Machine Learning-Based Comparative Analysis of Pan-Cancer and Pan-Normal Tissues Identifies Pan-Cancer Tissue-Enriched circRNAs Related to Cancer Mutations as Potential Exosomal Biomarkers

A growing body of evidence has shown that circular RNA (circRNA) is a promising exosomal cancer biomarker candidate. However, global circRNA alterations in cancer and the underlying mechanism, essential for identification of ideal circRNA cancer biomarkers, remain under investigation. We comparatively analyzed the circRNA landscape in pan-cancer and pan-normal tissues. Using co-expression and LASSO regularization analyses, as well as a support vector machine, we analyzed 265 pan-cancer and 319 pan-normal tissues in order to identify the circRNAs with the highest ability to distinguish between pan-cancer and pan-normal tissues. We further studied their expression in plasma exosomes from patients with cancer and their relation with cancer mutations and tumor microenvironment landscape. We discovered that circRNA expression was globally reduced in pan-cancer tissues and plasma exosomes from cancer patients than in pan-normal tissues and plasma exosomes from healthy controls. We identified dynein axonemal heavy chain 14 (DNAH14), the top back-spliced gene exclusive to pan-cancer tissues, as the host gene of three pan-cancer tissue-enriched circRNAs. Among these three circRNAs, chr1_224952669_224968874_+ was significantly elevated in plasma exosomes from hepatocellular carcinoma and colorectal cancer patients. It was also related to the cancer mutation chr1:224952669: G>A, a splice acceptor variant, and was increasingly transcription-driven in cancer tissues. Moreover, pan-cancer tissue-enriched and pan-normal tissue-enriched circRNAs were associated with distinct tumor microenvironment patterns. Our machine learning-based analysis provides insights into the aberrant landscape and biogenesis of circRNAs in cancer and highlights cancer mutation-related and DNAH14-derived circRNA, chr1_224952669_224968874_+, as a potential cancer biomarker.

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The Clinicopathological Significance and Prognostic Value of Obg-Like Atpase 1 (OLA1) in Gastric Cancer

10.21203/rs.3.rs-362393/v1 ◽

2021 ◽

Author(s):

Juan Wang ◽

Zihan Zheng ◽

Qinghua Cao ◽

Xiufen Liu ◽

Zhiqing Wang

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Prognostic Value ◽

Biological Significance ◽

High Expression ◽

Cancer Tissue ◽

Cox Regression Analysis ◽

Gastric Cancer Patients ◽

Cancer Tissues

Abstract Backgroud Obg-like ATPase 1 (OLA1) is a member of the Obg family of P-loop NTPases and has recently been detected in several human cancer cells. However, its expression type and clinical relevance in gastric cancer remains unclear. Methods In the present study, 2 datasets downloaded from the open Gene Expression Omnibus database were used to evaluate the mRNA level of OLA1 in gastric cancer. Quantitative Reverse Transcription PCR further validated the mRNA expression in gastric cancer tissues. Immunohistochemistry was performed on gastric cancer tissue microarray to assess OLA1 protein expression type, prognostic value, biological significance and its association with Snail in 334 patients of gastric cancer. The prognostic value of combination of OLA1 and Snail has been evaluated. Results The results showed that OLA1 mRNA and protein were elevated in gastric cancer tissues. High expression of OLA1 was significantly associated with aggressive features, such as tumor size, lymph node metastasis and TNM stage (P = 0.0146, P = 0.0037, P < 0.001, respectively). Moreover, high levels of OLA1 predicted worse overall survival. Multivariate Cox regression analysis indicated that high expression of OLA1 was an independent prognostic factor for poor overall survival (hazard ratio, 0.573; 95% confidence interval, 0.376–0.872; P = 0.009). Additionally, OLA1 expression was positively correlated with Snail, and combination of them revealed improved prognostic accuracy for gastric cancer patients. Conclusions Our results suggested that OLA1 high expression was considered as an independent factor for the prediction of unfavorable prognosis in gastric cancer patients, and we believe that OLA1 could serve as a biomarker of poor prognosis and a novel target in treating gastric cancers.

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Detection and Clinical Significance of Thrombomodulin in Both Plasma and Tissue Extracts of Cancer Patients.

Blood ◽

10.1182/blood.v104.11.3966.3966 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3966-3966

Author(s):

Xiaohua Xu ◽

Liansheng Huang ◽

Xingguo Lu ◽

Xiaohong Zhang ◽

Xiaoying Zhao

Keyword(s):

Cancer Patients ◽

Clinical Significance ◽

Enzyme Linked Immunosorbent Assay ◽

Cancer Tissue ◽

Lung Cancers ◽

Gastric Cancers ◽

Tissue Extracts ◽

Pancreatic Cancers ◽

Cancer Tissues ◽

And Diffusion

Abstract Objective: To study the changes of thrombomodulin(TM) in both plasma and tissue extracts of cancer patients for evaluating its clinical significance. Methods: Plasma TM levels were measured by enzyme-linked immunosorbent assay(ELISA) in both plasma of 188 cancer patients and 24 cancer tissue extracts including their adjacent non-cancer tissues. Results: The plasma TM levels both in cancer patients and in metastasis patients were significantly higher than that in controls [(33.47±14.25)ug/L/(41.68±16.96)ug/L, vs (20.40±7.22)ug/L, P<0.01]. The plasma TM levels in cancer patients after operation decreased obviously than that before operation [(18.45±9.96)ug/L, vs (28.29±11.74)ug/L, P<0.01], whereas, the plasma TM levels in patients with recurrence and metastasis after operation increased obviously [(34.50±12.57)ug/L]. Among the type of cancer, the plasma TM levels in metastasis including lung cancers and gastric cancers and pancreatic cancers were significantly higher than that in non-metastasis respectively, but no significant differences were foundPOST http://www.call4abstracts.com/hem/body.pincluding gastric cancers and pancreatic cancers and nasopharyngeal cancers and large intestine cancers and laryngeal cancers (P>0.05). The TM levels in cancer tissue extracts were significantly lower than that in their adjacent non-cancer tissue extracts [(647.71±317.51)ug/L vs (1455.63±772.22)ug/L, P<0.01]. On the contrary, the plasma TM levels in these cancers were significantly higher than that in controls. Conclusion: The rise of plasma TM levels in cancer patients was associated with metastasis and diffusion of cancers. The TM levels can be served as a sensitive index for judging progression and metastasis of cancers.

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Fascin is a circulating tumor marker for head and neck cancer as determined by a proteomic analysis of interstitial fluid from the tumor microenvironment

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-1016 ◽

2015 ◽

Vol 53 (10) ◽

Cited By ~ 8

Author(s):

Li-Yu Lee ◽

Yin-Ju Chen ◽

Ya-Ching Lu ◽

Chun-Ta Liao ◽

I-How Chen ◽

...

Keyword(s):

Cell Culture ◽

Head And Neck Cancer ◽

Tumor Microenvironment ◽

Head And Neck ◽

Cancer Patients ◽

Tumor Markers ◽

Interstitial Fluid ◽

Culture Supernatant ◽

Cell Culture Supernatant ◽

Cancer Tissues

AbstractHead and neck cancer (HNC) is a prevalent cancer worldwide; however, clinically useful tumor markers for HNC have not been identified. Here, we aimed to identify secretory proteins from the tumor microenvironment as candidate circulating tumor markers.Samples derived from seven pairs of tumor interstitial fluid (TIF) and normal interstitial fluid (NIF) samples from patients with HNC were analyzed. The proteomes were determined by gel-based-mass-spectrometry proteomic methods. The most up-regulated protein, fascin was confirmed in the cancer tissues and cell culture supernatant by immunoblotting and immunohistochemistry assays. Serum fascin was determined in 40 HNC and 40 normal individuals by ELISA.After proteomics analysis, 189 peptides were identified, corresponding to 75 proteins. Of the 21 proteins which were identified more than twice, five up-regulated proteins identified most frequently including fascin. The most elevated fascin was over-expressed in cancer tissues and cell culture supernatant. Serum fascin was significantly up-regulated in the cancer patients (p<0.001) and correlated with pathological lymph node metastasis (p=0.022). To assess the diagnostic efficacy, serum levels of fascin and another potential biomarker SCCA were determined. Fascin showed a high predictable value with an area under the curve (AUC) of 0.808 (95% CI 0.723–0.901) in the receiver operator curve (ROC), compared to 0.501 (95% CI 0.378–0.634) for SCCA.We have identified 75 potential circulating tumor markers associated with HNC, including fascin. Serum fascin could discriminate cancer patients from healthy individuals; thus, it may serve as a circulating biomarker for HNC.

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The expression and Clinical Significance of miRNA-135a and Bach1 in colorectal cancer

International Surgery ◽

10.9738/intsurg-d-20-00026.1 ◽

2021 ◽

Author(s):

Yang zhi Jiang ◽

Qing Guo Tao ◽

fei yan Zhu

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Clinical Information ◽

Control Group ◽

Tumor Control ◽

Cancer Tissue ◽

Expression Levels ◽

Real Time Quantitative Pcr ◽

Normal Tissues ◽

Cancer Tissues

BACKGROUND AIM To explore the correlation between the expression of miRNA-135a and Bach1 in colorectal cancer tissue and the patient's clinical information. Methods 60 patients with colorectal carcinoma were treated as a control group. Real-time quantitative PCR assays and immunohistochemistry method were performed to detect the expression of miRNA-135a and Bach1 in 60 colorectal carcinomas and adjacent normal tissues, and the clinical and pathological classifications had also been investigated. The SPSS 19.00 software was used. All data represented mean±SD of three independent experiments. P<0.05 was considered statistically significant. Results miRNA-135a expression levels increased significantly in the colon cancer tissues compared with the non-tumor control tissues(P<0.01). miRNA-135a expression levels were higher in stage III/IV than in stage I/II colon cancer patients. The expression level of Bach1 in colorectal cancer was significantly lower(P<0.01). Bach1 and miRNA-135a were negatively correlated. Conclusions: The levels of miRNA-135a and Bach1 were opposite, the over-expression of miRNA-135a might downregulated the expression of Bach1, which might be involved in the pathogenesis of colorectal cancer.

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Glutathione and GSH-dependent enzymes in patients with liver cirrhosis and hepatocellular carcinoma.

Acta Biochimica Polonica ◽

10.18388/abp.2006_3384 ◽

2006 ◽

Vol 53 (1) ◽

pp. 237-241 ◽

Cited By ~ 61

Author(s):

Hanna Czeczot ◽

Dorota Scibior ◽

Michał Skrzycki ◽

Małgorzata Podsiad

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Tissue ◽

Normal Liver ◽

Cancer Tissue ◽

Glutathione Level ◽

Normal Tissues ◽

Control Tissue ◽

Cirrhotic Tissue ◽

Cancer Tissues ◽

Gst Activity

We investigated glutathione level, activities of selenium independent GSH peroxidase, selenium dependent GSH peroxidase, GSH S-transferase, GSH reductase and the rate of lipid peroxidation expressed as the level of malondialdehyde in liver tissues obtained from patients diagnosed with cirrhosis or hepatocellular carcinoma. GSH level was found to be lower in malignant tissues compared to adjacent normal tissues and it was higher in cancer than in cirrhotic tissue. Non-Se-GSH-Px activity was lower in cancer tissue compared with adjacent normal liver or cirrhotic tissue, while Se-GSH-Px activity in cancer was found to be similar to its activity in cirrhotic tissue and lower compared to control tissue. An increase in GST activity was observed in cirrhotic tissue compared with cancer tissue, whereas the GST activity in cancer was lower than in adjacent normal tissue. The activity of GSH-R was similar in cirrhotic and cancer tissues, but higher in cancer tissue compared to control liver tissue. An increased level of MDA was found in cancer tissue in comparison with control tissue, besides its level was higher in cancer tissue than in cirrhotic tissue. Our results show that the antioxidant system of cirrhosis and hepatocellular carcinoma is severely impaired. This is associated with changes of glutathione level and activities of GSH-dependent enzymes in liver tissue. GSH and enzymes cooperating with it are important factors in the process of liver diseases development.

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Capturing the Differences between Humoral Immunity in the Normal and Tumor Environments from Repertoire-Seq of B-Cell Receptors Using Supervised Machine Learning

10.1101/187120 ◽

2017 ◽

Cited By ~ 1

Author(s):

Hiroki Konishi ◽

Daisuke Komura ◽

Hiroto Katoh ◽

Shinichiro Atsumi ◽

Hirotomo Koda ◽

...

Keyword(s):

Machine Learning ◽

Tumor Microenvironment ◽

B Cell ◽

Supervised Machine Learning ◽

B Cell Receptors ◽

Rna Sequences ◽

Cell Receptors ◽

Tumor Microenvironments ◽

Normal Tissues ◽

Tumor Tissues

ABSTRACTThe recent success of immunotherapy in treating tumors has attracted increasing interest in research related to the adaptive immune system in the tumor microenvironment. Recent advances in next-generation sequencing technology enabled the sequencing of whole T-cell receptors (TCRs) and B-cell receptors (BCRs)/immunoglobulins (Igs) in the tumor microenvironment. Since BCRs/Igs in tumor tissues have high affinities for tumor-specific antigens, the patterns of their amino acid sequences and other sequence-independent features such as the number of somatic hypermutations (SHMs) may differ between the normal and tumor microenvironments. However, given the high diversity of BCRs/Igs and the rarity of recurrent sequences among individuals, it is far more difficult to capture such differences in BCR/Ig sequences than in TCR sequences. The aim of this study was to explore the possibility of discriminating BCRs/Igs in tumor and in normal tissues, by capturing these differences using supervised machine learning methods applied to RNA sequences of BCRs/Igs.RNA sequences of BCRs/Igs were obtained from matched normal and tumor specimens from 90 gastric cancer patients. BCR/Ig-features obtained in Rep-Seq were used to classify individual BCR/Ig sequences into normal or tumor classes. Different machine learning models using various features were constructed as well as gradient boosting machine (GBM) classifier combining these models. The results demonstrated that BCR/Ig sequences between normal and tumor microenvironments exhibit their differences. Next, by using a GBM trained to classify individual BCR/Ig sequences, we tried to classify sets of BCR/Ig sequences into normal or tumor classes. As a result, an area under the curve (AUC) value of 0.826 was achieved, suggesting that BCR/Ig repertoires have distinct sequence-level features in normal and tumor tissues.To the best of our knowledge, this is the first study to show that BCR/Ig sequences derived from tumor and normal tissues have globally distinct patterns, and that these tissues can be effectively differentiated using BCR/Ig repertoires.

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Pan-Cancer Prognostic, Immunity, Stemness, and Anticancer Drug Sensitivity Characterization of N6-Methyladenosine RNA Modification Regulators in Human Cancers

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.644620 ◽

2021 ◽

Vol 8 ◽

Author(s):

Rui Li ◽

Yun-Hong Yin ◽

Xiu-Li Ji ◽

Xiao Liu ◽

Jian-Ping Li ◽

...

Keyword(s):

Tumor Microenvironment ◽

Anticancer Drug ◽

Drug Sensitivity ◽

Rna Modification ◽

Immune Microenvironment ◽

Normal Tissues ◽

Tumor Immune Microenvironment ◽

Cancer Types ◽

Pan Cancer

N6-methyladenosine RNA modification plays a significant role in the progression of multiple tumorigenesis. Our study identified the imperative role of m6A regulators in the tumor immune microenvironment, survival, stemness score, and anticancer drug sensitivity of pan-cancer. The Wilcox test was to identify the differential expression between 17 m6A regulators across 33 TCGA cancer types and their normal tissues from UCSC Xena GDC pan-cancer. Survival analysis of m6A-related regulators in 33 TCGA cancer types was identified using the “survival” and “survminer” package. The Spearman correlation test and Pearson correlation test were used to identify the correlation relationship between m6A regulators expression and tumor microenvironment, tumor stem cell score, and drug sensitivity of anticancer drugs. ConsensusPathDB was used for exploring m6A regulators functional enrichment. The 17 (METTL3, WTAP, METTL14, RBM15, RBM15B, VIRMA, HNRNPC, HNRNPA2B1, YTHDC1, ZC3H13, YTHDF1, YTHDC2, YTHDF2, IGF2BP3, IGF2BP1, FTO, and ALKBH5) m6A regulators were differentially expressed in 18 TCGA cancer types and adjacent normal tissues. Correlation analysis indicated that the relationship between the expression of 17 m6A regulators and tumor microenvironment indicated that the higher expression of m6A regulators, the higher the degree of tumor stem cells. The anticancer drug sensitivity analysis indicated that ZC3H13 expression had a positive relationship with anticancer drugs such as selumetinib, dabrafenib, cobimetinib, trametinib, and hypothemycin (p < 0.001). YTHDF2 expression was significantly negatively correlated with the anticancer drug dasatinib (p < 0.001). The pan-cancer immune subtype analysis showed that the 17 m6A regulators were significantly different in immune subtype C1 (wound healing), C3 (inflammatory), C2 (IFN-gamma dominant), C5 (immunological quiet), C4 (lymphocyte depleted), and C6 (TGF-beta dominant) (p < 0.001). Our study provides a comprehensive insight for revealing the significant role of m6A regulators in the tumor immune microenvironment, stemness score, and anticancer drug sensitivity of human cancers.

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miRactDB characterizes miRNA–gene relation switch between normal and cancer tissues across pan-cancer

Briefings in Bioinformatics ◽

10.1093/bib/bbaa089 ◽

2020 ◽

Cited By ~ 2

Author(s):

Hua Tan ◽

Pora Kim ◽

Peiqing Sun ◽

Xiaobo Zhou

Keyword(s):

Mirna Gene ◽

Gene Interaction ◽

Histological Change ◽

Gene Interactions ◽

Promoter Regions ◽

Critical Set ◽

Normal Tissues ◽

Gene Coding ◽

Cancer Tissues ◽

Pan Cancer

Abstract It has been increasingly accepted that microRNA (miRNA) can both activate and suppress gene expression, directly or indirectly, under particular circumstances. Yet, a systematic study on the switch in their interaction pattern between activation and suppression and between normal and cancer conditions based on multi-omics evidences is not available. We built miRactDB, a database for miRNA–gene interaction, at https://ccsm.uth.edu/miRactDB, to provide a versatile resource and platform for annotation and interpretation of miRNA–gene relations. We conducted a comprehensive investigation on miRNA–gene interactions and their biological implications across tissue types in both tumour and normal conditions, based on TCGA, CCLE and GTEx databases. We particularly explored the genetic and epigenetic mechanisms potentially contributing to the positive correlation, including identification of miRNA binding sites in the gene coding sequence (CDS) and promoter regions of partner genes. Integrative analysis based on this resource revealed that top-ranked genes derived from TCGA tumour and adjacent normal samples share an overwhelming part of biological processes, which are quite different than those from CCLE and GTEx. The most active miRNAs predicted to target CDS and promoter regions are largely overlapped. These findings corroborate that adjacent normal tissues might have undergone significant molecular transformations towards oncogenesis before phenotypic and histological change; and there probably exists a small yet critical set of miRNAs that profoundly influence various cancer hallmark processes. miRactDB provides a unique resource for the cancer and genomics communities to screen, prioritize and rationalize their candidates of miRNA–gene interactions, in both normal and cancer scenarios.

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Expression of PAWR predicts prognosis of ovarian cancer

Cancer Cell International ◽

10.1186/s12935-020-01704-y ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Jiahong Tan ◽

Kangjia Tao ◽

Xu Zheng ◽

Dan Liu ◽

Ding Ma ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Prognostic Value ◽

Interaction Network ◽

Clinical Samples ◽

Normal Tissues ◽

Cancer Management ◽

Disease Associations ◽

Drug Responsiveness ◽

Cancer Tissues

Abstract Background Ovarian cancer greatly threatens the general health of women worldwide. Implementation of predictive prognostic biomarkers aids in ovarian cancer management. Methods Using online databases, the general expression profile, target-disease associations, and interaction network of PAWR were explored. To identify the role of PAWR in ovarian cancer, gene correlation analysis, survival analysis, and combined analysis of drug responsiveness and PAWR expression were performed. The predictive prognostic value of PAWR was further validated in clinical samples. Results PAWR was widely expressed in normal and cancer tissues, with decreased expression in ovarian cancer tissues compared with normal tissues. PAWR was associated with various cancers including ovarian cancer. PAWR formed a regulatory network with a group of proteins and correlated with several genes, which were both implicated in ovarian cancer and drug responsiveness. High PAWR expression denoted better survival in ovarian cancer patients (OS: HR = 0.84, P = 0.0077; PFS, HR = 0.86, P = 0.049). Expression of PAWR could predict platinum responsiveness in ovarian cancer and there was a positive correlation between PAWR gene effect and paclitaxel sensitivity. In 12 paired clinical samples, the cancerous tissues exhibited significantly lower PAWR expression than matched normal fallopian tubes. The predictive prognostic value of PAWR was maintained in a cohort of 50 ovarian cancer patients. Conclusions High PAWR expression indicated better survival and higher drug responsiveness in ovarian cancer patients. PAWR could be exploited as a predictive prognostic biomarker in ovarian cancer.

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Correlation Between Preoperative Serum Carcinoembryonic Antigen Levels and Expression on Pancreatic and Rectal Cancer Tissue

Biomarkers in Cancer ◽

10.1177/1179299x17710016 ◽

2017 ◽

Vol 9 ◽

pp. 1179299X1771001 ◽

Cited By ~ 7

Author(s):

LSF Boogerd ◽

FA Vuijk ◽

CES Hoogstins ◽

HJM Handgraaf ◽

MJM van der Valk ◽

...

Keyword(s):

Pancreatic Cancer ◽

Rectal Cancer ◽

Carcinoembryonic Antigen ◽

Cancer Patients ◽

Cancer Tissue ◽

Targeted Agents ◽

Serum Carcinoembryonic Antigen ◽

Serum Cea ◽

Cancer Tissues ◽

Selection Of

Carcinoembryonic antigen (CEA)–targeted imaging and therapeutic agents are being tested in clinical trials. If CEA overexpression in malignant tissue corresponds with elevated serum CEA, serum CEA could assist in selecting patients who may benefit from CEA-targeted agents. This study aims to assess the relationship between serum CEA and CEA expression in pancreatic (n = 20) and rectal cancer tissues (n = 35) using histopathology. According to local laboratory standards, a serum CEA >3 ng/mL was considered elevated. In pancreatic cancer patients a significant correlation between serum CEA and percentage of CEA-expressing tumor cells was observed ( P = .04, ρ = .47). All 6 patients with homogeneous CEA expression in the tumor had a serum CEA >3 ng/mL. Most rectal cancer tissues (32/35) showed homogeneous CEA expression, independent of serum CEA levels. This study suggests that selection of pancreatic cancer patients for CEA-targeted agents via serum CEA appears adequate. For selection of rectal cancer patients, serum CEA levels are not informative.

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