Cancer Biomarkers - Volume 27, issue 1

Authors: Fang, Zhigang | Wang, Xiaozhen | Wu, Jieying | Xiao, Ruozhi | Liu, Jiajun

Article Type: Research Article

Abstract: BACKGROUND: Increasing evidence have demonstrated that serum extracellular vesicle microRNAs (EV-miRNAs) are promising noninvasive biomarkers for various cancer types. OBJECTIVE: In this study, we aimed to investigate and evaluate the potential clinical significance of serum EV-miR-10b for acute myeloid leukemia (AML). METHODS: Blood samples were collected from a cohort of 95 de novo AML patients and 80 healthy individuals. Of all AML patients, 51 patients were considered as cytogenetic normal AML (CN-AML). Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed to measure the expression levels of serum EV-miR-10b. RESULTS: …The extracellular vesicles we extracted from the serum samples were positive for EV/exosome markers including TSG101, CD63, Flotillin-1 and CD9. The expression levels of serum EV-miR-10b were significantly higher in AML/CN-AML patients than healthy controls. In addition, serum EV-miR-10b expression was strongly correlated with aggressive clinical characteristics. Moreover, receiver operating characteristic analysis showed serum EV-miR-10b yielded an area under the curve of 0.875, with 77.89% specificity and 82.50% sensitivity in identifying AML patients from normal controls. Furthermore, AML patients with higher serum EV-miR-10b expression had significantly shorter survival and serum EV-miR-10b was demonstrated to be an independent prognostic marker for overall survival in AML. CONCLUSIONS: Taken together, serum EV-miR-10b might serve as a promising biomarker for predicting the prognosis of AML. Show more

Keywords: miR-10b, extracellular vesicle, acute myeloid leukemia, prognosis

DOI: 10.3233/CBM-190211

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 1-9, 2020

Authors: Özgür, Emre | Ferhatoğlu, Ferhat | Şen, Fatma | Saip, Pinar | Gezer, Ugur

Article Type: Research Article

Abstract: BACKGROUND: Novel biomarkers are needed to predict the effectiveness of the treatment of presurgical neoadjuvant chemotherapy (NAC) in breast cancer (BC). OBJECTIVE: This is an exploratory study to assess the impact of 3 cancer-related long non-coding RNAs (lncRNAs) (H19, MALAT1 and GA5) in blood plasma of patients with BC in predicting the response to NAC. METHODS: The plasma levels of RNAs were relatively measured by quantitative PCR at baseline, and at the end of the fourth cycle of NAC in patients with locally advanced BC. RESULTS: Only H19 was associated …with patients’ characteristics, and with the response to NAC. Higher plasma expression of H19 was associated with younger age at diagnosis, triple negative tumors, and Ki-67 index. Patients with a pathological complete response (20%) had lower pre-therapeutic levels of H19 compared with the non-complete responders (relative levels 0.1 vs 0.2, respectively, P : 0.04). In addition, the patients with higher degree of downstaging of initial tumors had lower baseline levels of H19 among non-complete responders. CONCLUSION: Our study reveals that H19, but not MALAT1 and GAS5, may be a useful marker of response to NAC in BC. Show more

Keywords: Breast cancer, neoadjuvant chemotherapy, pathological complete response, long non-coding RNAs, blood plasma

DOI: 10.3233/CBM-190085

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 11-17, 2020

Authors: Zhao, Zhen | Li, Yingli | Wu, Yuanqing | Chen, Rongrong

Article Type: Research Article

Abstract: PURPOSE: This study endeavors to build a deep learning (DL)-based model for predicting disease progression in head and neck squamous cell carcinoma (HNSCC) patients by integrating multi-omics data. METHODS: RNA sequencing, miRNA sequencing, and methylation data from The Cancer Genome Atlas (TCGA) were used as input for autoencoder, a DL approach. An autoencoder-based prognosis model for PFS was built by SVM algorithm and tested in three confirmation sets. Predictive performance of the model was compared to two alternative approaches. Differential expression analysis for mRNAs, microRNAs (miRNA) and methylation was conducted. Moreover, functional annotation of differentially expressed …genes (DEGs) was achieved through function enrichment analysis. RESULT: The DL-based prognosis model identified two subgroups of patients with significantly different PFS, and showcased a good model fitness (C-index = 0.73). The two identified PFS subtypes were successfully validated in three confirmation sets. The DL-based model was more accurate and efficient than principal component analysis (PCA) or individual Cox-PH-based models. There were 348 DEGs, 23 differentially expressed miRNAs and 55 differentially methylated genes between the two PFS subtypes. These genes were significantly involved in several immune-related biological processes and primary immunodeficiency, cell adhesion molecules (CAMs), B cell receptor signaling and leukocyte transendothelial migration pathways. CONCLUSION: The DL-based model introduced in this study is reliable and robust in predicting disease progression in HNSCC patients. A number of pathways and genes targets are unraveled to be implicated in cancer progression. Utility of this model would facilitate development of more individualized therapy for HNSCC patients and improve prognosis. Show more

Keywords: Machine learning, deep learning, prognostic model, progress free survival, autoencoder

DOI: 10.3233/CBM-190380

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 19-28, 2020

Authors: Yu, Haiying | Han, Lan | Yuan, Jia | Sun, Yinyin

Article Type: Research Article

Abstract: BACKGROUND: Tissue biopsy remains the conventional technique for tumor genotyping. The main limitations are it is invasive and provides only partial snapshot during disease progression. Liquid biopsy approaches via plasma and urine are possible alternatives, and the current study aims to provide comparative analyses for plasma and urine derived disease genotyping. METHODS: Blood and urine specimens were collected from 150 individuals with metastatic colorectal cancer (mCRC). Patients had multiple metastases and advanced stages of cancer. Common genetic mutations including KRAS and BRAF genetic abnormalities were evaluated. Patients were also serially monitored and compared. …RESULTS: In all cases, plasma and urine cell free DNA were successfully recovered and were of good quality for genetic analysis. Median recovered DNA from both urine and plasma samples were higher in mCRC patients than healthy volunteers indicating disease associations. Among the identified mutations, matched tumor tissue profiles compared to results from plasma ctDNA was 92%. For urine cell free DNA, the concordance among the identified mutations was 91%. Both sample types were closely matched to reference standards of tissue biopsy and indicated good clinical utility. Serial measurements indicated trends within each patient group that was linked with disease outcome. CONCLUSIONS: In the current study, our data indicated that both plasma and urine cell free DNA can be utilized to address possible disease progression in colorectal cancer patients. More importantly, this also provide risk stratifications that correlated to disease outcome. This can potentially aid in early clinical intervention for patients with possibly worse outcomes. Show more

Keywords: Genetic mutations, colorectal cancer, KRAS, BRAF, survival analysis

DOI: 10.3233/CBM-182344

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 29-37, 2020

Authors: Sun, Chaonan | Zeng, Xue | Guo, Hong | Wang, Tianlu | Wei, Linlin | Zhang, Yaotian | Zhao, Jiaming | Ma, Xinchi | Zhang, Na

Article Type: Research Article

Abstract: BACKGROUND: Micro(mi)RNAs are a series of 20–24 nt non-coding small-molecule single-stranded RNAs that are believed to be closely related to tumor occurrence, development and other biological processes. MicroRNA-125a modulates radiochemotherapy sensitivity. However, the mechanism by which miRNA-125a regulates radiation resistance by lung cancer cells is yet to be elucidated. OBJECTIVE: The present study was designed to explore the biological role of miR-125a in regulating radioresistance in non-small cell lung carcinoma (NSCLC). METHODS AND RESULTS: The expression of miR-125a was assessed by quantitative real-time PCR in the human lung cancer cell lines, A549 and …LTEP-a2. Notably, we found that miRNA-125a-5p regulated lung cancer radiosensitivity. We found that miRNA-125a-5p was more highly expressed in LTEP-a2 cells, which showed radiosensitivity compared to A549 cells with lower expression of miRNA-125a-5p. In addition, we up-regulated or down-regulated miR-125a-5p expression using an miR-125a-5p mimic or inhibitor, respectively, to reverse radioresistance. Flow cytometry revealed that the mimic increased the apoptotic rate as well as the expression of the apoptosis-related protein, cleaved poly ADP-ribose polymerase (PARP). Gene detection by luciferase reporter showed that sirtuin (SIRT)7 is a direct target of miR-125a-5p. Inhibiting SIRT7 using a small interfering RNA (siSIRT) abrogated resistance to radiation. In addition, the overexpression of SIRT7 decreased radiation-induced cell apoptosis. CONCLUSION: Our results indicated that the miR-125a level varies in NSCLC cell lines with different radiosensitivities. We demonstrated that miR-125a-5p upregulated SIRT7 and further upregulated apoptosis in lung cancer cells to increase their radiosensitivity. Our findings provide new directions for improving radiosensitivity in malignant lung tumors. Show more

Keywords: NSCLC, microRNA-125a-5p, radiosensitivity, SIRT7, apoptosis

DOI: 10.3233/CBM-190381

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 39-49, 2020

Authors: Song, Jiandong | Yang, Pengxia | Lu, Jianjun

Article Type: Research Article

Abstract: BACKGROUND: Ovarian cancer remains one of the most lethal malignancies in women and the unfavorable prognosis and frequent recurrence are mainly due to the chemoresistance. However, the main mechanism underlying chemoresistance is still elusive. OBJECTIVE: To determine the role and biological function of ITGBL1 in ovarian cancer chemoresistance. METHODS: Immunohistochemical staining was used to determine the expression of ITGBL1 in ovarian cancer tissues. The association between ITGBL1 expression and clinicopathological features and survival was determined. Functional analysis including cell viability, apoptosis assays were performed after chemo drugs treatment to confirm the role of …ITGBL1 in chemoresistance. In vivo tumor growth assay was used to detect the chemosensitivity of tumor cells. Western blot was used to detect the expression of indicated proteins. RESULTS: We noticed that ITGBL1 expression was significantly upregulated in ovarian cancer tissues compared to that in adjacent non-cancer tissues and high expression of ITGBL1 was significantly associated with lymph node invasion and advanced FIGO stage. More importantly, high ITGBL1 was an independent prognostic factor of ovarian cancer. Further experiments demonstrated that ITGBL1 promoted tumor cell resistant to chemo drugs both in vitro and in vivo . Mechanically, we found that ITGBL1 could activate PI3K/Akt signaling and using PI3K/Akt inhibitor could abrogate ITGBL1 induced chemoresistance. CONCLUSIONS: Our findings indicate that upregulation of ITGBL1 has important clinical significance and drives chemoresistance in ovarian cancer. Detection and depletion of ITGBL1 might be the potential approaches for diagnosis and therapy for ovarian cancer patients. Show more

Keywords: ITGBL1, ovarian cancer, PI3K/Akt, chemoresistance, prognosis

DOI: 10.3233/CBM-190460

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 51-61, 2020

Authors: Boubaker, Nouha Setti | Gurtner, Aymone | Trabelsi, Nesrine | Manni, Isabella | Said, Rahma | Ayed, Haroun | Ksentini, Meriem | Karray, Omar | Saadi, Ahmed | Essid, Mohamed Ali | Blel, Ahlem | Rammeh, Soumaya | Chebil, Mohamed | Piaggio, Giulia | Ouerhani, Slah

Article Type: Research Article

Abstract: BACKGROUND: Stratification and risk-evaluation of bladder cancer (BCa) patients are far-reached issues, especially for those with non muscle invasive disease. Thus, setting-up biomarkers, especially after resection of the primary tumor, is crucial. Specifically, Neutrophil to lymphocyte ratio NLR and let-7 deregulation which have been preliminarily but not consistently described to be associated to unfavorable prognosis. OBJECTIVE: To explore the clinical value of pre-treatment Neutrophil to Lymphocyte Ratio (NLR), let-7c and let-7g’s deregulation. METHODS: Data were extracted from ninety BCa samples. Pre-treatment NLR was estimated as the absolute neutrophil count divided by the absolute …lymphocyte count. Expression patterns of let-7c and let-7g were assessed by qRT-PCR. Correlation with clinical characteristics was performed by descriptive statistics. RESULTS: Both let-7 miRs were upregulated. Interestingly, let-7g was associated to pathological stage (p = 0.001) and tumor multiplicity (p = 0.003). NLR was associated to histological grade (p = 0.005) and clinical stage (p = 0.006). They were both associated to more aggressive phenotype and their worth as potential stratification biomarkers was confirmed by ROC curve. CONCLUSIONS: Our data demonstrated the potential clinical value of all markers, especially pretreatment NLR and let-7g. Further studies are recommended to confirm their utility in improving the clinical decision-making regarding treatment and follow-up scheduling. Show more

Keywords: Urinary bladder, neoplasms, NLR, let-7, biomarkers, stratification

DOI: 10.3233/CBM-190483

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 63-73, 2020

Authors: Tian, Xudong | Wang, Yadong | Li, Shuhai | Yue, Weiming | Tian, Hui

Article Type: Research Article

Abstract: OBJECTIVE: To investigate the effect of ZHX2 on lung cancer cells proliferation and apoptosis. MATERIALS AND METHODS: The mRNA and protein expression of ZHX2 were detected by qRT-PCR and western blot, respectively. The human lung cancer cells were divided into Control, NC, ZHX2, SB, and ZHX2 + Ani groups. The cell proliferation was detected by CCK-8 assay and the cell migration and invasion were detected by Transwell assay. Cell apoptosis was detected by flow cytometry. Apoptosis and p38MAPK signaling pathway related proteins were detected by western blot. The nude mice model of lung …cancer xenograft was constructed. The tumor volume and tumor weight were measured. The expression of PCNA protein in tumor tissues was detected by immunohistochemistry. The apoptosis of tumor cells was detected by TUNEL staining. The ZHX2 and p38MAPK signaling pathway related proteins in tumor tissues were detected by western blot. RESULTS: The expression of ZHX2 gene and protein in the cancer cell lines were significantly decreased. Compared with control and NC groups, the cells proliferation, migration and invasion were inhibited in ZHX2 and SB groups, while the apoptosis and apoptosis related proteins were increased (p < 0.05). Meanwhile, compared with ZHX2 group, the tumor growth rate, volume, weight, the percentage of PCNA-positive cells, and p-P38 MAPK/P38 MAPK were increased significantly in ZHX2 + Ani group, while the apoptotic index and the expression of MMP-9 protein were significantly decreased (p < 0.05). CONCLUSION: ZHX2 could inhibit proliferation and promote apoptosis of lung cancer cells by inhibiting p38MAPK signaling pathway. Show more

Keywords: Lung cancer, Zinc-fingers and homeoboxes 2, proliferation, migration, apoptosis

DOI: 10.3233/CBM-190514

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 75-84, 2020

Authors: Wang, Yumei | Cai, Xinglong

Article Type: Research Article

Abstract: BACKGROUND: Breast cancer has become a major threat to women’s physical and mental health. Many long noncoding RNAs (lncRNAs) have been reported to exert effect in the progression of breast cancer. However, the regulatory mechanism of HAND2-AS1 remains unclear. Therefore, this study aimed to elucidate the role of HAND2-AS1 in breast cancer. METHODS: The expression of HAND2-AS1, miR-1275 and SOX7 was assessed using RT-qPCR and Western blot analysis. CCK-8, Transwell and luciferase reporter assays were used to investigate their regulatory mechanisms. RESULTS: Downregulation of HAND2-AS1 was detected in breast cancer and was associated …with adverse clinical features and prognosis. Furthermore, overexpression of HAND2-AS1 restrained cell viability, migration and invasion in breast cancer. In addition, reciprocal suppression between HAND2-AS1 and miR-1275 was identified in breast cancer cells. Further, SOX7, a target of miR-1275, strengthened the effect of HAND2-AS1 in breast cancer. CONCLUSION: LncRNA HAND2-AS1 sponging miR-1275 restrains proliferation and metastasis of breast cancer cells by regulating SOX7 expression. Show more

Keywords: HAND2-AS1, breast cancer, miR-1275, SOX7

DOI: 10.3233/CBM-190530

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 85-94, 2020

Authors: Pérez-Sayáns, Mario | Chamorro-Petronacci, Cintia M. | Lorenzo-Pouso, Alejandro I. | Peñaranda, José M. Suárez | López-López, José | Blanco-Carrión, Andrés | García-García, Abel

Article Type: Research Article

Abstract: BACKGROUND: Oral squamous cell carcinoma (OSCC) represents 95% of all cancers of the head and neck region. The five-year survival rate of OSCC patients is about 60% and has not gone throw significant improvements despite recent advances in molecular biology, or the identification of key pathways in its pathophysiology such as cell cycle. OBJECTIVE: 1) to analyse the inmunoexpression of cell cycle checkpoints (CPs) in an OSCC institutional cohort and to relate it to clinicopathological features and survival, and 2) to study CPs-related genes in the OSCC subset of the TCGA database. METHODS: …Immunohistochemistry (IHC) for p16 INK4a , p21 CIP1 , cyclin D1 and p27 KIP1 protein expression was quantified by tissue microarray analysis in 68 samples from OSCC patients. In order to analyse its correlation with genetic information, a cohort belonging to The Cancer Genome Atlas (TCGA) database was analysed. RESULTS: Of 68 patients, 34 (50%) developed recurrence, and 36 (52.09%) died as a result of disease progression (mean survival 34.09 months). IHC staining for nuclear cyclin D1 was associated with worse staging and tobacco use. p16 INK4a , p21 CIP1 , cyclin D1, and p27 KIP1 expression was unrelated to overall survival. No statistically significant correlation linked the CPs-related genes mutations to OSCC overall survival in the TCGA database. CONCLUSIONS: CPs variations at a phenotype and genotype level seem not to affect significantly clinicopathological features and survival in the studied OSCC cohorts. Show more

Keywords: Oral squamous cell carcinoma, cell cycle, cellular pathways/molecular mechanisms, expression profiling, molecular diagnosis

DOI: 10.3233/CBM-190776

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 95-103, 2020

Authors: Li, Xiaoting | Liu, Kun | Zhou, Wei | Jiang, Zhe

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF replaced with this retraction notice.

Keywords: Oral cancer, DDP, resistance, miR-155, FoxO3a

DOI: 10.3233/CBM-190555

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 105-111, 2020

Authors: Liu, Wenqi | Liu, Jing | Zhang, Qiangqiang | Wei, Li

Article Type: Research Article

Abstract: BACKGROUND: Increasing evidence have shown that miRNAs play an important role in the development and progression of non-small cell lung cancer (NSCLC). OBJECTIVE: In this study, we aimed to analyze serum exosomal miR-216b expression in NSCLC patients and its potential clinical significance. METHODS: A total of 105 NSCLC patients and 60 healthy controls were enrolled, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to detect serum exosomal miR-216b expression. RESULTS: The results demonstrated that serum exosomal miR-216b levels were significantly lower in NSCLC patients compared to controls. In …addition, receiver operating characteristic analysis revealed that serum exosomal miR-216b had better diagnostic accuracy than CEA, CYFRA21-1 or SCCA. Moreover, serum exosomal miR-216b levels in early-stage NSCLC patients were dramatically increased after surgical resection, and patients with low serum exosomal miR-216b expression had higher lymph node metastasis probability. Furthermore, low serum exosomal miR-216b expression was closely associated with poor prognosis. Finally, multivariate analysis showed that serum exosomal miR-216b could serve as an independent predictor of NSCLC. CONCLUSIONS: Collectively, serum exosomal miR-216b might be used as a potential diagnostic and prognostic biomarker for NSCLC. Show more

Keywords: non-small cell lung cancer, exosomes, miR-216b, prognosis

DOI: 10.3233/CBM-190914

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 113-120, 2020

Authors: Yamada, Keita | Higashi, Kiyoshi | Nagahori, Hirohisa | Saito, Koichi

Article Type: Research Article

Abstract: BACKGROUND: Pancreatic ductal adenocarcinoma is a devastating malignancy with an extremely poor prognosis. Although the most widely used biomarker for pancreatic cancer is carbohydrate antigen CA19-9, it is elevated mainly in the late stage of pancreatic cancer. Some serum natural antibodies against carbohydrates have been shown to be possible diagnostic markers for cancer. OBJECTIVE: This study was conducted to determine whether the level of natural antibodies against carbohydrates fluctuates in pancreatic ductal adenocarcinoma. METHODS: Serum from pancreatic cancer subjects (n = 55) and 43 subjects free of malignant …disease were studied. The contents of natural antibodies against sialyl glycans and CA19-9 in serum were determined by enzyme-linked immunosorbent assay. RESULTS: The level of serum anti-3’-sialyllactose antibodies in pancreatic cancer subjects was significantly lower than that in healthy controls. In contrast, the amounts of serum antibodies against other sialyl glycans were comparable between the two groups. Concentration of serum anti-3’-sialyllactose IgG provided excellent AUC of 0.86, with sensitivity 82%, specificity 81%, and accuracy 82%. The combination of serum anti-3’-sialyllactose IgG with CA19-9 improved the sensitivity of pancreatic cancer detection at an early stage. CONCLUSIONS: Natural antibodies against 3’-sialyllactose constitute a promising biomarker for pancreatic cancer detection. The measurement of serum anti-3’-sialyllactose antibodies could play a supportive role in diagnostics and complement the performance of CA19-9 for the early detection of pancreatic ductal adenocarcinoma. Show more

Keywords: Pancreatic ductal adenocarcinoma, natural antibody, 3’-sialyllactose, CA19-9

DOI: 10.3233/CBM-190158

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 121-128, 2020

Authors: Saman, S. | Stagno, M.J. | Warmann, S.W. | Malek, N.P. | Plentz, R.R. | Schmid, E.

Article Type: Research Article

Abstract: OBJECTIVE: The EDIM (Epitope detection in monocytes) blood test is based on two biomarkers Apo10 and TKTL1. Apo10 is responsible for cell proliferation and resistance to apoptosis. TKTL1 plays a major role in anaerobic glycolysis of tumor cells, leading to destruction of the basal membrane and metastasis as well as in controlling cell cycle. For the first time we analyzed Apo10 and TKLT1 in patients with cholangiocellular (CCC), pancreatic (PC), and colorectal carcinoma (CRC). METHODS: Blood samples of 62 patients with CCC, PC, and CRC were measured and compared to 29 control patients. We also investigated …13 patients with inflammatory conditions, because elevated TKTL1 and Apo10 have been previously described in affected individuals. Flow cytometry was used to detect surface antigens CD14 + /CD16 + (activated monocytes/macrophages). Percentages of macrophages harboring TKTL1 and Apo10 were determined. A combined EDIM score (EDIM-CS: TKTL1 plus Apo10) was calculated. Results were correlated with serum tumor markers CEA and CA19-9. RESULTS: Patients with CCC had 100% positive EDIM-CS but CEA and CA19-9 were positive in only 22.2% and 70%, respectively. Patients with PC had 100% positive EDIM-CS but positive tumor markers in only 37.5% (CEA) and 72.7% (CA19-9). Patients with CRC had 100% positive EDIM-CS but only 50% positive CEA. EDIM-CS was positive in 100% (62/62) of all cancer patients and in 0% of healthy individuals. Of the individuals with inflammation, 7.7% had a positive EDIM-CS. CONCLUSION: The sensitivity of the EDIM blood test and the comparison with traditional tumor markers indicate that this new test might improve the detection of carcinomas (CCC, PC and, CRC) and might be relevant for the diagnosis of all tumor entities. Show more

Keywords: Biomarker, Apo10, TKTL1, EDIM blood test, PanTum detect, biologic biopsy, pancreas cancer, cholangiocellular carcinoma, colorectal carcinoma

DOI: 10.3233/CBM-190414

Citation: Cancer Biomarkers, vol. 27, no. 1, pp. 129-137, 2020