, brigatinib, ceritinib, erdafitinib, infigratinib and pemigatinib were selected as putative therapeutic candidates, since they were already used in routine clinical practice in other cancer types and target genes of the drugs were involved in multiple cancer-pathways.

Expression profiling of mRNA and functional network analyses of genes regulated by human papilloma virus E6 and E7 proteins in HaCaT cells.

Human papillomavirus (HPV) oncogenes E6 and E7 are essential for HPV-related cancer development. Here, we developed a cell line model using lentiviruses for transfection of the HPV16 oncogenes E6 and E7 and investigated the differences in mRNA expression during cell adhesion and chemokine secretion. Subsequently, RNA sequencing (RNA-seq) analysis was performed to explore the differences in mRNA expression. Compared to levels in the control group, 2,905 differentially expressed mRNAs (1,261 downregulated and 1,644 upregulated) were identified in the HaCaT-HPV16E6E7 cell line. To predict the functions of these differentially expressed genes (DEGs) the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used. Protein–protein interactions were established, and the hub gene was identified based on this network. Real-time quantitative-PCR (RT-qPCR) was conducted to confirm the levels of 14 hub genes, which were consistent with the RNA-seq data. According to this, we found that these DEGs participate in the extracellular matrix (ECM), cell adhesion, immune control, and cancer-related signaling pathways. Currently, an increasing number of clinicians depend on E6/E7mRNA results to make a comprehensive judgment of cervical precancerous lesions. In this study, 14 hub genes closely related to the expression of cell adhesion ability and chemokines were analyzed in HPV16E6E7-stably expressing cell lines, which will open up new research ideas for targeting E6E7 in the treatment of HPV-related cancers.

MJDs family members: Potential prognostic targets and immune-associated biomarkers in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal malignancies. It is not easy to be diagnosed in the early stage and is prone to relapse, with a very poor prognosis. And immune cell infiltration and tumor microenvironment play important roles in predicting therapeutic response and prognosis of HCC. Machado-Joseph domain-containing proteases (MJDs), as a gene family extensively involved in tumor progression, has pro-cancer and anti-cancer effects. However, the relationship between MJDs family members and immune cell infiltration and tumor microenvironment in HCC remains unclear. Therefore, cBio Cancer Genomics Portal (cBioPortal), The Cancer Genome Atlas (TCGA), UALCAN, Human Protein Atlas (HPA), MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were performed to investigate the mRNA expression, DNA methylation, clinicopathologic features, immune cell infiltration and other related functions of MJDs family members in HCC. The results indicated that the expression of ATXN3, JOSD1, and JOSD2 was dramatically increased in HCC tissues and cell lines, and was correlated with histological grade, specimen type, TP53 mutation, lymph node metastatic, gender, and age of patients with HCC. Meanwhile, these genes also showed clinical value in improving the overall survival (OS), disease-specific survival (DSS), progression free survival (PFS), and relapse-free survival (RFS) in patients with HCC. The prognostic model indicated that the worse survival was associated with overall high expression of MJDs members. Next, the results suggested that promotor methylation levels of the MJDs family were closely related to these family mRNA expression levels, clinicopathologic features, and prognostic values in HCC. Moreover, the MJDs family were significantly correlated with CD4+ T cells, CD8+ T cells, B cells, neutrophils, macrophages, and DCs. And MJDs family members’ expression were substantially associated with the levels of several lymphocytes, immunomoinhibitors, immunomostimulators, chemokine ligands, and chemokine receptors. In addition, the expression levels of MJDs family were significantly correlated with cancer-related signaling pathways. Taken together, our results indicated that the aberrant expression of MJDs family in HCC played a critical role in clinical feature, prognosis, tumor microenvironment, immune-related molecules, mutation, gene copy number, and promoter methylation level. And MJDs family may be effective immunotherapeutic targets for patients with HCC and have the potential to be prognostic biomarkers.

Characterization of chromatin regulators in hepatocellular carcinoma to guide clinical therapy.

Background: Hepatocellular carcinoma (HCC) is notorious for its high mortality and incidence. Accumulating evidence confirms that chromatin regulators (CRs) have a significant impact on cancer. Therefore, exploring the mode of action and prognostic value of CRs is imminent for the treatment of hepatocellular carcinoma. Method: Transcriptome and clinical data for this study have been downloaded from TCGA (https://portal.gdc.cancer.gov/) and ICGC (https://dcc.icgc.org/). Univariate analysis was used to screen CRs with prognostic value, and our prognostic risk score signature was developed using least absolute shrinkage along with selection operator (lasso) Cox regression analysis. The CRs-based prognostic model was constructed in the TCGA dataset, and low-risk HCC patients had a better prognosis, which was finally validated in the ICGC dataset. We used the receiver operating characteristic curve to identify the accuracy of the prediction model and establish a line chart to prove the clinical effectiveness of the model. We also discussed the differences in drug sensitivity via CellMiner database, tumor immune microenvironment via ssGSEA algorithm, and clinical characteristics among different risk groups. Results: A prognostic model consisting of seven CRs was constructed and verified in HCC patients. Furthermore, we found that this risk score prognostic signature could independently predict the prognosis of HCC patients. Functional enrichment analysis revealed that CRs are mainly associated with cancer-related signaling pathways and metabolic pathways. In addition, immune cell abundance correlates with risk score levels Conclusion: In brief, we systematically explored the mode of action of CRs in HCC patients and established a reliable prognostic prediction model.

Mutational signatures representative transcriptomic perturbations in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a primary malignancy with increasing incidence and poor prognosis. Heterogeneity originating from genomic instability is one of the critical reasons of poor outcomes. However, the studies of underlying mechanisms and pathways affected by mutations are still not intelligible. Currently, integrative molecular-level studies using multiomics approaches enable comprehensive analysis for cancers, which is pivotal for personalized therapy and mortality reduction. In this study, genomic and transcriptomic data of HCC are obtained from The Cancer Genome Atlas (TCGA) to investigate the affected coding and non-coding RNAs, as well as their regulatory network due to certain mutational signatures of HCC. Different types of RNAs have their specific enriched biological functions in mutational signature-specific HCCs, upregulated coding RNAs are predominantly associated with lipid metabolism-related pathways, and downregulated coding RNAs are enriched in axonogenesis for tumor microenvironment generation. Additionally, differentially expressed miRNAs are inclined to concentrate in cancer-related signaling pathways. Some of these RNAs also serve as prognostic factors that help predict the survival outcome of HCCs with certain mutational signatures. Furthermore, deregulation of competing endogenous RNA (ceRNA) regulatory network is identified, which suggests a potential therapy via interference of miRNA activity for mutational signature-specific HCC. This study proposes a projection approach to reduce therapeutic complexity from genomic mutations to transcriptomic alterations. Through this method, we identify genes and pathways critical for mutational signature-specific HCC and further discover a series of prognostic markers indicating patient survival outcome.

Construction of circRNA-associated ceRNA network reveals the regulation of fibroblast proliferation in cervical cancer

BackgroundCervical cancer is one of the major cancers that threaten the health of women. CircRNA is an important factor in the regulation of cancer development and progression. The role of circRNA in cervical cancer is less well studied. The aim of this study was to explore the mechanism of circRNA effects on cervical cancer using circRNA-seq technology to study the expression profile data of 9 pairs of primary cervical cancer and paracancerous tissues. MethodDESeq2 was used to analyse differentially expressed circRNA and mRNA in cervical cancer and paracancerous tissues. MiRanda and TargetScan are used to predict miRNAs that interact with circRNAs and mRNAs and to construct circRNA-miRNA-mRNA regulatory networks. KEGG and GO are used for functional annotation of differentially expressed genes. TIDE, TIMER2.0 was used to assess the status of the tumour immune microenvironment in cervical cancer. GEPIA2 was used to validate the results of differential expression analysis. ResultsWe eventually obtained 22 differentially expressed circRNAs (7 up-regulated and 15 down-regulated) and 1834 differentially expressed genes (613 up-regulated and 1221 down-regulated). The results of the KEGG analysis showed that the differentially expressed genes were mainly enriched in cell cycle and cancer-related signalling pathways. The new circRNA: circZNF208 was identified to promote fibroblast proliferation by interfering with its downstream hsa-miR-324-3p regulating four downstream genes LPHN3. The level of fibroblast infiltration is implicated in the poor prognosis of cervical cancer. ConclusionWe have identified a novel circRNA: circZNF208 that can interfere with fibroblast proliferation in cervical cancer through a ceRNA regulatory network, thereby promoting fibroblast proliferation in cervical cancer and affecting the prognosis of cancer patients.

Porcn as a novel therapeutic target in cancer therapy: A review.

Wingless-related integration site (Wnt) signaling is one of the main oncogenic pathways in different malignancies. Therefore, targeting this pathway has been considered an exciting strategy in cancer treatment. Porcn is among the central enzymes in this pathway that has recently been considered for cancer-targeted therapy. As a membrane-bound O-acyltransferase, Porcn plays a critical role in wnt ligand palmitoylation and its subsequent secretion. In addition to Porcn's role in stem cell signaling and differentiation, recent findings have shown its role in developing and progressing colorectal, pancreatic, liver, head, and neck cancers. Developed small molecule inhibitors have also opened a promising window toward cancer treatment strategies. In this review, the structure and biological role of Porcn in different cancer-related signaling pathways and inhibitors used for inhibiting this enzyme are discussed.

MTUS1 is a promising diagnostic and prognostic biomarker for colorectal cancer

BackgroundThe morbidity and mortality of colorectal cancer (CRC) remain high, posing a serious threat to human life and health. The early diagnosis and prognostic evaluation of CRC are two major challenges in clinical practice. MTUS1 is considered a tumour suppressor and can play an important role in inhibiting cell proliferation, migration, and tumour growth. Moreover, the expression of MTUS1 is decreased in different human cancers, including CRC. However, the biological functions and molecular mechanisms of MTUS1 in CRC remain unclear.MethodsIn the present study, data from The Cancer Genome Atlas (TCGA) database were analysed using R statistical software (version 3.6.3.) to evaluate the expression of MTUS1 in tumour tissues and adjacent normal tissues using public databases such as the TIMER and Oncomine databases. Then, 38 clinical samples were collected, and qPCR was performed to verify MTUS1 expression. We also investigated the relationship between MTUS1 expression and clinicopathological characteristics and elucidated the diagnostic and prognostic value of MTUS1 in CRC. In addition, the correlation between MTUS1 expression and immune infiltration levels was identified using the TIMER and GEPIA databases. Furthermore, we constructed and analysed a PPI network and coexpression modules of MTUS1 to explore its molecular functions and mechanisms.ResultsCRC tissues exhibited lower levels of MTUS1 than normal tissues. The logistic regression analysis indicated that the expression of MTUS1 was associated with N stage, TNM stage, and neoplasm type. Moreover, CRC patients with low MTUS1 expression had poor overall survival (OS). Multivariate analysis revealed that the downregulation of MTUS1 was an independent prognostic factor and was correlated with poor OS in CRC patients. MTUS1 expression had good diagnostic value based on ROC analysis. Furthermore, we identified a group of potential MTUS1-interacting proteins and coexpressed genes. GO and KEGG enrichment analyses showed that MTUS1 was involved in multiple cancer-related signalling pathways. Moreover, the expression of MTUS1 was significantly related to the infiltration levels of multiple cells. Finally, MTUS1 expression was strongly correlated with various immune marker sets.ConclusionsOur results indicated that MTUS1 is a promising biomarker for predicting the diagnosis and prognosis of CRC patients. MTUS1 can also become a new molecular target for tumour immunotherapy.

High expression of HOXA4 in patients with glioma indicates unfavorable clinical outcomes

ABSTRACT HOXA4 is a novel oncogene that has been observed in many kinds of tumors, but its role during glioma carcinogenesis and its clinical significance in diagnosing and prognosis human glioma remains unknown. In the present study, the Chinese Glioma Atlas (CGGA)-RNA sequencing database, CGGA microarray, and The Cancer Genome Atlas (TCGA)-RNA seq data from 1674 glioma patients were obtained from online databases and analyzed using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) to detect changes in the expression level of HOXA4 and characterize the relationship between HOXA4 and the clinical characteristics and prognosis of patients with glioma. Gene set enrichment analysis (GSEA) was used to reveal how HOXA4 regulates tumor-related pathways. HOXA4 mRNA levels in glioma tissue were higher than those in adjacent brain tissue. HOXA4 expression was also closely related to the clinical and molecular characteristics of gliomas, such as tumor grade and isocitrate dehydrogenase (IDH) mutation. Functional enrichment analysis revealed that HOXA4 could regulate cancer-related signal pathways, such as Cell cycle, Cell adhesion molecules cams, and JAK/STAT signaling pathway. Results of in vitro experiments confirmed that knockdown of HOXA4 blocks the cell cycle pathway and inhibits the proliferation, invasion and chemotherapy resistance in gliomas. We concluded that HOXA4 was an independent risk factor for glioma and may have clinical diagnostic potential. Meanwhile, our findings revealed that HOXA4 could be used as a biomarker for glioma diagnosis and treatment.

Study on the Mechanism of Xiaotan Sanjie Recipe in the Treatment of Colon Cancer Based on Network Pharmacology.

The aim of the study is to investigate the mechanism of action of Disulfiram against colon cancer through a network pharmacology approach. The targets were then imported into the Cytoscape 3.7.2 software to construct a network of active ingredient targets and were imported into the STRING database to construct a protein-protein interaction (PPI) network, and the Bisogenet plug-in in Cytoscape 3.7.2 was used for network topology analysis. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the potential targets of Yiqi and Baiyu Tang for colon cancer using the R-language Bioconductor platform, and the results were imported into Cytoscape 3.7.2 to obtain KEGG network relationship maps. Molecular docking software Autodock Vina was used to map the core targets to the active ingredients. A total of 119 chemical components and 694 disease targets were obtained, including 113 intersecting targets. The key targets included AKT1 and TP53, and GO functional analysis mainly related to ubiquitination and apoptosis, etc. KEGG analysis showed that the treatment of colon cancer with Ganchenzan mainly acted through cancer-related signaling pathways such as AGE-RAGE and P13K-Akt, and the molecular docking results showed the best binding performance with TP53.