Cancer Biomarkers - Volume 34, issue 1

Authors: Du, Bingqing | Su, Fang | Wang, Hao | Liang, Huihong | Song, Xiaodong | Shao, Zili | Wei, Yisheng

Article Type: Research Article

Abstract: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) prognosis has not improved over the last decades because of the lack of effective diagnostic and therapeutic methods in the early stage of the disease. METHODS: Several gene expression profiles were downloaded from the Expression Omnibus (GEO) database. We calculated the differentially expressed mRNAs (DEGs) and miRNAs (DEmiRs). Then, we constructed a miRNA-mRNA regulatory network by using the miRWalk database. For the DEGs regulated by DEmiRs, we introduced GEPIA to confirm these DEGs’ expression and effect on overall survival. We used other GEO datasets and mRNA-miRNA target databases to validate these …DEGs and their relationship with DEmiRs. All these potential core DEGs regulated by DEmiRs were also analyzed at the single-cell level to confirm their cell type source. RESULTS: CCNB2 and KCNN4, which were regulated by several micro RNAs, showed relatively high expression levels in PDAC patients and significant association with worse overall survival. Furthermore, we identified many DEGs at single-cell level and found that 10 oncogenes were significantly upregulated in type 2 ductal cell type, thereby further demonstrating that type 2 ductal cells might be major sources of malignant cells and are valuable therapeutic targets in PDAC. CONCLUSIONS: Our data added some new insights into the molecular mechanism of PDAC and may be helpful for finding potential biomarkers for diagnosis. These discovery at single-cell level may also be useful for developing new therapeutic targets for PDAC patients. Show more

Keywords: Pancreatic ductal adenocarcinoma, miRNA-mRNA network, GEO, TCGA, single-cell RNA-seq, CCNB2, KCNN4

DOI: 10.3233/CBM-210271

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 1-12, 2022

Authors: Xiong, Dan-Lei | Li, Qian | Wang, Heng | Jin, Wei-Li | Fan, Xiao-Ming | Ma, Ying-Yu

Article Type: Research Article

Abstract: BACKGROUND: PPM1G, a member of the serine/threonine protease family, dephosphorylates various proteins and may be involved in cancer development. The role and mechanism of PPM1G in HCC still needs to be verified. OBJECTIVE: This study aims to explore the role of PPM1G in the occurrence, development and prognosis of HCC. METHODS: Using bioinformatics (UALCAN, cBioPortal, Linkedomics, STRING and GSEA) to analyze the expression of PPM1G mRNA in HCC, its clinical relevance and possible involved signaling pathways. The expression of PPM1G protein was determined by immunohistochemistry in 311 cases of HCC to evaluate the …association between PPM1G and clinical features and prognosis. RESULTS: The expression of PPM1G was significantly upregulated in HCC (P < 0.001), correlated with the metastasis (P = 0.020), pathological grade of HCC (P = 0.032), microvascular invasion (P = 0.040), and HBV infection (P = 0.041). Cox multivariate regression showed high expression of PPM1G was an independent prognostic factor for HCC. Its role in HCC may relate to methylation and frequency mutation. Furthermore, the database showed PPM1G is involved in the signal pathway such as cell cycle, WNT pathway, and mTOR pathway in HCC. CONCLUSION: PPM1G showed an essential function involving in tumor-related pathways in HCC, providing a biological basis for targeted treatment of HCC clinically. Show more

Keywords: PPM1G, HCC, progression, prognosis

DOI: 10.3233/CBM-203248

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 13-22, 2022

Authors: Hua, Youwei | He, Zhihui | Zhang, Xu

Article Type: Research Article

Abstract: Emerging evidence has revealed a relationship between lamin B1 (LMNB1) and several cancers such as cervical cancer, liver cancer, and prostate cancer. But no systematic pan-cancer analysis is available. Little is known about the clinical significance and biomarker utility of LMNB1. In this study, we first revealed the key role of LMNB1 in esophageal carcinoma (ESCA) through weighted gene co-expression network analysis (WGCNA) and disease-free survival (DFS) analysis. Based on this result and the datasets of the cancer genome atlas (TCGA), we explored the biomarker utility of LMNB1 across thirty-three tumors. We found that LMNB1 was highly expressed in most …of the cancers and significant associations existed between LMNB1 expression and prognosis of cases of nearly half of the cancers. We also found that LMNB1 expression was associated with the infiltration level of Macrophages M1 and T cells CD4 memory activated in some cancers. Moreover, LMNB1 was mainly involved in the functional mechanisms of MRNA binding, olfactory transduction, and gene silencing. Our study first provides a pan-cancer study of LMNB1, thereby offering a relatively comprehensive understanding of the biomarker utility of LMNB1 across thirty-three tumors. Show more

Keywords: Pan-cancer, LMNB1, WGCNA, prognosis, esophageal carcinoma

DOI: 10.3233/CBM-203247

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 23-39, 2022

Authors: Cui, Zhi | Wang, Qi | Deng, Mu-Hong | Han, Quan-Li

Article Type: Research Article

Abstract: BACKGROUND: Colorectal cancer (CRC), one of the most common human malignancies, is a leading cause of the cancer-related mortality. 5-FU is a first-line chemotherapeutic agent against CRC. Although CRC patients responded to 5-FU therapy initially, a part of patients succumbed to CRC due to the acquired drug resistance. Thus, investigating molecular mechanisms underlying chemoresistance will contribute to developing novel strategies against colorectal cancer. OBJECTIVE: Accumulation evidence revealed pivotal roles of long non-coding RNAs (lncRNAs) in tumorigenesis and chemoresistance of CRC. However, the precise roles and molecular mechanisms of lncRNA-HCG11 in CRC remain unclear. This study aimed …to investigate the biological roles and underlying mechanisms of HCG11 as well as its molecular targets in regulating the cellular metabolism processes, which facilitate the chemoresistance of CRC. METHODS AND RESULTS: This study uncovers that HCG11 was significantly upregulated in CRC tumors tissues and cell lines. Moreover, HCG11 was elevated in 5-FU resistant CRC tumors. Silencing HCG11 inhibited colon cancer cell proliferation, migration, invasion and glucose metabolism and sensitized CRC cells to 5-FU. In addition, we detected increased HCG11 expression level and glucose metabolism in the established 5-FU resistant CRC cell line (DLD-1 5-FU Res). Furthermore, microRNA-microArray, RNA pull-down and luciferase assays demonstrated that HCG11 inhibited miR-144-3p which displays suppressive roles in colon cancer via sponging it to form a ceRNA network. We identified pyruvate dehydrogenase kinase 4 (PDK4), which is a glucose metabolism key enzyme, was directly targeted by miR-144-3p in CRC cells. Rescue studies validated that the miR-144-3p-inhibited glucose metabolism and 5-FU sensitization were through targeting PDK4. Finally, restoration of miR-144-3p in HCG11-overexpressing DLD-1 5-FU resistant cells successfully overcame the HCG11-faciliated 5-FU resistance via targeting PDK4. CONCLUSION: In summary, this study reveals critical roles and molecular mechanisms of the HCG11-mediated 5-FU resistance through modulating the miR-144-3p-PDK4-glucose metabolism pathway in CRC. Show more

Keywords: Colorectal cancer, 5-FU resistance, lncRNA-HCG11, PDK4, glycolysis, Warburg effect

DOI: 10.3233/CBM-210212

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 41-53, 2022

Authors: You, Yanjie | Hu, Shengjuan

Article Type: Research Article

Abstract: BACKGROUND: We have previously characterized esophageal carcinoma-related gene 4 (ECRG4) as a novel tumor suppressor gene, which is frequently inactivated in nasopharyngeal carcinoma and breast cancer. Nevertheless, the expression status and prognostic significance of ECRG4 maintain elusive in human gastric cancer. Herein, we examined ECRG4 expression profile in gastric cancer and assessed its association with clinicopathological characteristics and patient survival. METHODS: Online data mining, real-time RT-PCR and immunohistochemistry were employed to determined ECRG4 expression at transcriptional and protein levels in tumors vs . noncancerous tissues. Statistical analyses including the Kaplan-Meier survival analysis and the Cox hazard …model were utilized to detect the impact on clinical outcome. Moreover, ECRG4 expression was silenced in gastric cancer SGC7901 cells, and cell proliferation, colony formation and invasion assays were carried out. RESULTS: ECRG4 mRNA and protein levels were obviously downregulated in cancer tissues than noncancerous tissues. Statistical analyses demonstrated that low ECRG4 expression was found in 34.5% (58/168) of primary gastric cancer tissues, which was associated with higher histological grade (P = 0.018), lymph node metastasis (P = 0.011), invasive depth (P = 0.020), advanced tumor stage (P = 0.002) and poor overall survival (P < 0.001). Multivariate analysis showed ECRG4 expression is an independent prognostic predictor (P < 0.001). Silencing ECRG4 expression promoted gastric cancer cell growth and invasion. Western blot analysis revealed the anti-metastatic functions of ECRG4 by downregulating of E-cadherin and α -Catenin, as well as upregulating N-cadherin and Vimentin. CONCLUSIONS: Our observations reveal that ECRG4 expression is involved in gastric cancer pathogenesis and progression, and may serve as a candidate prognostic biomarker for this disease. Show more

Keywords: ECRG4, gastric cancer, immunohistochemistry, prognosis, data mining

DOI: 10.3233/CBM-210334

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 55-66, 2022

Authors: Karaosmanoglu Yoneten, Kubra | Kasap, Murat | Arga, Kazim Yalcin | Akpinar, Gurler | Utkan, Nihat Zafer

Article Type: Research Article

Abstract: BACKGROUND: Breast cancer (BC) is one of the most life-threatening cancer types among women. Despite major developments in medical sciences and technologies, the incidence and mortality rates of BC cases are still increasing. One of the reasons for this increase is the absence of an easy to perform early-diagnostic tool. Although there are defined BC biomarkers routinely used for diagnostic and prognostic purposes, none of these biomarkers is useful for early diagnosis. Therefore, early diagnosis of BC remains an important challenge and there is a great need for the early-diagnostic biomarker(s). OBJECTIVE: In this study, we aimed to …evaluate the diagnostic and prognostic values of glycerol-3-phosphate dehydrogenase (GPD1) and monoacylglycerol lipase (MAGL) proteins as non-invasive serum biomarkers. METHODS: GPD1 and MAGL serum levels were determined by ELISA for BC patients (n = 100) from five different subtypes, and healthy controls (n = 20), and a comparative analysis was performed to determine statistically significant expression differences among the groups. RESULTS: The results provided evidence that GPD1 acted as a diagnostic biomarker in distinguishing triple-negative breast cancer (TNBC) patients from other subtypes, and MAGL acted as a diagnostic biomarker in distinguishing healthy individuals from BC patients. CONCLUSION: GPD1 and MAGL might be proposed as non-invasive diagnostic biomarkers for BC with high sensitivity and specificity. Show more

Keywords: Breast cancer, monoacylglycerol lipase, glycerol-3-phosphate dehydrogenase, diagnostic biomarkers, ELISA

DOI: 10.3233/CBM-203093

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 67-76, 2022

Authors: Huang, Zhihao | He, Aoxiao | Wang, Jiakun | Lu, Hongcheng | Xu, Xiaoyun | Zhang, Rongguiyi | Liao, Wenjun | Feng, Qian | Wu, Linquan

Article Type: Research Article

Abstract: BACKGROUND: Toll-like receptors participate in various biological mechanisms, mainly including the immune response and inflammatory response. Nevertheless, the role of TLRs in STAD remains unclear. OBJECTIVE: We aimed to explore the expression, prognosis performance of TLRs in STAD and their relationship with immune infiltration. METHODS: Student’s t-test was used to evaluate the expression of TLRs between STAD tissues and normal tissues. Kaplan-Meier method was applied to explored the prognosis value of TLRs in STAD. And qRT-PCR validated their expression and prognosis value. Spearman’s correlation analysis and Wilcoxon rank-sum test were used to assess …the association between TLRs and immune infiltration in STAD. RESULTS: The mRNA level of TLR3 was downregulated in STAD. We summarized genetic mutations and CNV alteration of TLRs in STAD cohort. Prognosis analysis revealed that STAD patients with high TLR3 expression showed better prognosis in OS, FP and PPS. The result of qRT-PCR suggested that TLR3 expression was decreased in STAD tissues and STAD patients with high TLR3 mRNA level had a better OS. Univariate and multivariate cox regression analysis suggested TLR3 expression and clinical stage as independent factors affecting STAD patients’ prognosis. A positive association existed between TLR3 expression and the abundance of immune cells and the expression of various immune biomarkers. Furthermore, key targets related to TLR3 were identified in STAD, mainly including MIR-129 (GCAAAAA), PLK1, and V$IRF1_01. CONCLUSIONS: Our result demonstrated TLR3 as a prognosis marker and associated with immune infiltration in STAD. Show more

Keywords: Biomarker, bioinformatics analysis, immune cell infiltration, stomach adenocarcinoma, Toll-like receptor

DOI: 10.3233/CBM-210354

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 77-93, 2022

Authors: Zakir, Umaira | Siddiqui, Nadir Naveed | Naqvi, Faizan-ul-Hassan | Khan, Rizma

Article Type: Research Article

Abstract: BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of cancer in the world and a reason behind different oncogenes activation and tumor suppressor genes inactivation. Hyper-methylation of tumor suppressor genes including RASSF1a, GSTP1, p16, and APC cause gene silencing as well as tumor cell invasion. STAT 1 gene is a part of signaling cascade of JAK/STAT and any dysregulation in signaling has been implicated in tumor formation. OBJECTIVE: The current investigation focus on the methylation role of STAT1 gene as a non-invasive biomarker in the progression and diagnosis of hepatocellular carcinoma. …METHODS: STAT1 gene methylation status in 46 HCV induced hepatocellular carcinoma patients and 40 non-HCC controls were examined by methylation specific PCR. STAT1 gene expression was examined by real time PCR and further validated by various bioinformatics tools. RESULTS: STAT1 methylation in HCV-induced HCC (67.4%) was significantly higher compared to the non-HCC controls (p < 0.01). However, mRNA expression of STAT1 gene in methylated groups was significantly lower compared to unmethylated groups (p < 0.05). Furthermore, insilco analysis of STAT1 validated our results and shown expression of STAT1 mRNA was lower in liver cancer with the median 24.3 (p = 0.085). CONCLUSION: After using peripheral blood samples we observed that STAT1 silencing caused by aberrant methylation could be used as potential non-invasive biomarker for the diagnosis of HCV induced hepatocellular carcinoma. We conclude that blood as a sample source could be used instead of biopsy for early detection of HCC. Show more

Keywords: Hepatocellular carcinoma, STAT1, cancer biomarker, methylation, CpG Island

DOI: 10.3233/CBM-210216

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 95-103, 2022

Authors: Aref, Salah | Atia, Doaa | Ramez, Ahmed | Zeid, Tarek Abou | Gouda, Enas

Article Type: Research Article

Abstract: BACKGROUND: Recent reports indicated the importance of chemotractant CXCL-13 in solid tumors and lymphoid malignancies. However, the prognostic value of the mentioned cytokines as biomarkers in chronic lymphocytic leukemia patient’s remains to be identified. Therefore; this study was designed in order to address the relation between CXCL-13 concentrations levels and markers of severity in CLL patients. METHODS: Our study included 150 CLL patients and 20 controls. Serum CXCL-13 was determined by ELISA for CLL patients at diagnosis as well as controls. RESULTS: The serum CXCL-13 levels were significantly higher in CLL patients as …compared to controls. The high CXCL-13 concentration levels was significantly associated with high number of smudge cells; high LDH; high grade of Rai stage, short time to first treatment (TTT). Cox regression analysis was conducted for prediction of TTT, using age, gender, WBCs, smudge cells, CXCL-13, LDH, ZAP70, CD38, β 2-microglobulin, Rai staging as covariates. High LDH, CXCL-13 and CD38% were significantly independent predictor for shorter TTT. CONCLUSION: High CXCL-13 serum levels at CLL diagnosis is correlated with other markers of disease activity; and could be served as biomarkers that predict CLL patient’s outcome. Show more

Keywords: CXCL-13, CLL, time to first time treatment

DOI: 10.3233/CBM-210207

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 105-111, 2022

Authors: Lázár, József | Kovács, András | Tornyi, Ilona | Takács, László | Kurucz, István

Article Type: Research Article

Abstract: BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide. With the expectation of improved survival, tremendous efforts and resources have been invested in the discovery of specific biomarkers for early detection of the disease. Several investigators have reported the presence of cancer-associated autoantibodies in the plasma or serum of lung cancer patients. Previously, we used a monoclonal antibody (mAb) proteomics technology platform for the discovery of novel lung cancer-associated proteins. OBJECTIVE: The identification of specific protein epitopes associated with various cancers is a promising method in biomarker discovery. Here, in a preliminary study, we …aimed to detect autoantibody-leucine-rich alpha-2-glycoprotein 1 (LRG1) immunocomplexes using epitope-specific monoclonal antibodies (mAbs). METHODS: We performed sandwich ELISA assays using the LRG1 epitope-specific capture mAbs, Bsi0352 and Bsi0392, and an IgG-specific polyclonal antibody coupled to a reporter system as the detection reagent. We tested the plasma of lung cancer patients and apparently healthy controls. RESULTS: Depending on the epitope specificity of the capture mAb, we were either unable to distinguish the control from LC-groups or showed a higher level of LRG1 and IgG autoantibody containing immunocomplexes in the plasma of non-small cell lung cancer and small cell lung cancer subgroups of lung cancer patients than in the plasma of control subjects. CONCLUSIONS: Our findings underline the importance of protein epitope-specific antibody targeted approaches in biomarker research, as this may increase the accuracy of previously described tests, which will need further validation in large clinical cohorts. Show more

Keywords: LRG1, autoantibody immunocomplexes, biomarker, lung cancer, epitope-oriented ELISA

DOI: 10.3233/CBM-210164

Citation: Cancer Biomarkers, vol. 34, no. 1, pp. 113-122, 2022