Cancer Biomarkers - Volume 31, issue 4

Authors: Bao, Xian-Yi | Sun, Ming | Peng, Ting-Ting | Han, Dong-Mei

Article Type: Research Article

Abstract: BACKGROUND: Tribbles pseudokinase 3 (TRIB3) is a member of the tribbles-related family, which has been determined in various cancers, including renal cell carcinoma, acute promyelocytic leukemia, colorectal cancer, endometrial cancer, and glioma. However, its role in retinoblastoma (RB) has not yet been explored. METHODS: The expression level of TRIB3 was detected in RB tissues and cell lines using qRT-PCR. The effects of TRIB3 on cell proliferation and invasion capacities were analyzed with MTT, crystal violet, and transwell assays. Western blot and rescue assays were conducted to explore the underlying mechanism. RESULTS: This study …found that TRIB3 was upregulated in human RB tissues compared to adjacent normal tissues both at the mRNA and protein levels. Overexpression of TRIB3 significantly promoted cell proliferation and invasion of RB cells, while TRIB3 knockdown inhibited these processes. Moreover, the mechanism deciphering experiments showed that TRIB3 overexpression can increase AKT and mTOR phosphorylation. Conversely, TRIB3 knockdown decreased the phosphorylation of AKT and mTOR. Additionally, MK2206, a potent AKT inhibitor, blocked the promotive effects of TRIB3 in RB cells. CONCLUSION: This study demonstrated that TRIB3 acts as an oncogene and plays a crucial role in the proliferation and invasion of RB cells via regulating the AKT/mTOR signaling pathway. Therefore, TRIB3 may serve as a potential target in the diagnosis and/or treatment of RB. Show more

Keywords: TRIB3 retinoblastoma, proliferation migration invasion, AKT

DOI: 10.3233/CBM-200050

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 307-315, 2021

Authors: Kang, Yingzhu | Chen, Jiao | Li, Xiaoying | Luo, Min | Chen, Hongli | Cui, Bomiao | Wang, Liwei | Lv, Die | Feng, Yun | Zhang, Ping

Article Type: Research Article

Abstract: BACKGROUND: Oral squamous cell carcinoma (OSCC) usually originates from oral potentially malignant disorders (OPMD), such as oral leukoplakia (OLK) and oral lichen planus (OLP). Identifying biomarkers for the early diagnosis and evaluation of malignant transformation in OPMD could improve the survival rate of OSCC patients. OBJECTIVE: The present study aimed to screen for potential salivary biomarkers for evaluating the malignant transformation of OPMD. METHODS: Salivary proteases from OLK and OSCC patients or healthy donors and proteases in cultural medium from DOK and Cal-27 cells were detected with a human protease array kit. The …concentrations of the salivary Kallikrein 5 (KLK5) and urokinase-type plasminogen activator (uPA) proteases were measured by ELISA. Receiver operating characteristics (ROC) to determine the potential value of these proteases in clinical diagnosis were calculated using SPSS software. Immunohistochemistry was used to detect the KLK5 and uPA expression in the oral organizations. RESULTS: The salivary protease spectrum was different among patients with OLK and OSCC and healthy donors. KLK5 and uPA levels in saliva tended to increase as the disease progressed (healthy < OPMD [OLK and OLP] < OSCC). ROC curves showed the optimum diagnostic cutoffs for KLK5 as a biomarker for OLK, OLP, and OSCC were 5.97, 6.03, and 9.45 pg/mL, respectively, while the cutoffs for uPA were 17.19, 17.26, and 20.96 pg/mL. Their combined analysis showed a higher sensitivity for the differential diagnosis of disease. Furthermore, higher levels of KLK5 and uPA were observed in OSCC tissues than in OLK and OLP. CONCLUSIONS: Salivary KLK5 and uPA are potential biomarkers for evaluating OLK and OLP malignant transformation and early diagnosis of OSCC. Show more

Keywords: Saliva protease spectrum, oral leukoplakia, oral lichen planus, oral squamous cell carcinoma, kallikrein 5, urokinase-type plasminogen activator

DOI: 10.3233/CBM-203105

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 317-328, 2021

Authors: Yang, Zhongyin | Yan, Chao | Liu, Wentao | Xu, Wei | Li, Chen | Yan, Min | Liu, Bingya | Zhu, Zhenggang

Article Type: Research Article

Abstract: BACKGROUND: Gastric cancer (GC) patients with peritoneal metastasis usually have extremely poor prognosis. Intraperitoneal infusion of paclitaxel (PTX) provides an effective treatment, but relapse and PTX-resistance are unavoidable disadvantages, and it is difficult to monitor the occurrence of PTX-resistance. OBJECTIVE: The aim of this study was to explore novel autoantibodies in the ascites of individuals with relapsed PTX-resistant GC with peritoneal metastasis. METHODS: Ascites samples were collected before PTX infusion and after the relapse in 3 GC patients. To determine the expression of significantly changed proteins, we performed autoantibody profiling with immunome protein …microarrays and tandem mass tag (TMT) quantitative proteomics, and then, the overlapping proteins were selected. RESULTS: Thirty-eight autoantibodies that were differentially expressed between the ascites in the untreated group and relapsed PTX-resistant group were identified. For confirmation of the results, TMT quantitative proteomics was performed, and 842 dysregulated proteins were identified. Four proteins, TPM3, EFHD2, KRT19 and vimentin, overlapped between these two assays. CONCLUSIONS: Our results first revealed that TPM3, EFHD2, KRT19 and vimentin were novel autoantibodies in the ascites of relapsed PTX-resistant GC patients. These autoantibodies may be used as potential biomarkers to monitor the occurrence of PTX-resistance. Show more

Keywords: Gastric cancer, peritoneal metastasis, ascites, paclitaxel-resistance, autoantibody

DOI: 10.3233/CBM-203142

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 329-338, 2021

Authors: Wang, Shan | Yu, Xiaorong | Li, Fang | Fan, Haixia | Zhao, Eryang | Hu, Zheng

Article Type: Research Article

Abstract: BACKGROUND: Resistance to PD-1 blocking agents is not uncommon, limiting their wide clinical success. Certain tumor-infiltrating immune cells (e.g., TILs/CTLs) have emerged as biomarkers of response, and absence of such immune cells contributes to resistance. OBJECTIVE: We deconvoluted the dynamic immune microenvironment in a mouse model of oral carcinogenesis for augmenting the resistance to PD-1 blocking agents by combination. METHODS: Bioinformatics methods and routine biological experiments were adopted such as morphological analysis and ELISA in the 4NQO-treated mice model. RESULTS: Our findings revealed that dysplastic tongue tissues from 4NQO-treated mice …were characterized by an immunosuppressive tumor microenvironment. Tongue tissues from mice treated with 4NQO for 12 weeks had higher levels of Th2 cells and Tregs compared to tissues taken from control mice or mice treated with 4NQO for 28 weeks; these results suggested a potential therapeutic benefit of anti-PD-1 in the oral cancer. The IL-17 pathway was significantly upregulated during progression from normal mucosa to hyperplasia and tumor formation in mice. Inhibition of IL-17α combined with PD-1 blockade delayed the development of 4NQO-induced precancerous and cancerous lesions and prolonged the survival of 4NQO-treated mice. CONCLUSIONS: Our data suggested a strong rationale of IL-17α blockade as a potential approach to augment the tumor-eliminating effects of anti-PD-1 therapy. Show more

Keywords: Immunotherapy, programmed death receptor 1, IL-17alpha, resistance, pre-cancerous lesions, squamous cell carcinomas

DOI: 10.3233/CBM-203092

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 339-350, 2021

Authors: Wang, Wen | Wang, Guangyu | Fu, Shuang | Zhang, Beibei | Liu, Zengyao | Wang, Ruitao

Article Type: Research Article

Abstract: BACKGROUND: Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) generally have a better prognosis and a more effective immune response than patients with microsatellite stable (MSS) CRC. Moreover, activated platelets play a crucial role in modulating innate immune cells. Mean platelet volume (MPV) is an indicator of platelet activation. This study is to examine the association between MPV and MSI status in CRC. METHODS: We collected the clinical and pathological variables of 424 CRC patients diagnosed at the Harbin Medical University Cancer Hospital from January 2018 to December 2018. Associations between MPV levels and MSI status were …examined. Propensity score matching (PSM) was performed to reduce the possibility of selection bias. RESULTS: 424 CRC patients were divided into low-MPV group and high-MPV group according to the optimal cut-off value of MPV. 131 high-MPV patients were matched to low-MPV counterparts in a 1:1 ratio by propensity score matching. As MPV levels increased, the percentage of patients with MSI-H reduced. Furthermore, compared with MSS group, the MSI-H group had a significantly lower MPV levels (p = 0.003 after matching). In addition, logistic regression analysis identified reduced MPV as an independent risk factor for MSI-H in CRC patients after controlling for other potential parameters. CONCLUSION: Lower MPV is associated with MSI-H subtype of CRC. Further study on MPV in MSI-H CRC is warranted. Show more

Keywords: Colorectal cancer, microsatellite instability, platelet activation, mean platelet volume

DOI: 10.3233/CBM-203250

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 351-359, 2021

Authors: Mohanty, Varshasnata | Subbannayya, Yashwanth | Patil, Shankargouda | Abdulla, Riaz | Ganesh, Mandakulutur S. | Pal, Arnab | Ray, Jay Gopal | Sidransky, David | Gowda, Harsha | Prasad, T.S. Keshava | Chatterjee, Aditi

Article Type: Research Article

Abstract: BACKGROUND: Tobacco exposure (through smoking or chewing) is one of the predominant risk factors associated with the development of oral squamous cell carcinoma (OSCC). Despite the growing number of patients diagnosed with OSCC, there are few circulating biomarkers for identifying individuals at a higher risk of developing the disease. Successful identification of candidate molecular markers for risk assessment could aid in the early detection of oral lesions and potentially be used for community screening of high-risk populations. OBJECTIVE: Identification of differentially expressed proteins in the serum of oral cancer patients which can serve as biomarkers for …the diagnosis of the onset of oral cancer among tobacco users. METHODS: We employed a tandem mass tag (TMT)-based quantitative proteomics approach to study alterations in the serum proteomes of OSCC patients based on their tobacco exposure habits (chewing and smoking) compared to healthy individuals with no history of using any form of tobacco or any symptoms of the disease. RESULTS: Mass spectrometry-based analysis resulted in the identification of distinct signatures in the serum of OSCC patients who either chewed or smoked tobacco. Pathway analysis revealed opposing effects of dysregulated proteins enriched in the complement-coagulation signaling cascades with a high expression of the Serpin family of proteins observed in OSCC patients who chewed tobacco compared to healthy individuals whereas these proteins showed decreased levels in OSCC patients who smoked. ELISA-based validation further confirmed our findings revealing higher expression of SERPINA6 and SERPINF1 across serum of OSCC patients who chewed tobacco compared to healthy individuals. CONCLUSIONS : This study serves as a benchmark for the identification of serum-based protein markers that may aid in the identification of high-risk patients who either chew tobacco or smoke tobacco. Show more

Keywords: Oral cancer, squamous cell carcinoma, tobacco, mass spectrometry, serum proteomics, cigarette smoke

DOI: 10.3233/CBM-203077

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 361-373, 2021

Authors: Zhang, Hanyu | Zhang, Biru | Chen, Yuling | Zhang, Ying | Qian, Min | Yuan, Lin | Shen, Yuehong | Yang, Hongyu

Article Type: Research Article

Abstract: BACKGROUND: As a novel class of endogenous ncRNAs, Circular RNAs (circRNAs) have been verified to be involved in the carcinogenesis and tumor progression. OBJECTIVE: This study aimed to investigate the potential function of a candidate circRNA hsa_circ_0036988 in oral squamous cell carcinoma (OSCC). METHODS: The altered expression of hsa_circ_0036988 was validated by quantitative real-time polymerase chain reaction (qRT-PCR) in OSCC samples and OSCC cell lines. The associations between the levels of hsa_circ_0036988 and the clinicopathological features were statistically analysed. The function of hsa_circ_0036988 in OSCC were evaluated via a series of in vitro …experiments by using constructed plasmids or siRNA. Western blotting assays were conducted to evaluate changes in protein expression levels. RESULTS: Hsa_circ_0036988 was significantly downregulated in OSCC tissues compared with adjacent normal tissues. While low expression of hsa_circ_0036988 was highly correlated with lymph nodes metastasis. Overexpression or knockdown of hsa_circ_0036988 significantly affected the proliferation, migration and invasion of OSCC cells. Furthermore, the altered expression of hsa_circ_0036988 have an impact on the epithelial-to-mesenchymal transition (EMT)-related protein expression levels. CONCLUSIONS: Our findings indicated that hsa_circ_0036988 may affect cell proliferation, migration and invasion by regulating EMT progress, which might provide a therapeutic strategy for the treatment of OSCC. Show more

Keywords: hsa_circ_0036988, oral squamous cell carcinoma, metastasis, EMT

DOI: 10.3233/CBM-210082

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 375-383, 2021

Authors: Khaligh, Ali | Fazeli, Mohammad Sadegh | Mahmoodzadeh, Habibollah | Mehrtash, Amirhosein | Kompanian, Setareh | Zeinali, Sirous | Teimoori-Toolabi, Ladan

Article Type: Research Article

Abstract: BACKGROUND: Microsatellite instability (MSI) results from genetic and epigenetic changes. Studying Microsatellite instability can help in treatment and categorization of colorectal cancer (CRC) patients. OBJECTIVES: We aimed to investigate whether 14 genomic markers consisting of BAT-62, BAT-60, BAT-59a, BAT-56a, BAT-56b, DCD, RIOX, RNF, FOXP, ACVR, CASP2, HSP110, MT1X, and DNMT3a can increase the detection rate of MSI in CRC. METHODS: Samples were stratified by pentaplex panel (Promega) and 14 markers using multiplex PCR and fragment analysis. In MSI+ samples, to identify the pattern of BRAF V600E mutation and MLH1 promoter methylation, ARMS-scorpion, and …Methylation-Specific High-Resolution Melting Curve analysis, were applied respectively. RESULTS: Totally, 35 MSI+ cases identified by 14 marker panel. Only 18 cases of them were detected by both panels which are pentaplex and 14 marker. On the other hand, 17 new MSI+ cases just were identified by 14 markers panel. The highest diagnostic value among 14 markers is related to three makers, namely DCD, MT1X, and DNMT3a. In MSI+ cases, the rate of MLH1 promoter methylation was insignificant, (P value = 0.3979) while the rate of observed BRAFV600E mutation was significantly higher (P value = 0.0002). CONCLUSION: Fourteen marker panel showed higher sensitivity in comparison with the pentaplex panel increasing the detection rate of MSI+ cases up to 1.94 fold. Three markers namely DNMT3a, DCD, and MT1X of 14 marker panel were the best among them showing excellent diagnostic value. A combination of these markers showed 100% sensitivity and specificity in the studied group. In contrary to the markers in the pentaplex panel, these markers had the ability to detect MSI without any bias for the clinicopathological features. These markers will help to identify more end-stage MSI+ tumors which are located distal colon. Show more

Keywords: Colorectal Neoplasm, Microsatellite Instability, Biomarker, tumor, DNA methyltransferase 3A

DOI: 10.3233/CBM-203226

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 385-397, 2021

Authors: Wang, Ganbiao | Wang, Yigao | Yang, Xiaodong | Zhang, Yaqin | Lu, Yida | Li, Yongxiang

Article Type: Research Article

Abstract: BACKGROUND: Several molecules are highly expressed in the serum of cancer patients, and can be used as serological markers. This approach has become one of the important auxiliary diagnostic methods for cancer. AIM: To investigate the correlation between the serum levels of EphA2 and VEGF-A and the pathogenesis of colorectal cancer (CRC) as well as the potential value of these molecules in the diagnosis of CRC. METHODS: ELISA was used to detect the levels of EphA2 and VEGF-A in the peripheral venous serum of 106 newly diagnosed patients with CRC and 69 normal …controls. The relationship between the serum EphA2 and VEGF-A levels and the clinicopathological characteristics of CRC patients was analyzed. ROC analysis was used to investigate the diagnostic value of the serum EphA2 and VEGF-A levels in CRC, and the optimal cutoff value was calculated. RESULTS: The serum levels of EphA2 and VEGF-A in the CRC group were higher than those in the control as well as CEA, the serum level of EphA2 was positively correlated with the VEGF-A levels, but neither was significantly associated with the clinicopathological parameters of CRC. The ROC curve showed that the single index AUC was < 0.7 except for VEGF-A, and the accuracy of the combined diagnosis was higher than that of any other single index. The diagnosis scheme involving all three markers was the best (the sensitivity was 60.40%, the specificity was 92.8%, and the accuracy was 53.1%). The best critical values calculated were EphA2 > 297.92 ng/ml, EphA2 > 183.92 pg/ml and CEA > 5.19 ng/ml. CONCLUSION: The serum levels of EphA2 and VEGF-A are high in CRC patients, and the combine detection of CEA, EphA2 and VEGF-A can significantly improve the diagnostic accuracy of CRC. Show more

Keywords: Colorectal cancer, EphA2, VEGF-A, cutoff value, diagnosis

DOI: 10.3233/CBM-201745

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 399-408, 2021

Authors: Yildirim, Murat | Koca, Bulent

Article Type: Research Article

Abstract: BACKGROUND: Lymphocyte-to-C-reactive protein ratio (LCR) has been used as a post-surgical prognostic biomarker in patients with gastric and colorectal cancer. However, its relationship with early postoperative complications in these patients is unknown. In this study, we aimed to reveal the relationship between LCR and postoperative complications. METHODS: Eighty-one patients operated for stomach and colorectal cancer between January 2020 and August 2020 were prospectively analyzed. On preoperative and postoperative days 1, 3 and 5, other inflammatory parameters, mainly LCR, neutrophil lymphocyte ratio (NLR), were recorded. The patients were divided into two groups according to Clavien-Dindo classification as …stage III and higher complications major, stage I-II/non-complication minor. RESULTS: Fifty seven patients were operated for colorectal cancer, 24 patients for gastric cancer. The mean age of the patients was 65.6 ± 12.6, 34.6% of them was women. Age, operation time and hospital stay were significantly different between the groups (p = 0.004, p = 0.002, p < 0.001). Major complications developed in 18 patients. On postoperative day 5, LCR found superior diagnostic accuracy in predicting major postoperative complications compared to other inflammatory markers. On the postoperative 5th day, the cut-off value of LCR was 0.0034, 88.8% (71.9–94.8) sensitivity, and 85.7% (73.6–95.4) selectivity. CONCLUSION: Among different inflammatory markers, postoperative LCR is a safe and effective predictor of postoperative complications, especially after gastric and colorectal cancer surgery on day 5. Show more

Keywords: Lymphocyte-to-C-reactive protein ratio, gastric cancer, colorectal cancer

DOI: 10.3233/CBM-210251

Citation: Cancer Biomarkers, vol. 31, no. 4, pp. 409-417, 2021