Prognostic Biomarker In Human Cancer Research Articles

Multiomics Analysis of the PHLDA Gene Family in Different Cancers and Their Clinical Prognostic Value.

The PHLDA (pleckstrin homology-like domain family) gene family is popularly known as a potential biomarker for cancer identification, and members of the PHLDA family have become considered potentially viable targets for cancer treatments. The PHLDA gene family consists of PHLDA1, PHLDA2, and PHLDA3. The predictive significance of PHLDA genes in cancer remains unclear. To determine the role of pleckstrin as a prognostic biomarker in human cancers, we conducted a systematic multiomics investigation. Through various survival analyses, pleckstrin expression was evaluated, and their predictive significance in human tumors was discovered using a variety of online platforms. By analyzing the protein-protein interactions, we also chose a collection of well-known functional protein partners for pleckstrin. Investigations were also carried out on the relationship between pleckstrins and other cancers regarding mutations and copy number alterations. The cumulative impact of pleckstrin and their associated genes on various cancers, Gene Ontology (GO), and pathway analyses were used for their evaluation. Thus, the expression profiles of PHLDA family members and their prognosis in various cancers may be revealed by this study. During this multiomics analysis, we found that among the PHLDA family, PHLDA1 may be a therapeutic target for several cancers, including kidney, colon, and brain cancer, while PHLDA2 can be a therapeutic target for cancers of the colon, esophagus, and pancreas. Additionally, PHLDA3 may be a useful therapeutic target for ovarian, renal, and gastric cancer.

Long non-coding RNA LINC-PINT as a novel prognostic biomarker in human cancer: a meta-analysis and machine learning

Long intergenic non-protein coding RNA, P53 induced transcript (LINC-PINT) exhibits different expression patterns in the majority of tumors, yet its relationship with cancer prognosis remains a subject of debate. This study aims to comprehensively investigate the prognostic significance of LINC-PINT in diverse human cancer. A systematic search was conducted in PubMed, Embase, Cochrane Library, and Web of Science databases to identify pertinent studies exploring the correlation between LINC-PINT expression and cancer patients. Moreover, bioinformatics analysis and in vitro validation were used to validate the results of the meta-analysis and to investigate the potential oncogenic mechanism of LINC-PINT. The meta-analysis encompassed 8 studies, involving 911 patients. The pooled analysis demonstrated a significant association between upregulation of LINC-PINT expression and better survival (P = 0.002) during the cancers. Meanwhile, its downregulation was correlated with advanced tumor staging (P = 0.04) and tumor differentiation (P = 0.03). Additionally, bioinformatics analysis showed that LINC-PINT expression was observed to be linked with Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI) in tumors, the results of bioinformatics were verified by qRT-PCR. And functional enrichment analysis hinted at its involvement in tumorigenesis and tumor progression. Dysregulated LICN-PINT expression is associated with the clinical prognostic and pathological features of various cancers, exhibiting substantial potential as a novel prognostic biomarker.

LAMC2 as a prognostic biomarker in human cancer: a systematic review and meta-analysis

ObjectivesAccumulating evidence suggested that the laminin γ2 (LAMC2) expression level was upregulated in various cancers. However, the potential prognostic value of LAMC2 in cancers remains unclear. We conducted a meta-analysis...

Bioinformatics analysis of BIRC5 in human cancers.

BackgroundAn inhibitor of apoptosis (IAP) family member, baculoviral IAP repeat containing five (BIRC5) plays an important role in the occurrence and development of tumors. However, the underlying mechanism in human cancers remains unclear.MethodsIn this study, we investigated BIRC5 expression and explored the prognostic value of BIRC5 in different human cancers via bioinformatics analysis, including the databases of Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, GEPIA, DriverDBv3, GeneMANIA, WEB-based Gene Set Analysis Tool (WebGestalt) and TIMER.ResultsIn most human cancers, BIRC5 usually had higher expression compared to normal human tissues. High expression of BIRC5 could increase the mortality of patients with adrenocortical carcinoma (ACC), kidney renal clear cell carcinoma (KIRC), low-grade glioma (LGG), liver hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD) (P<0.05). Cox analysis demonstrated that high BIRC5 expression was an independent factor for poor overall survival (OS) [hazard ratio, (HR) >1, P<0.05]. There were differences in BIRC5 expression in the case of TP53 mutation, different tumor grades, and stages. Interactive genes for BIRC5 mainly participated in apoptosis, cell division, cell cycle, and cancer pathways, strongly suggesting its oncogenic role in promoting cancer cell proliferation and cancer development. In addition, BIRC5 expression exhibited a close correlation with immune infiltration, which was related to the cumulative survival rate, especially in LGG. The elevated expression of BIRC5 could be regulated through TP53 mutation, tumor stage, and tumor grade (P<0.05).ConclusionsAs a result of our findings, BIRC5 appears to be an independent unfavourable prognostic biomarker in human cancers. BIRC5 may become a potential clinical target in the future for the treatment of cancers.

Identification of pivotal microRNAs involved in the development and progression of salivary adenoid cystic carcinoma.

miRNAs and mRNAs have been significantly implicated in tumorigenesis and served as promising prognostic biomarkers for human cancer. Hence, this study was aimed to develop the pivotal miRNA biomarkers-based prognostic signature for salivary adenoid cystic carcinoma. The miRNA and mRNA expression data were integrated from the gene expression omnibus database to study their involvement in salivary adenoid cystic carcinoma development and progression. Gene ontology and kyoto encyclopedia of genes and genomes were conducted to analyze the biological pathways. Reverse transcription-quantitative PCR was used to verify the expression of selected miRNAs in salivary adenoid cystic carcinoma and corresponding normal tissues. There were 386 differentially expressed genes: 158 upregulated and 228 downregulated genes and 102 differentially expressed miRNAs: 78 upregulated and 24 downregulated miRNAs in the salivary adenoid cystic carcinoma samples. A miRNA-mRNA network containing 11miRNAs and 199 genes was subsequently constructed. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis revealed that the genes targeted by the 11miRNAs were mostly involved in tumor-related pathways and processes, such as miRNAs in cancer, focal adhesion, neurotrophin signaling pathway, and the PI3K-Akt signaling pathway. Among them, 4miRNAs (miR-375, miR-494, miR-34c-5p, and miR-331-3p) were selected to verify by reverse transcription-quantitative PCR in 36 pairs of collected salivary adenoid cystic carcinoma and adjacent nontumor samples. Overall survival analysis revealed that the higher expression of miR-331-3p was significantly associated with a worst overall survival and multivariate Cox regression analysis suggested that hsa-miR-331-3p could be an independent prognostic factor for salivary adenoid cystic carcinoma. Our results revealed that 4-miRNAs signature was a powerful prognostic biomarker for salivary adenoid cystic carcinoma, which provide a basis for exploring deeper mechanisms regarding the progression of salivary adenoid cystic carcinoma, and leading to the development of potential therapeutic strategies.

CancerMIRNome: an interactive analysis and visualization database for miRNome profiles of human cancer.

MicroRNAs (miRNAs), which play critical roles in gene regulatory networks, have emerged as promising diagnostic and prognostic biomarkers for human cancer. In particular, circulating miRNAs that are secreted into circulation exist in remarkably stable forms, and have enormous potential to be leveraged as non-invasive biomarkers for early cancer detection. Novel and user-friendly tools are desperately needed to facilitate data mining of the vast amount of miRNA expression data from The Cancer Genome Atlas (TCGA) and large-scale circulating miRNA profiling studies. To fill this void, we developed CancerMIRNome, a comprehensive database for the interactive analysis and visualization of miRNA expression profiles based on 10 554 samples from 33 TCGA projects and 28 633 samples from 40 public circulating miRNome datasets. A series of cutting-edge bioinformatics tools and machine learning algorithms have been packaged in CancerMIRNome, allowing for the pan-cancer analysis of a miRNA of interest across multiple cancer types and the comprehensive analysis of miRNome profiles to identify dysregulated miRNAs and develop diagnostic or prognostic signatures. The data analysis and visualization modules will greatly facilitate the exploit of the valuable resources and promote translational application of miRNA biomarkers in cancer. The CancerMIRNome database is publicly available at http://bioinfo.jialab-ucr.org/CancerMIRNome.

Identification of an autophagy-related prognostic signature in head and neck squamous cell carcinoma.

Autophagy-related genes (ARGs) have been significantly implicated in tumorigenesis and served as promising prognostic biomarkers for human cancer. Hence, this study was aimed to develop an ARGs-based prognostic signature for Head and neck squamous cell carcinoma (HNSCC). Prognostic ARG candidates were identified by univariate and multivariate Cox regression analysis in the training dataset (TCGA-HNSC) and incorporated into a 3-ARGs (EGFR, FADD, and PARK2) prognostic signature which was further verified in two independent validation cohorts (GSE41613 and GSE42743). Kaplan-Meier plots, Cox regression analyses, and receiver operating characteristics curves (ROC) were employed to evaluate the prognostic prediction of 3-ARGs signature. Differential expression of these 3 ARG between cancer and normal counterparts as well as their associations with autophagy markers were assessed in 60 pairs of freshly collected HNSCC and adjacent non-tumor samples and datasets from Human Protein Atlas, respectively. Patients with high-risk score had significantly inferior overall survival. Multivariate regression analyses revealed that 3-ARGs signature could be an independent prognostic factor after adjusting various clinicopathological parameters. ROC analyses revealed high predictive accuracy and sensitivity of the 3-ARGs signature. Increased mRNA and protein expression of EGFR, FADD, and PARK2 were found in HNSCC samples, and their expression significantly correlated with the abundances of ATG5, Beclin1, and LC3. Our results reveal that 3-ARGs signature is a powerful prognostic biomarker for HNSCC, which could be integrated into the current prognostic regime to realize individualized outcome prediction. EGFR, FADD, and PARK2likely contributed to autophagy during HNSCC tumorigenesis.

Prognostic and clinicopathological value of circPVT1 in human cancers: A meta-analysis.

BackgroundCircular RNA PVT1 (circPVT1) is significantly upregulated in various human cancers and is related to poor clinical outcome of cancer patients. However, the prognostic and clinicopathological value of circPVT1 in diverse human cancers remains controversial and inconclusive.AimThe objective of our study is to evaluate the prognostic and clinicopathological role of circPVT1 for cancer patients.Methods and resultsPubMed, Embase, Web of Science, and Cochrane Library were searched for eligible studies by October 1, 2020. The correlation between circPVT1 expression, and overall survival (OS) and clinical parameters was assessed by pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses, heterogeneity, and publication bias were conducted to further enhance reliability. Twelve studies (1282 patients) were selected for this meta‐analysis, including 11 on prognosis and 10 on clinicopathological parameters. Elevated expression of circPVT1 was associated with a worse OS in cancer patients (HR, 2.009; 95% CI, 1.667‐2.408, 1.892; P < .001). For clinicopathological value, upregulation of circPVT1 was closely related to poor clinical parameters lymph node metastasis (OR = 2.019; 95% CI, 1.026‐3.976; P = .042; I 2 = 77.5%; PH = 0.000), late clinical stage (OR = 3.594; 95% CI, 1.828‐7.065; P < .001; I 2 = 71.7%; PH = 0.001), distant metastasis (OR = 4.598; 95% CI, 1.411‐14.988; P = .011; I 2 = 78.1%; PH = 0.001), and chemoresistant (OR = 6.400; 95% CI, 2.107‐19.441; P = .001; I 2 = 49.6%; PH = 0.159).ConclusionHigh expression of circPVT1 is correlated with unfavorable prognosis of cancer patients, indicating that circPVT1 can function as a potential prognostic biomarker in human cancer.

Clinicopathological Significance of Long Non-Coding RNA GHET1 in Human Cancers: A Meta-Analysis.

Cancer is considered as the main public health problem and the second leading cause of morbidity and mortality worldwide. Numerous environmental-lifestyle related risk factors account for around one-third of cancer deaths. Recently, the key role of lncRNAs has been widely investigated in a variety of disorders, including cancer. The lncRNA GHET1 has been considered as an essential oncogenic lncRNA in many types of human cancers. Clinical investigations indicated that expression of lncRNA GHET1 is correlated with clinicopathological characteristics in cancer. This metaanalysis investigated the correlation between the lncRNA GHET1 expression and clinicopathological features in different types of cancers. Comprehensive literature searches in PubMed, Scopus, and Web of Knowledge were conducted up to April 11, 2019. Sixteen studies were included in this meta-analysis. All statistical analyses were conducted using Stata software, version 12.0. The pooled OR and 95%CIs of the sixteen relevant studies showed that over expression of lncRNA GHET1 was associated with tumor-size ≥5 cm (OR= 2.51, 95% CI: 1.89-3.33, p=0.00, I2=38.30%), positive lymph node metastasis (OR= 2.83, 95% CI: 1.78-4.52, p=0.00, I2=45.60%), advanced tumor stage (OR= 3.92, 95% CI: 2.97-5.19, p=0.00, I2=0.00%), positive distant metastasis (OR= 5.74, 95% CI: 2.58-12.77, p=0.00, I2=0.00%), advanced tumor status (OR= 2.97, 95% CI: 1.40- 6.29, p=0.01, I2=34.70%), and positive vascular invasion (OR= 2.69, 95% CI: 1.61-4.50, p=0.00, I2=29.20%). Taken together, the current study demonstrated that overexpression of lncRNA GHET1 is significantly associated with clinicopathological features in human cancers. Our results suggested that lncRNA GHET1 can be utilized as a prognostic biomarker in human cancer.

Aberrant Expression of Gastric Carcinoma High Expressed Transcript 1 is a Diagnostic and Prognostic Biomarker in Human Cancer

BackgroundGastric carcinoma high expressed transcript 1 (GHET1), a long noncoding RNA (LncRNA), has been reported to be involved in tumor genesis and cancer progression. High GHET1 expression is correlated with a poor prognosis in cancer. In this meta-analysis, we investigated the association between GHET1 and lymph node metastasis, differentiation, vascular invasion and so on in human cancer. MethodsWe performed systematic search in PubMed, EMBASE, Wiley Online Library, Wiley Online Library, and Medline from January 1, 1996 to September 25, 2017. A total of 8 studies were selected for further research. ResultsThe result showed that GHET1 expression was significantly associated with OS (hazard ratio [HR] = 2.23; 95% CI, 1.86–2.67; P < 0.0001), including digestive system tumor (HR = 2.17; 95% CI, 1.63–2.89; P < 0.0001). Moreover, high GHET1 expression was related to tumor size (odds ratio [OR] = 2.15, 95% CI: 1.57–2.94; P < 0.00001), TNM stage (Ⅲ+Ⅳ vs.Ⅰ+Ⅱ; OR = 4.02, 95% CI:3.06–5.28; P < 0.00001), lymph node metastasis (Yes vs. No; OR = 3.55, 95% CI:2.54–4.95; P < 0.00001), differentiation (poor vs. well or moderate; OR = 1.72, 95% CI:1.22–2.42; P = 0.002), vascular invasion (Yes vs. No; OR = 3.03, 95% CI:1.80–5.12; P = 0.00001). Also, we found that high expression of GHET1 has a significant relationship with analysis method and sample size. It almost higher in different human cancers. ConclusionsGHET1 may serve as a potential clinical biomarker and poor survival and high-risk recurrence in cancers.

Prognostic Significance of Matrix Metalloproteinase 14 in Patients with Cancer: a Systematic Review and Meta-Analysis.

There is increasing evidence that matrix metalloproteinase 14 (MMP-14) is involved in tumor progression and prognosis. MMP-14 exhibits different expression in patients with various cancers, suggesting that it may be considered as a potential prognostic biomarker for cancer. Therefore, this meta-analysis was performed to elucidate the prognostic value and association of MMP-14 over-expression in several types of cancers. Eligible studies based on eligibility criteria from various online databases were searched. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) were analyzed to determine the prognostic value of MMP-14 using STATA software 12.0. We identified sixteen applicable studies in this meta-analysis comprising 2,766 samples. Over-expression MMP-14 was significantly correlated with a poor overall survival (OS) outcome in multiple cancers (HR: 2.22; 95% CI: 1.72 - 2.87). Moreover, high levels of MMP-14 were markedly associated with tumor progression and metastasis (HR: 1.83; 95% CI: 1.36 - 2.46). MMP-14 expression was also associated with histological differentiation (OR: 0.37; 95% CI: 0.18 - 0.77). MMP-14 over-expression suggested aggressive biological behaviors and implied that MMP-14 may be a useful prognostic biomarker in human cancers.

Pseudogene DUXAP10 can be used as a diagnostic and prognostic biomarker in human cancers.

The pseudogene DUXAP10 is overexpressed in numerous types of human cancers. However, the diagnostic and prognostic value of DUXAP10 in cancers has yet to be characterized. PubMed, EMBASE, Web of Science, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus databases were comprehensively searched in this study. A total of 50 studies comprising 11,292 patients were collected in this integrated analysis. DUXAP10 was confirmed to be significantly overexpressed in various human cancers (p < .05). Summary receiver operating characteristic (SROC) curve analysis was implemented, which indicated that DUXAP10 was a potential diagnostic biomarker for human cancers (area under the curve [AUC] of SROC curve = 0.81 [0.77-0.84]; pooled sensitivity = 0.69 [0.62-0.75]; pooled specificity = 0.81 [0.73-0.87]). In addition, hazard ratios (HRs) with 95% confidence intervals (CIs) were obtained to evaluate the association of DUXAP10 expression with overall survival (OS) time of cancer patients. Outcomes of meta-analysis suggested that upregulation of DUXAP10 was closely associated with poor OS (pooled HR = 1.11 [1.03-1.18]). Our study revealed that the pseudogene DUXAP10 was upregulated in multiple types of cancers and could be a potential biomarker with good diagnostic and prognostic value for human cancers.

Deleted in breast cancer 1 as a potential prognostic biomarker in human cancers: a pooled analysis of 2,254 patients.

BackgroundDeleted in breast cancer 1 (DBC1) is believed to be involved in human cancers. However, it is still uncertain whether DBC1 expression can be regarded as a prognostic factor in patients with various cancers. This meta-analysis aimed to evaluate the relationship between high levels of DBC1 and prognosis in tumor patients.MethodsElectronic databases were searched and 14 studies meeting the selection criteria were included. Overall survival (OS), relapse-free survival (RFS), and 95% CIs were extracted and analyzed. HRs from individual studies were pooled using fixed-or random-effects models, depending on the heterogeneity of the included studies, and publication bias analyses were also performed to increase the reliability of the results.ResultsA total of 2,254 patients with tumors from 14 published studies were included in the meta-analysis. DBC1 overexpression was associated with worse OS (univariate analysis: HR=2.94; 95% CI: [2.38–3.63]; multivariate analysis: HR=1.98, 95% CI: [1.21–3.25]) and RFS (univariate analysis: HR=2.83, 95% CI: [2.30–3.49]; multivariate analysis: HR=2.71, 95% CI: [2.07–3.53]) for various tumors. No publication bias was observed according to test of funnel plot asymmetry and Egger’s test.ConclusionCurrent evidence supports the conclusion that the upregulation of DBC1 is correlated with poor survival among tumor patients, suggesting that DBC1 represents an independent prognostic factor significantly associated with OS and RFS, and could serve as a novel therapeutic target in patients with tumors. Nevertheless, further large-scale prospective trials and well-designed studies are warranted to confirm this finding.

A three-lncRNA expression signature predicts survival in head and neck squamous cell carcinoma (HNSCC).

Increasing evidence has shown that long non-coding RNAs (lncRNAs) have important biological functions and can be used as a prognostic biomarker in human cancers. However, investigation of the prognostic value of lncRNAs in head and neck squamous cell carcinoma (HNSCC) is in infancy. In the present study, we analyzed the lncRNA expression data in a large number of HNSCC patients (n=425) derived from The Cancer Genome Atlas (TCGA) to identify an lncRNA expression signature for improving the prognosis of HNSCC. Three lncRNAs are identified to be significantly associated with survival in the training dataset using Cox regression analysis. Three lncRNAs were integrated to construct an lncRNA expression signature that could stratify patients of training dataset into the high-risk group and low-risk group with significantly different survival time (median survival 1.85 years vs. 5.48 years; P=0.0018, log-rank test). The prognostic value of this three-lncRNA signature was confirmed in the testing and entire datasets, respectively. Further analysis revealed that the prognostic power of three-lncRNA signature was independent of clinical features by multivariate Cox regression and stratified analysis. These three lncRNAs were significantly associated with known genetic and epigenetic events by means of functional enrichment analysis. Therefore, our results indicated that the three-lncRNA expression signature can predict HNSCC patients’ survival.

Long noncoding RNA HOXD-AS1 in various cancers: a meta-analysis and TCGA data review.

Background and aims: HOXD antisense growth-associated long noncoding RNA (HOXD-AS1) was reported to be upregulated in various cancers, such as gastric cancer, hepatocellular carcinoma, colorectal cancer, and glioma. Here, we conducted a meta-analysis and The Cancer Genome Atlas data review to investigate the clinicopathologic and prognostic value of HOXD-AS1 in patients with malignant tumors.Materials and methods: Systematic literatures were searched from PubMed, Medline, Cochrane Library, Web of Science, EMBASE database, Ovid, Chinese CNKI, and the Chinese WanFang database. The role of HOXD-AS1 in cancers was evaluated by pooled ORs and HRs with 95% CIs. The Cancer Genome Atlas dataset was used to explore the prognostic value of HOXD-AS1 in various cancers.ResultsFifteen studies with 1,678 patients were included in this meta-analysis. The results indicated that HOXD-AS1 was associated with tumor size, differentiation, lymph node metastasis, and TNM stage. Moreover, the high HOXD-AS1 expression indicated a poor overall survival (OS) rate and can be an independent predictive factor for OS. The TCGA dataset, which included 9,502 cancer patients, showed that the expression of HOXD-AS1 was related to poor OS and disease-free survival. We also analyzed the prognostic role in different kinds of cancers such as digestive cancers, female reproductive system cancers, respiratory system cancers, and urinary system cancers.ConclusionThis study demonstrated that HOXD-AS1 was closely correlated with tumor size, lymph node metastasis, distant metastasis, and TNM stage, and an increased HOXD-AS1 expression could be a reliable prognostic biomarker in human cancers. However, more studies are needed to confirm this conclusion.

Long non-coding RNA CASC2 in solid tumors: A meta-analysis

Background and aimRecently, several studies have reported that the long non-coding RNA cancer susceptibility 2 (CASC2) is downregulated in human solid tumors. However, as the sample size in those studies was limited, the role of CASC2 in cancer remains unknown. Accordingly, we conducted this meta-analysis to explore the role of CASC2 in solid tumors. MethodsWe systematically searched the PubMed, Medline, Cochrane Library, Web of Science, EMBASE, Ovid, Chinese CNKI, and Chinese WanFang databases. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (CI) were used to evaluate the relation between CASC2 and the clinicopathological characteristics and prognosis of patients with cancer. Additionally, we also use The Cancer Genome Atlas (TCGA) dataset to analyze CASC2 expression. ResultsA total of 15 studies with 1158 patients were included in this meta-analysis. The pooled results demonstrated that the expression of CASC2 was related to tumor size (large vs. small: OR = 0.40, 95% CI = [0.30, 0.52]), differentiation (low vs. high+ moderate: OR = 0.42, 95% CI = [0.29, 0.62]) and TNM stage (I + II vs. III + IV: OR = 2.74, 95% CI = [2.08, 3.60]), but not to age, gender and differentiation. High CASC2 expression indicated better overall survival (OS) (HR = 0.41, 95% CI = [0.32, 0.50]) and disease-free survival (DFS) (HR = 0.48, 95% CI = [0.26, 0.66]). Additionally, similar results were obtained through analysis of the TCGA data set. Moreover, it was determined that CASC2 could be an independent predictive factor for OS (HR = 0.38, 95% CI = [0.22, 0.54]) in patients with cancer. ConclusionThis analysis revealed that low CASC2 expression was correlated with advanced clinicopathological characteristics of cancer tumors, and CASC2 may thus be a potential prognostic biomarker in human cancer. However, more studies are needed to further corroborate these findings.

Abstract 584: Conquering undruggable oncogenic K-RAS-driven incurable metastatic cancer, and delivering precision medicine at neoadjuvant settings

Abstract SIAH is a new and potent anti-K-RAS drug target in human cancer. The oncogenic EGFR/HER2/K-RAS pathway activation is pivotal in driving uncontrolled tumor growth and systemic metastasis. Thus, counteracting ERBB/K-RAS hyperactivation in attempt to reverse malignant transformation and inhibit latent tumor growth is an important area for new therapy development against late-stage and metastatic cancer. Guided by Drosophila studies, we found that SIAH (Seven-In-Absentia Homologue) is the most downstream “gatekeeper” required for proper K-RAS signaling. Based on its extraordinarily evolutionary conservation, SIAH E3 ligase is well positioned to serve as an ideal drug target for developing new anti-K-RAS and anticancer therapy. We have shown that anti-SIAH-based therapy is indeed effective in inhibiting tumorigenesis and metastasis of pancreatic, lung and breast cancer cells in xenograft models. Importantly, we have shown that anti-SIAH-based anti-K-RAS strategy is effective against well-established, super-large and late-stage pancreatic and triple-negative breast tumors in a xenograft model in vivo. Through these studies, we have successfully identified a new oncogenic K-RAS "vulnerability," SIAH, in high-grade metastatic cancer. We aim to design and develop potent SIAH inhibitor, and translate these findings to the clinic to benefit more cancer patients with therapy-refractory, relapsed and metastatic diseases in the future. SIAH is a therapy-responsive and prognostic biomarker in human cancer: SIAH expression can be used to monitor tumor responses, and identify resistant tumor clones post-NST. SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two robust, sensitive and prognostic biomarkers to predict survival in breast cancer patients with lymph node metastases. The prognostic power of SIAH and EGFR, alone or in combination, is comparable to the clinical gold standards of clinical predictors (LN positivity, mammary tumor size, grade, stage and molecular subtypes in combination), and imaging-guided technology. A marked reduction in SIAH/EGFR expression post-NST would indicate effective therapy and increased survival, while persistent high SIAH/EGFR expression post-NST would indicate ineffective therapy and decreased survival. The therapy-induced changes in SIAH expression are prognostic in quantifying effective/ineffective therapies, differentiating partial responders, identifying resistant tumor clones, and predicting remission/relapse in breast cancer at neoadjuvant settings. The identification of therapy-responsive and prognostic biomarkers is of paramount importance to stratify patients and guide therapies in clinical oncology and personalized medicine. By validating the RAS/SIAH pathway-centered prognostic biomarkers, we hope to guide standard therapies and improve patient survival in the future. Citation Format: Amy H. Tang, Robert E. Van Sciver, Elizaveta Svyatova, Kevin Kanda, Michael P. Lee, Caroline Dasom Lee, Lauren L. Siewertsz Van Reesema, Alex C, Lafever, Amber L. Collier, Apoorva S. Iyer, L.D. Britt, Janet S. Winston, Cynthia A. Allen, David Z. Chang, Gloria M. Petersen, Richard A. Hoefer. Conquering undruggable oncogenic K-RAS-driven incurable metastatic cancer, and delivering precision medicine at neoadjuvant settings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 584.

The clinicopathological and prognostic value of long non-coding RNA ZEB1-AS1 in solid tumors: A meta-analysis

Background and aimStudies have reported that Zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) is overexpressed in many malignant tumors. However, the sample size in those studies was limited, so the clinicopathological and prognostic value of ZEB1-AS1 in solid tumors remains undetermined, Accordingly, the aim of this meta-analysis was to evaluate the relationship between the expression of lncRNA ZEB1-AS1 and clinicopathological characteristics and prognosis in patients with solid tumors. MethodsPooled odds ratios (ORs) and hazard ratios (HRs) were estimated with 95% confidence interval (CI) to assess the relation between ZEB1-AS1 and the clinicopathological characteristics and prognosis of patients with cancer. ResultsA total of 10 studies, comprising 861 patients, were included in this meta-analysis. The pooled results suggested that high ZEB1-AS1 expression was related to low differentiation (low vs. high + moderate: OR = 2.99, 95% CI = [2.03, 4.39]), increased lymph node metastasis (YES vs. NO: OR = 4.62, 95% CI = [2.90, 7.37]) and advanced TNM stage (I + II vs. III + IV: OR = 0.41, 95% CI = [0.23, 0.75]), but not to gender and tumor size. Moreover, high ZEB1-AS1 expression was associated with poor overall survival (OS; HR = 1.86, 95% CI = [1.57, 2.14]) and disease-free survival (DFS; HR = 2.03, 95% CI = [1.28, 2.77]). Thus, ZEB1-AS1 could be an independent predictive factor for OS (HR = 2.07, 95% CI = [1.57, 2.56]) in patients with cancers. ConclusionHigh expression of ZEB1-AS1 was associated with advanced clinicopathological characteristics, and ZEB1-AS1overexpression may be a potential prognostic biomarker in human cancer. However, more studies involving various tumor types and large sample size are needed.

Prognostic Value of miR-375 for Survival Outcomes in Various Cancers: A Systematic Review and Meta-Analysis

Background: miR-375 plays a role in tumor progression; however, its potential as a prognostic factor in cancer remains unclear. This meta-analysis assessed the value of miR-375 as a global prognostic biomarker in human cancer. Methods: A systematic literature review was performed to retrieve publications with relevant survival data. Pooled hazard ratios (HRs) were calculated for low miR-375 expression. Publication bias was examined. Results: Data were extracted from 11 studies of 1,797 patients (low expression in 769 cases; high in 1,028 cases). The pooled HR for overall/cumulative survival (OS/CS) was 1.90 (95% confidence interval (CI) 1.57-2.29) and the pooled HR for disease-free, recurrence-free or progression-free survival (DFS/RFS/PFS) was 1.93 (95% CI 1.39-2.67), indicating low miR-375 expression was associated with significantly poorer outcomes compared to normal/high miR-375 expression. Subgroup analysis revealed miR-375 might be a good prognostic factor in cancer, regardless of population, sample type, and cancer type. The prognostic value of miR-375 in non-Chinese patients was particularly high (pooled HR > 2). Conclusion: Low miR-375 expression could represent a valuable prognostic marker in various cancers. Circulating miR-375 levels may provide a useful non-invasive, practical prognostic biomarker. However, the prognostic value of miR-375 in specific cancer types remains unclear; further studies are warranted.

Long non-coding RNA XIST as a potential prognostic biomarker in human cancers: a meta-analysis.

Growing studies have confirmed that long non-coding RNAs (lncRNAs) involve in the occurrence and development of various cancers. XIST, as a lncRNA, was dysregulated in different cancers. This meta-analysis was performed to evaluate the prognostic potential of XIST in malignant tumors. Eight databases of PubMed, Web of Science, Embase, Cochrane library, CNKI, VIP, SinoMed and Wang Fang were comprehensively searched from their initiation date to August 15, 2017. A total of nine studies with 853 cancer patients met the including criteria were finally included in this meta-analysis after independently screening the literatures by two researchers. Any discrepancies were resolved by a consensus. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for the primary endpoints were extracted and pooled for meta-analysis. Our results showed that expression level of XIST was markedly associated with overall survival (function as oncogene, HR = 0.53, 95% CI: 0.42–0.68, p < 0.00001; function as tumor suppressor, HR = 2.25, 95% CI: 1.15–4.37, p = 0.02), disease free survival (DFS)(HR = 0.45; 95% CI: 0.31–0.67, p < 0.0001), tumor type (digestive system carcinoma, HR = 0.50; 95% CI: 0.37–0.69, p < 0.00001; non-digestive system carcinoma, HR = 0.58; 95% CI: 0.39–0.87, p = 0.008), lymph node metastasis (OR = 0.32, 95% CI: 0.20–0.52, p < 0.00001), distant metastasis (OR = 0.36, 95% CI: 0.22–0.60, p < 0.0001) and tumor stage (OR = 0.43, 95% CI: 0.31–0.60, p < 0.00001). In conclusion, the pooled results in our current work suggest that XIST is an important prognostic biomarker in cancer patients.