Cancer Biomarkers - Volume 33, issue 3

Authors: Kalantari, Elham | Ghods, Roya | Saeednejad Zanjani, Leili | Rahimi, Mandana | Eini, Leila | Razmi, Mahdieh | Asadi-Lari, Mohsen | Madjd, Zahra

Article Type: Research Article

Abstract: BACKGROUND: Isoform-specific function of doublecortin-like kinase 1 (DCLK1) has highlighted the key role of the DCLK1-S (short isoform) in the maintenance, progression, and invasion of the tumor. OBJECTIVE: This study was designed to produce an anti-DCLK1-S polyclonal antibody to evaluate DCLK1-S in human colorectal cancer (CRC) specifically. METHODS: The expression pattern and clinical significance of DCLK1-S were assessed in a well-defined tissue microarray (TMA) series of 348 CRC and 51 adjacent normal tissues during a follow-up period of 108 months. RESULTS: Expression of DCLK1-S was significantly higher in CRC samples …compared to adjacent normal samples (P < 0.001). Cytoplasmic expression of DCLK1-S was significantly higher in the tumors at the advanced stage of cancer and with poorer differentiation (P < 0.001, P = 0.02). The patients with CRC whose tumors showed higher cytoplasmic expression of DCLK1-S had worse disease-specific survival (DSS) (log-rank test, P = 0.03) and 5-year DSS rates (P = 0.01). Additionally, an improved prognostic value was observed in the patients with CRC with high DCLK1-S expression vs. its moderate expression (HR: 2.70, 95% CI: 0.98–7.38; p = 0.04) by multivariate analysis. CONCLUSIONS: Our findings strongly supported that high cytoplasmic expression of DCLK1-S compared to its moderate expression could be considered an independent prognostic factor influencing DSS. Show more

Keywords: Colorectal cancer, DCLK1-S, polyclonal antibody, immunohistochemistry, tissue microarray

DOI: 10.3233/CBM-210330

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 277-289, 2022

Authors: Flores-Bustamante, Al | Hernández-Regino, Laura | Castillejos-López, Manuel-De-Jesús | Martínez-Rodríguez, Daniel | Aquino-Gálvez, Arnoldo | Zapata-Tarrés, Marta | de Uña-Flores, Armando | Salinas-Lara, Citlaltepetl | Sierra-Vargas, Patricia | Torres-Espíndola, Luz María

Article Type: Research Article

Abstract: BACKGROUND: Changes in neutrophil to lymphocyte ratio (Δ NLR) have been used as a clinical tool for stratification and prognosis of patients with solid tumors, there is scarce evidence of their clinical relevance in patients with tumors of the central nervous system who have also undergone surgical resection. OBJECTIVE: Determine if (Δ NLR) are associated with poor response to treatment and worse prognosis in pediatric patients with central nervous system tumors (CNST) who underwent surgical resection. METHODS: We performed a retrospective cohort study; demographic, clinical, and hematological variables were …evaluated, Kaplan-Meier survival curves and Cox proportional hazards regression model were performed to evaluate prognosis. RESULTS: The Δ NLR cutoff value obtained through the third interquartile range was 4.30; The probability of survival and complete response to treatment was different between patients with high Δ NLR when compared to patients with low Δ NLR (p = 0.013, p = ≪ 0.001, respectively). A high Δ NLR behaved as an independent predictor of worse Overall Survival (HR 2,297; 95% CI: 1,075–4.908, p = 0.032). CONCLUSION: An elevated Δ NLR was a predictor of poor response to treatment and a prognostic factor for worse Overall Survival in pediatric patients with CNST undergoing surgical resection. Show more

Keywords: Central nervous system tumors, pediatric, neutrophil-to-lymphocyte ratio, prognostic factor, survival, tumor resection

DOI: 10.3233/CBM-200857

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 291-298, 2022

Authors: Zhang, Xixun

Article Type: Research Article

Abstract: Breast cancer (BC) is an aggressive cancer with a high percentage recurrence and metastasis. As one of the most common distant metastasis organ in BC, lung metastasis has a worse prognosis than that of liver and bone. Therefore, it’s important to explore some potential prognostic markers associated with the lung metastasis in BC for preventive treatment. In this study, transcriptomic data and clinical information of BC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Co-expression modules constructed by weighted gene co-expression network analysis (WGCNA) found the royal blue module was significantly associated with lung metastasis in BC. Then, …co-expression genes of this module were analyzed for functional enrichment. Furthermore, the prognostic value of these genes was assessed by GEPIA Database and Kaplan-Meier Plotter. Results showed that the hub genes, LMNB and CDC20, were up-regulated in BC and had a worse survival of the patients. Therefore, we speculate that these two genes play crucial roles in the process of lung metastasis in BC, which can be used as potential prognostic markers in lung metastasis of BC. Collectively, our study identified two potential key genes in the lung metastasis of BC, which might be applied as the prognostic markers of the precise treatment in breast cancer with lung metastasis. Show more

Keywords: Breast cancer, lung metastasis, WGCNA, prognostic markers

DOI: 10.3233/CBM-210199

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 299-310, 2022

Authors: Fan, Liming | Yang, Hualiang | Zhang, Bo | Ding, Hong

Article Type: Research Article

Abstract: PURPOSE: To propose MCUR1 gene as a potential biomarker for ovarian cancer prognosis. METHODS: The ovarian cancer patient specimen from TCGA database were analyzed using survival analysis. The immune cell infiltration ratio and checkpoints had also been investigated for different expression group of MCUR1. The function of MCUR1 as a ovarian cancer prognosis biomarker was verified in clinic. RESULTS: The low expression of MCUR1 was associated with the poor prognosis of ovarian cancer patients. The expressions of majority of immune cells and 6 checkpoints in low expression group of MCUR1 were significantly lower …than that in high expression group of MCUR1 (P < 0.05). The MCUR1 could be utilized as a prognostic biomarker for ovarian cancer patients in clinic. CONCLUSION: This study has proposed a potential prognostic biomarker for ovarian cancer patients, which offers a beneficial reference for future ovarian cancer administration. Show more

Keywords: Ovarian cancer, MCUR1, immune checkpoint

DOI: 10.3233/CBM-210166

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 311-316, 2022

Authors: Xing, Baichun | Yang, Linlin | Cui, Yanan

Article Type: Research Article

Abstract: BACKGROUND: Lidocaine is a local anesthetic that wildly used in surgical treatment and postoperative medical care for lung cancers. We hypothesized that lidocaine at clinical plasma concentration can inhibit CXCL12/CXCR4 axis-regulated cytoskeletal remodeling thereby reduce the migration of Non-small-cell lung cancers (NSCLC) cells. METHODS: We determined the effect of lidocaine at clinical plasma concentration on CXCL12-induced cell viability, apoptosis, cell death, monolayer cell wound healing rate, individual cell migration indicators, expression of CXCR4, CD44, and ICAM-1, intracellular Ca 2 + level, and filamentous actin level alteration of NSCLC cells A549 and …CXCR4-knocked down A549 cells using CCK-8, Bcl-2 ELISA, Cell death ELISA, wound healing assay, chemotaxis assay, western blotting, QPCR, Fura-2-based intracellular Ca 2 + assay, and Fluorescein Phalloidin staining respectively. RESULTS: Lidocaine did not affect cell viability, apoptosis, and cell death but inhibited CXCL12-induced migration, intracellular Ca 2 + releasing, and filamentous actin increase. Lidocaine decreased expression of CXCR4, increased CD44, but had no effect on ICAM-1. CXCL12 induced the increase of CD44 and ICAM-1 but did not affect CD44 in the presence of lidocaine. The knockdown of CXCR4 eliminated all the effects of lidocaine. The overexpression of CXCR4 promoted migration but the migration was inhibited by lidocaine. CONCLUSION: Lidocaine at clinical plasma concentrations inhibited CXCL12-induced CXCR4 activation, thereby reduced the intracellular Ca 2 + -dependent cytoskeleton remodeling, resulting in slower migration of A549 cells. Show more

Keywords: Lidocaine, A549, CXCR, CXCL12, CD44, ICAM-1, cytoskeleton remodeling

DOI: 10.3233/CBM-210249

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 317-330, 2022

Authors: Weiss, Bernhard G. | Anczykowski, Mahalia Zoe | Ihler, Friedrich | Bertlich, Mattis | Spiegel, Jennifer L. | Haubner, Frank | Canis, Martin | Küffer, Stefan | Hess, Julia | Unger, Kristian | Kitz, Julia | Jakob, Mark

Article Type: Research Article

Abstract: BACKGROUND: MicroRNAs constitute promising biomarkers. OBJECTIVE: The aim was to investigate diagnostic and prognostic implications of miR-182-5p and miR-205-5p in p16-positive and p16-negative oropharyngeal squamous cell carcinomas (OPSCCs). METHODS: Expression of miR-182-5p, miR-205-5p were determined via quantitative real-time-PCR in fresh frozen tissues of 26 p16-positive, 19 p16-negative OPSCCs and 18 HPV-negative oropharyngeal controls. Associations between miRNA-expression, clinicopathological characteristics and prognosis were analyzed. RESULTS: Higher miR-182-5p expression was associated with significant inferior disease-specific survival for p16-positive OPSCCs (HR = 1.98E+ 09, 95% CI 0–Inf; P = …0.028) and a similar trend was observed for p16-negative OPSCCs (HR = 1.56E+ 09, 95% CI 0–Inf; P = 0.051). Higher miR-205-5p expression was associated with an inferior progression-free survival (HR = 4.62, 95% CI 0.98–21.83; P = 0.034) and local control rate (HR = 2.18E+ 09, 95% CI 0–Inf; P = 0.048) for p16-positive OPSCCs. CONCLUSIONS: Results indicate that miR-182-5p and miR-205-5p can further stratify patients with p16-positive OPSCC into prognostic groups. Show more

Keywords: Oropharyngeal squamous cell carcinomas, p16, microRNA, miR-182-5p, miR-205-5p

DOI: 10.3233/CBM-203149

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 331-347, 2022

Authors: Ma, Jianfei

Article Type: Research Article

Abstract: BACKGROUND: Immunomodulatory genes play significant roles in the regulation of immunological properties of gastric cancer, but the effect of epigenetic regulation of these genes on the immune properties is unknown. METHOD: I analyzed the methylation-expression correlation among all immunomodulators and compared with the non-immunomodulators. The association between epigenetically regulated immunomodulators (ERI) and tumor microenvironment is evaluated. A key immunomodulator TIGIT is further selected to investigate the potential value in the regulation of immunologic properties. Furthermore, the prognostic value and the immunotherapeutic potential of TIGIT are also explored. RESULT: Four genes are identified as …ERIs based on the negative correlation between expression and methylation. Association analysis shows that three ERIs participate in the regulation of the immune microenvironment of gastric cancer. Among these ERIs, TIGIT is identified as a key immunomodulator. TIGIT is found to be significantly associated with immune properties. The high TIGIT expression group tends to display an active immune landscape. TIGIT expression is also found to be associated with survival and immunotherapeutic sensitivity. High TIGIT expression group has a favorable prognosis and is more likely to respond to immunotherapy than the low expression group. CONCLUSION: TIGIT is an epigenetically regulated immunomodulator of gastric cancer which can modify the immune activity and affect immunotherapeutic sensitivity. These findings can promote the research of epigenetic therapies and improve the survival of cancer patients by sensitizing tumors to immune therapies. Show more

Keywords: Immunomodulator, methylation, immunotherapy, gastric cancer, prognosis

DOI: 10.3233/CBM-210159

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 349-358, 2022

Authors: Qin, Wen-Hao | Liu, Jun-Teng | Wang, Shu-Ping | Yang, Zhi-Shi | Wang, Kun-Ke | Hu, Bing

Article Type: Research Article

Abstract: BACKGROUND: Distinguishing between benign and malignant bile duct strictures has long been a diagnostic challenge in clinical practice. OBJECTIVE: This study aimed to discover novel biomarkers in bile to improve the diagnostic accuracy of malignant biliary strictures. METHODS: Bile samples were collected from 6 patients with malignant or benign biliary stricture, respectively. Protein profiles of the bile were analyzed with a semi-quantitative human antibody array of 440 proteins. Then the differential expressed proteins were screened by Venn diagram analysis. Following this, the accuracy of these potential biomarkers for discriminating between malignant and non-malignant …biliary strictures was validated in a larger (n = 40) group of patients using ROC analysis and the best biomarker combination was further selected by lasso analysis. Results: Twenty proteins were found differentially expressed in malignant versus benign biliary strictures, 6 of which were identified by Venn diagram analysis to be up-regulated regardless of the location of biliary strictures. Among the 6 biomarkers, bile lipocalin-2, P-cadherin, and adipsin showed better diagnostic utility than that of bile CA19-9. Lasso analysis identified that lipocalin-2, P-cadherin and CA19-9 as a group of makers best distinguished malignant from benign strictures. CONCLUSIONS: Lipocalin-2 and P-cadherin measurements in bile could be clinically useful for the detection of malignant biliary strictures. Show more

Keywords: Biliary stricture, biomarkers, CA19-9, lipocalin-2, P-cadherin

DOI: 10.3233/CBM-210095

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 359-368, 2022

Authors: Kuo, I-Ying | Liu, Danping | Lai, Wu-Wei | Wang, Yi-Ching | Loh, Y. Peng

Article Type: Research Article

Abstract: BACKGROUND: Effective biomarkers for prediction of recurrence of lung adenocarcinoma cancer (LADC) patients are needed to determine treatment strategies post-surgery to improve outcome. OBJECTIVE: This study evaluates the efficacy of carboxypeptidase E (CPE) mRNA including its splice isoforms, CPE-Δ N , as a biomarker for predicting recurrence in adenocarcinoma patients. METHODS: RNA was extracted from resected tumors from 86 patients with different stages of non-small cell LADC. cDNA was synthesized and qRT-PCR carried out to determine the copy numbers of CPE/CPE-Δ N mRNA. Patients were followed for 7 years …post-tumor resection to determine recurrence and death. RESULTS: ROC curve analysis showed the overall AUC for CPE/CPE-Δ N copy number was 0.563 in predicting recurrence and 0.562 in predicting death. Kaplan-Meier survival analysis showed statistical difference (p = 0.018), indicating that patients with high CPE/CPE-Δ N copy numbers had a shorter time of disease-free survival and also shorter time to death (p = 0.035). Subgroup analyses showed that association of disease-free survival time with CPE/CPE-Δ N copy number was stronger among stage I and II LADC patients (p = 0.047). CONCLUSIONS: CPE/CPE-Δ N mRNA is a potentially useful biomarker for predicting recurrence and death in LADC patients, especially in identifying patients at high risk of recurrence at early stages I and II. Show more

Keywords: Lung cancer, carboxypeptidase E, cancer biomarker, adenocarcinoma

DOI: 10.3233/CBM-210206

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 369-377, 2022

Authors: Liu, Fengsong | Pang, Xiaojian | Yu, Ziqi | Wang, Kai

Article Type: Research Article

Abstract: PURPOSE: To explore the exact molecular mechanisms underline osteosarcoma (OS) patients with lung metastases. METHODS: The differentially expressed gene (DEG) as well as differentially expressed miRNAs (DEMs) for OS lung metastases were deeply investigated with two independent sources of databases (GEO dataset and clinical participants); The enriched biological processes and signaling pathways were explored; the miRNAs-mRNAs network was constructed; the functions of potential DEGs and DEMs were also verified with external analysis. RESULTS: The OS patients with lung metastases displayed 323 DEGs as C-C motif chemokine ligand 3 (CCL3), sorting nexin 10 (SNX10), …alpha-2-macroglobulin (A2M), carboxypeptidase E (CPE), Rap guanine nucleotide exchange factor 4 (RAPGEF4), PDZ domain containing 2 (PDZD2), calpain 10 (CAPN10), four and a half LIM domains 2 (FHL2), alkaline phosphatase, biomineralization associated (ALPL), interleukin 6 (IL6), solute carrier family 26 member 1 (SLC26A1) as well as smoothened, frizzled class receptor (SMO) were significant differentially expressed. At the same time, 21 DEMs were potential for the progress of OS lung metastasis with hsa-miR-638, hsa-miR-451, hsa-miR-486-5p, hsa-miR-134 and hsa-miR-648 were significant distinct. It could been shown that hsa-miR-638 manipulated the largest number of target genes. The functions of hsa-miR-638 and target mRNAs for the development of lung metastasis in OS could be confirmed by quantitative Real-time PCR analysis. CONCLUSION: This integrated study hypothesized several miRNA dependent signaling pathway for OS patients with lung metastases and initiated a potential strategy for better understanding the lung metastases in clinic. Show more

Keywords: Osteosarcoma, lung metastases, differential gene analysis

DOI: 10.3233/CBM-210232

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 379-387, 2022

Authors: Cui, Mingxin | Qu, Fengzhi | Wang, Libing | Liu, Xiaogang | Yu, Jingkun | Tang, Zhaoyuan | Cheng, Daming

Article Type: Research Article

Abstract: Hepatocellular carcinoma (HCC) is a cancer with relatively high mortality, yet little attention has been devoted for related prognostic biomarkers. This study analyzed differential expression of m5C RNA methyltransferase-related genes in normal samples and tumors samples in TCGA-LIHC using Wilcoxon test. K-means consensus clustering analysis was implemented to subdivide samples. Independent prognostic factors were screened by univariate and multivariate Cox regression analyses. KEGG pathway enrichment analysis was performed on the screened independent prognostic factor using GSEA tools. qPCR was conducted to test mRNA expression of key m5C RNA methyltransferase-related genes in tissues and cells. There were 7 m5C RNA methyltransferase-related …genes (NOP2, NSUN4, etc.) differentially expressed in HCC tumor tissues. HCC samples were classified into 3 subgroups through clustering analysis according to the expression mode of m5C RNA methyltransferase-related genes. It was also discovered that patients in different subgroups presented significant differences in survival rate and distribution of grade. Additionally, NOP2, NSUN4 and NSUN5 expression notable varied in different grades. Through regression analyses combined with various clinical pathological factors, it was displayed that NSUN4 could work as an independent prognostic factor. KEGG analysis showed that NSUN4 mainly enriched in signaling pathways involved in ADHERENS JUNCTION, RNA DEGRADATION, MTOR SIGNALING PATHWAY, COMPLEMENT and COAGULATION CASCADES. As examined by qPCR, NSUN4 was conspicuously upregulated in HCC patient’s tissues and cells. Altogether, our study preliminarily developed a novel biomarker that could be independently used in prognosis of HCC, which may provide a new direction for the study of related molecular mechanism or treatment regimen. Show more

Keywords: m5C RNA methyltransferase, NSUN4, HCC, prognosis, biomarker

DOI: 10.3233/CBM-210154

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 389-400, 2022

Authors: Zhang, Bin | Jin, Zhou | Zhang, Hao

Article Type: Research Article

Abstract: BACKGROUND: The disorder of LINC01207 has a significant regulatory effect on cancers, nevertheless its role in non-small cell lung cancer (NSCLC) have not been illustrated. This study investigated the regulatory effect of LINC01207 on NSCLC and clarify its molecular mechanism. METHODS: Bioinformatics analysis was used to find the target lncRNA, miRNA and mRNA. LncBase and TargetScan databases predicted the relationship between LINC01207, miR-525-5p and ARHGAP11A. Dual-luciferase reporter gene assay and RNA binding protein immunoprecipitation assay were used to verify the binding relationship between genes. Fluorescence in situ hybridization assay was used to localize the expression of LINC01207 …in NSCLC tissue. qRT-PCR and Western blot assays were used to measure the expression of LINC01207, miR-525-5p and ARHGAP11A. CCK-8 assay, Transwell assay and flow cytometry assay were used to detect NSCLC cell abilities. Mouse xenograft models further determined the effect of LINC01207 on the growth of NSCLC in vivo . RESULTS: LINC01207 was up-regulated in NSCLC tissue and cells, which was mainly localized in the cytoplasm. LINC01207 knockdown could inhibit the proliferation, migration and invasion of cancer cells and induce cell apoptosis. In addition, silencing LINC01207 could suppress tumor growth in vivo . LINC01207 could sponge and inhibit the expression of miR-525-5p in NSCLC cells, and inhibiting LINC01207 and miR-525-5p simultaneously could reverse the effect of miR-525-5p on the progression of NSCLC cells. Further study on downstream target genes showed that miR-525-5p could restrain the expression of ARHGAP11A, and then affect the progression of NSCLC. LINC01207 acting as a competing endogenous RNA (ceRNA) could regulate the expression of ARHGAP11A by competitively binding with miR-525-5p. CONCLUSION: LINC01207 regulates the progression of NSCLC by regulating the miR-525-5p/ARHGAP11A axis as a ceRNA and plays a carcinogenic role. In conclusion, our study elucidates the mechanism of LINC01207 regulating the progression of NSCLC, and provides a new idea for the diagnosis and treatment of NSCLC guided by lncRNA. Show more

Keywords: Non-small cell lung cancer, LINC01207, miR-525-5p, ARHGAP11A, proliferation, migration, invasion

DOI: 10.3233/CBM-203197

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 401-414, 2022

Authors: Zhang, Zixi | Li, Xiao | Yan, Xueli | Qiu, He | Li, Gai | Guo, Xiaowen | Lu, Yan | Yang, Jingyi | Jiao, Min | Chen, Xue | Zhu, Shaojun | Dang, Chengxue | Wang, Weizhong | Chu, Dake

Article Type: Research Article

Abstract: BACKGROUND: The Notch signaling regulates numerous cell growth, differentiation, and death. However, the expression pattern of its ligand Delta-like 4 (DLL4) in tumors is still uncertain. OBJECTIVE: In the present study, we examined DLL4 expression in colorectal cancer as well as assessed its role as a prognostic indicator in the present study. METHODS: DLL4 expression was examined by immunohistochemistry in 289 surgically resected specimens of colorectal cancer and adjacent normal tissues. The relationship between DLL4 expression and clinicopathological characteristics was analyzed. The association of DLL4 expression with the patients’ overall survival rate was …assessed by Kaplan-Meier and Cox proportional-hazards regression. RESULTS: Increased DLL4 level was detected in colorectal cancer compared with that of normal tissues. Elevated DLL4 level in colorectal cancer was associated with increased body mass index of patients. Moreover, increased DLL4 level was also found to be correlated with tumor invasion, metastases and unfavorable clinical outcom of patients. CONCLUSIONS: DLL4 level is increased in colorectal cancer, especially in patients with increased body mass index, indicating potential involvement of obesity-related tumorigenesis and development. It might also serve as a novel molecular marker to predicate outcome of patients. Show more

Keywords: DLL4, colorectal cancer, immunohistochemistry, body mass index, prognosis

DOI: 10.3233/CBM-200986

Citation: Cancer Biomarkers, vol. 33, no. 3, pp. 415-422, 2022