Cancer Biomarkers - Volume 30, issue 2

Authors: Białek, Łukasz | Czerwińska, Katarzyna | Fus, Łukasz | Krajewski, Wojciech | Sadowska, Anna | Radziszewski, Piotr | Dobruch, Jakub | Kryst, Piotr | Poletajew, Sławomir

Article Type: Research Article

Abstract: BACKGROUND: Mini Chromosome Maintenance 5 (MCM5) is considered as a urinary biomarker of bladder cancer. ADXBLADDER is a commercially available test to detect MCM5 antibodies. OBJECTIVE: External validation of ADXBLADDER test as a urinary biomarker of histopathologically confirmed non-muscle invasive bladder cancer (NMIBC) recurrence. METHODS: The study enrolled 119 consecutive patients with a history of NMIBC and 37 healthy volunteers matched as controls. Single, full-void urine samples were collected from patients before cystoscopy ± TUR. To measure MCM5 expression, Arquer Diagnostics ADXBLADDER test was used. The study protocol was registered …within the clinical trials database (NCT03796299). RESULTS: Among patients with NMIBC history, recurrence was diagnosed in 83 patients (69.7%). ADXBLADDER demonstrated sensitivity of 73.5% (95% confidence interval (CI) 62.7%–82.6%), specificity of 33.3% (95% CI 18.6% to 51%), overall negative predictive value (NPV) of 35.3% (95% CI 23.3% to 49.5%) and overall positive predictive value of 71.8% (95% CI 66.1% to 76.8%) for detecting recurrence. In a control group, false positive ADXBLADDER results were noticed in 18 patients (48.6%). The sensitivity and NPV were the highest in invasive tumors (100% and 100%, respectively) and in high-grade recurrences (81.8% and 94.1%, respectively). CONCLUSIONS: ADXBLADDER has a moderate sensitivity and poor specificity in detecting NMIBC recurrence. However, it properly diagnoses patients with T1+ stage recurrence or high-grade tumors. Show more

Keywords: Urothelial cancer, MCM5, ADXBLADDER, biomarker

DOI: 10.3233/CBM-200316

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 139-143, 2021

Authors: Chen, Lingjiao | Xie, Guiyuan | Feng, Juan | Wen, Qiuyuan | Zang, Hongjing | Lu, Junmi | Zhan, Yuting | Fan, Songqing

Article Type: Research Article

Abstract: BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most widespread cancer with increasing morbidity and mortality. FAS-associated protein with death domain (FADD) is considered as an essential instrument in cell death, whereas Bcl-XS promotes apoptosis through inhibiting the activity of Bcl-2 and Bcl-XL. OBJECTIVE AND METHODS: We detected the expression of FADD and Bcl-XS in resected NSCLC tissues by immunohistochemistry, and investigated their association with clinicopathological characteristics and prognostic significance of NSCLC patients. RESULTS: Bcl-XS expression was significantly increased in well and moderate differentiated lung SCC (P = …0.004). Lung ADC patients with overexpression of FADD and lung SCC patients with low expression of Bcl-XS had importantly lower overall survival rates by Kaplan-Meier analysis (P = 0.033, P = 0.02, respectively). Multivariate analysis confirmed that elevated expression of FADD was an independent poor prognostic factor for patients with surgically resected lung ADC (P = 0.027) and increased expression of Bcl-XS was an independent good prognostic factor for patients with surgically resected lung SCC (P = 0.016) CONCLUSION: Elevated expression of FADD was identified as independent poor prognostic factor for patients with surgically resected lung ADC, however, increased expression of Bcl-XS was an independent good prognostic biomarker for patients with surgically resected lung SCC. Show more

Keywords: Non-small cell lung cancer, FADD, Bcl-XS, prognosis, biomarker

DOI: 10.3233/CBM-190018

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 145-154, 2021

Authors: Shen, Daqing | Xu, Jing | Cao, Xiande | Cao, Xianxiang | Tan, Hailin | Deng, Huanghao

Article Type: Research Article

Abstract: BACKGROUND: Long noncoding RNA (lncRNA) are critical regulators of tumor progression. OBJECTIVE: To determine how the lncRNA membrane associated guanylate kinase, WW and PDZ domain-containing 2 (MAG12) antisense RNA 3 (MAGI2-AS3) and the phosphatase and tensin homolog (PTEN) gene function in regulating bladder cancer (Bca) progression. METHODS: Total RNA from 80 Bca tissues and 30 paired para-cancerous tissues from patients was sequentially extracted, quantified, purified, and reverse transcribed using RT-PCR. A library was constructed and sequenced. Four Bca cell lines and a normal urothelial cell line were transfected with lentiviral plasmids, and cell …migration and invasion were assayed in vitro . An orthotopic mouse model of Bca was created for in vivo studies. RESULTS: MAGI2-AS3 expression was significantly downregulated in Bca, compared with normal tissues, and negatively associated with tumor stage and a poor prognosis. MAGI2-AS3 and its sense RNA MAGI2 showed significant and positive correlation. The expression of MAGI2 and its downstream gene, PTEN, increased in Bca cells overexpressing MAGI2-AS3, and interference by MAGI2 expression reversed the migration and invasion inhibited by MAGI2-AS3 overexpression. CONCLUSION: MAGI2-AS3 overexpression inhibited Bca cell progression by regulating the MAGI2/PTEN/epithelial-mesenchymal transition, offering novel insights into the mechanism of Bca progression. Show more

Keywords: Bladder cancer, lncRNA, MAGI2-AS3, progression

DOI: 10.3233/CBM-201421

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 155-165, 2021

Authors: Fan, Dengguo | Wang, Changjiang | Wang, Deyuan | Zhang, Ning | Yi, Tao

Article Type: Research Article

Abstract: BACKGROUND: Circular RNA (circRNA) is a class of non-coding RNA that is vital for regulating gene expression and biological functions. Mounting studies demonstrate that circRNA is crucial for human cancer development. However, the role of circ_0000039 in gastric cancer (GC) remains uncertain. METHODS: Normal human gastric tissues and GC tissue samples were collected, and quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the expression levels of circ_0000039, miR-1292-5p, and DEK. GC cell lines with overexpression and low expression of circ_0000039 were constructed. Cell counting kit-8 (CCK-8), scratch healing and Transwell experiments were used to …assess the function of circ_0000039 on the proliferation, migration and invasion of GC cells. Bioinformatics analysis and dual-luciferase reporter assays were employed to detect the targeting relationship between circ_0000039 and miR-1292-5p. RESULTS: Circ_0000039 expression was up-regulated in GC tissues and cell lines, and it was significantly related with poor differentiation of tumor tissues. In addition, circ_0000039 overexpression enhanced the proliferation, migration and invasion of GC cells, while circ_0000039 depletion inhibited these malignant biological behaviors. In terms of mechanism, it was found that circ_0000039 promoted the proliferation and progression of GC cells by adsorbing miR-1292-5p and up-regulating the expression of DEK. CONCLUSION: Circ_0000039 is a new oncogenic circRNA in GC, which regulates the miR-1292-5p/DEK axis to modulate the malignant biological behaviors of GC. Show more

Keywords: Gastric cancer, circ_0000039, miR-1292-5p, DEK, proliferation, metastasis

DOI: 10.3233/CBM-201754

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 167-177, 2021

Authors: Li, Chenglin | Zhou, Yanfei | Deng, Hanshun | Ye, Yuanshen | Zhao, Shuizhen | Liang, Shangnan | Cai, Shirong | Lin, Jincai | Tang, Yaolong | Wu, Yanyu

Article Type: Research Article

Abstract: BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor with a high mortality rate. Aberrant activation of signal transducers and activators of transcription (STAT) signaling results in tumor pathogenesis and progression by regulating cell cycle, cell survival and immune response. METHODS: Therapeutic targets and prognostic biomarkers within the STAT family in GBM were explored using web applications and databases. RESULTS: High levels of STAT1/3/5A/5B/6 and low levels of STAT4 were observed in GBM patients. GBM patients expressing high STAT1/2/3/5A/6 and low STAT4/5B levels had the worse overall survival. Among …the STAT family, STAT4 and STAT6 were the most frequently mutated genes. A low to moderate correlation among members of the STAT family was observed. Additionally, the STATs were involved in activation or inhibition of cancer related pathways. Analysis of immune infiltrates showed STAT5A levels to be significantly correlated with abundance of immune cells and levels of immune gene biomarkers. Gene ontology (GO) functions and KEGG pathway analysis indicated that STAT5A is involved in immune response-regulating signaling pathway, neutrophil and lymphocyte mediated immunity, single-stranded DNA binding, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, NF-kappa B signaling pathway and TNF signaling pathway. Moreover, several kinase and transcription factor targets of STAT5A in GBM were identified. CONCLUSION: We report here therapeutic targets, prognostic biomarkers and regulation network of STAT family in GBM. These findings lay a foundation for further studies on the role of STAT family in therapy and prognosis of GBM. Further studies are required to verify our results. Show more

Keywords: Glioblastoma, STAT family, STAT5A, immunotherapy, prognostic biomarker

DOI: 10.3233/CBM-201746

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 179-191, 2021

Authors: Li, Guangyao | Zhang, Zhengjun | Ge, Guochao | Fang, Ke | Zhu, Jianyu

Article Type: Research Article

Abstract: BACKGROUND: Contactin1 (CNTN1), a member of the immunoglobulin superfamily, is known to correlate with tumor development and progression. Although recent studies have found that elevated CNTN1 has been demonstrated in some types of cancers, the expression and prognosis of CNTN1 in colorectal cancer (CRC) are unclear. Here, we aimed to determine the clinicopathological characteristics and prognostic role of CNTN1 in CRC patients. METHODS: The protein expression of CNTN1 in tumor tissues was evaluated by immunohistochemistry. In addition, the mRNA and protein expressions of CNTN1 were examined by qRT-PCR and Western blotting analysis in 40 matched adjacent …normal mucosa samples. The relationships of CNTN1 with clinicopathological data and prognosis significance were analyzed. RESULTS: Immunohistochemical consequence suggested that the protein level of CNTN1 was obviously raised in CRC compared with adjacent normal mucosa tissues (56.9% vs 10.3%, P < 0.05). In addition, we detected a significant increase in CNTN1 mRNA and protein levels in CRC tissues compared with the matched adjacent normal mucosa tissues. Moreover, increased CNTN1 exprssion was significantly associated with tumor size, lymph node metastasis (LNM), tumor node-metastasis (TNM) stage and carcino-embryonic antigen (CEA) in clinical analysis. Kaplan-Meier analysis suggested that patients with CNTN1 over-expression showed worse overall survival (OS) (P = 0.001). Multivariate analysis indicated that high CNTN1 expression was an independent predictor for poor OS in CRC patients (P = 0.028). Further analysis revealed that patients with high CNTN1 combined with LNM present accurately predicted poorer outcome. CONCLUSION: Taken together, the findingsindicate that CNTN1 plays a significant role and serve as a potential biomarker for the prediction of adverse prognosis in CRC. Intriguingly, high express of CNTN1 + LNM-present combination may improve the accuracy of prognosis. Show more

Keywords: CNTN1, colorectal cancer, prognosis, immunohis- tochemistry

DOI: 10.3233/CBM-190981

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 193-201, 2021

Authors: Wu, Dongdi | Zhu, Jia | Fu, Ying | Li, Chenqin | Wu, Biao

Article Type: Research Article

Abstract: Breast cancer is the most common malignancies worldwide. LncRNA HOX transcript antisense intergenic RNA (HOTAIR) has been shown to promote progression and metastasis of various cancers, including breast cancer. This reasearch aimed to investigate the downstream regulatory pathways of HOTAIR in breast cancer. The levels of HOTAIR and miR-129-5p were examined in breast cancer tissues and SKBR3 and MCF7 cells by quantitative real-time PCR (qRT-PCR). Cell proliferation was examined by Cell Counting Kit-8 (CCK-8) assay. Cell migration and invasion were estimated by transwell assay. Epithelial-to-mesenchymal transition (EMT)-related markers (E-cadherin, N-cadherin and Vimentin) were measured by Western blot assay. The expression …of Frizzled 7 (FZD7) was detected using qRT-PCR or Western blot assay. Bioinformatics analysis, luciferase reporter assay or RNA Immunoprecipitation (RIP) assay was performed to explore the molecular mechanism of HOTAIR in breast cancer. Xenograft analysis was utilized to evaluate the tumor growth in vivo . HOTAIR and FZD7 were upregulated, while miR-129-5p was down-regulated in breast cancer tissues and cells. Knockdown of miR-129-5p reversed the effect of HOTAIR knockdown on cell proliferation, migration, invasion and EMT. FZD7 restored the inhibition of miR-129-5p on breast cancer progression. Furthermore, HOTAIR was a sponge of miR-129-5p and FZD7 was a target of miR-129-5p. Knockdown of HOTAIR inhibited the tumor growth in vivo . HOTAIR facilitated breast cancer progression by regulating the miR-129-5p/FZD7 axis, indicating that HOTAIR may be a potential biomarker and therapeutic target for breast cancer. Show more

Keywords: HOTAIR, miR-129-5p, FZD7, breast cancer, progression

DOI: 10.3233/CBM-190913

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 203-212, 2021

Authors: Yaiche, Hamza | Tounsi-Kettiti, Haifa | Ben Jemii, Nadia | Jaballah Gabteni, Amira | Mezghanni, Najla | Ardhaoui, Monia | Fehri, Emna | Maaloul, Afifa | Abdelhak, Sonia | Boubaker, Samir

Article Type: Research Article

Abstract: BACKGROUND: Homeobox A5 (HOXA5) is a member of the HOX protein family which is involved in several carcinogenesis pathways, and is dysregulated in many cancer types. However, its expression and function in human colorectal cancer (CRC) is still largely unknown. OBJECTIVE: This study aimed to evaluate HOXA5 expression in Tunisian patients with CRC in order to define new potential biomarker. METHODS: An immunohistochemical labeling using an HOXA5 antibody was performed on 85 formalin fixed paraffin embedded specimens from patients with CRC. Six normal colon mucosa cases were used as controls. RESULTS: …HOXA5 expression showed a cytoplasmic staining in both tumor and stromal/endothelial cells. Loss or low HOXA5 expression was seen in tumor cells in 74/85 cases (87.06%) and in stromal/endothelial cells, in 77/85 (90.59%). In control group of normal colon mucosa HOXA5 was moderately expressed in all the cases. The abnormal expression, was significantly associated to lymph nodes metastasis in tumor cells (p = 0.043) and in stromal/endothelial cells (p = 0.024). CONCLUSION: HOXA5 immunostaining results suggest the valuable role of this protein in colorectal carcinogenesis. Moreover, the association of lymph node metastasis to HOXA5 abnormal expression underlies its crucial role in colorectal cancer dissemination and prognosis. Show more

Keywords: HOXA5, colorectal cancer, immunohistochemistry, prognosis, biomarker

DOI: 10.3233/CBM-201758

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 213-221, 2021

Authors: Deng, Lu | Wang, Chang | He, Chao | Chen, Li

Article Type: Research Article

Abstract: OBJECTIVE: Bone mesenchymal stem cells (BMSCs) have been widely researched in cancer treatment, including hepatocellular carcinoma (HCC). This study intended to discuss the mechanism of miR-20a-3p in BMSCs-extracellular vesicles (EVs) in HCC apoptosis. METHODS: BMSCs were isolated and identified. EVs derived from BMSCs were extracted and identified. After overexpressing or inhibiting miR-20a-3p expression in BMSCs, EVs were extracted and acted on HCC cells and transplanted tumors. HCC cell apoptosis in the treatment of BMSCs-conditioned medium, BMSCs-EVs and/or miR-20a-3p mimic/inhibitor was evaluated, with the detection of levels of TRAIL and TRAIL-related proteins. A functional rescue experiment about …c-FLIP was carried out in HCC cells. The target binding relationship between miR-20a-3p and c-FLIP was detected. The subcutaneous tumorigenesis model of mice was established and injected with BMSCs-EVs to estimate the effect of BMSCs-EVs-miR-20a-3p on HCC growth. RESULTS: EVs isolated from BMSCs conditioned medium promoted the apoptosis of HCC cells. After BMSCs-EVs treatment, TRAIL levels, downstream proteins and miR-20a-3p were increased significantly, but the expression of c-FLIP was decreased. miR-20a-3p could target c-FLIP. BMSCs-EVs inhibited the growth of HCC cells, decreased c-FLIP expression, increased TRAIL levels, and promote the of HCC cell apoptosis. BMSCs-EVs with overexpressing miR-20a-3p further enhanced the apoptotic effect of HCC cells in vitro and in vivo . CONCLUSION: BMSCs-EVs-carried miR-20a-3p targets c-FLIP and increases TRAIL levels in HCC cells, thus promoting TRAIL-related apoptosis. Show more

Keywords: Hepatocellular carcinoma, extracellular vesicles, bone mesenchymal stem cells, miR-20a-39, c-FLIP, TRAIL

DOI: 10.3233/CBM-201633

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 223-235, 2021

Authors: Cai, Weiyang | Ni, Wei | Jin, Yin | Li, Yanyan

Article Type: Research Article

Abstract: BACKGROUND: Lung adenocarcinoma (LUAD) is a primary cause of cancer-patient mortality throughout the world. Thyroid hormone receptor interactor 13 (TRIP13 ) is a gene that expresses a protein involved in cell division, including tumorigenesis. Its expression is high in various human tumors; however, its role in LUAD cells remains undetermined. OBJECTIVE: To investigate the TRIP13 ’s role in the development of LUAD. METHODS: Bioinformation analysis was used to analyze the expression of TRIP13 in LUAD tissues and the impact on the prognosis of LUAD; CRISPR/Cas9 was used to construct the cell …lines; CCK-8 was used to explore the cell proliferation; Transwell assays was applied to exam the cell migration and cell invasion abilities; Western blot and immunoprecipitation was used to explore the relation between TRIP13 and AKT/mTORC1/c-Myc signaling pathway. RESULTS: By analyzing LUAD data from The Cancer Genome Atlas and the Gene Expression Omnibus databases, we determined that TRIP13 is highly expressed in LUAD tissues and that this expression level has a negative impact on the patient mortality. TRIP13 has also proved to promote LUAD cell proliferation, migration, and invasion. In this study, we demonstrated that TRIP13 activates AKT/mTORC1/c-Myc signaling in these cells. CONCLUSION: Our results have identified the role and potential mechanism by which TRIP13 affects LUAD cells, which may provide a useful marker for helping to diagnose this disease and create new therapies against it. Show more

Keywords: TRIP13, lung adenocarcinoma (LUAD), proliferation, metastasis, mTORC1

DOI: 10.3233/CBM-200039

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 237-248, 2021

Authors: Hussein, Samia | Fathi, Anan | Abouhashem, Nehal S. | Amer, Samar | Hemeda, Mohamed | Mosaad, Hala

Article Type: Research Article

Abstract: Studying bladder cancer molecular biology revealed the presence of genetic alterations. So, detection of molecular biomarkers that help in monitoring the disease, evaluating the prognosis of the patients, and their response to therapy is needed. In this study, we investigated the expression and the prognostic significance of SATB-1 and ERBB2 mRNA and protein by quantitative RT-PCR and immunohistochemical analysis in urothelial bladder cancer cases and the surrounding normal bladder tissue. The correlations between the expression of both markers and the clinicopathological parameters were performed with further analysis of the correlation between the expression of SATB-1 and ERBB2. Compared to control, …the expression of SATB-1 and ERBB2 mRNA and protein in cancer tissues were significantly up-regulated (p < 0.05). Also, a positive correlation between both markers was found (r = 0.53, p < 0.001). Moreover, elevated levels of both markers were significantly associated with the stage, lymph node involvement at both mRNA and protein levels (p < 0.001). In conclusion, there is a clinical significance of SATB-1 and ERBB2 as potential biomarkers for predicting bladder cancer patients of aggressive behavior and poor prognosis. Show more

Keywords: RT-PCR, immunohistochemistry, bladder cancer, SATB-1, ERBB2

DOI: 10.3233/CBM-200072

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 249-259, 2021

Authors: Zhong, Youqing | Lin, Hui | Li, Qi | Liu, Chang | Shen, Jinmei

Article Type: Research Article

Abstract: Circular RNAs (circRNAs) have been revealed to involve in the chemoresistance of various cancers, including non-small cell lung cancer (NSCLC). Here, we further investigate the role of circRNA_100565 in NSCLC cisplatin (DDP) resistance. The expression of circRNA_100565 and microRNA (miR)-337-3p, and ADAM metallopeptidase domain 28 (ADAM28) mRNA was detected using quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit-8 assay and flow cytometry, respectively. Western blot was used to detect the level of ADAM28 and autophagy-related protein. The interaction between miR-337-3p and circRNA_100565 or ADAM28 was confirmed by dual-luciferase reporter assay or pull-down assay. …In vivo experiments were conducted via the murine xenograft model. We found CircRNA_100565 was up-regulated in NSCLC DDP-resistant tissues and cell lines, and its high expression was associated with shorter overall survival of NSCLC patients. CircRNA_100565 deletion mitigated DDP resistance, reflected by the suppression of proliferation and autophagy, the reduction of IC50 value, as well as enhancement of apoptosis in DDP-resistant NSCLC cells. MiR-377-3p was confirmed to directly bind to circRNA_100565 or ADAM28 3’-UTR. Moreover, circRNA_100565 indirectly regulated ADAM28 expression by sponging miR-377-3p in NSCLC cells. Additionally, circRNA_100565 deletion-induced sensitivity of NSCLC resistant cells to DDP could be remarkably attenuated by miR-377-3p inhibition or ADAM28 re-expression. Meanwhile, circRNA_100565 knockdown contributed to the anti-tumor effects of DDP on NSCLC in vivo . CONCLUSION: CircRNA_100565 was an independent prognostic factor for NSCLC patient survival, and enhanced the resistance of NSCLC cells to cisplatin by regulating cell proliferation, apoptosis and autophagy via miR-337-3p/ADAM28 axis, shedding light on the development of a novel therapeutic strategy to boost the effectiveness of NSCLC chemotherapy. Show more

Keywords: circRNA_100565, miR-337-3p, ADAM28, NSCLC, cisplatin resistance

DOI: 10.3233/CBM-201705

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 261-273, 2021

Article Type: Correction

DOI: 10.3233/CBM-210950

Citation: Cancer Biomarkers, vol. 30, no. 2, pp. 275-, 2021