Cancer Biomarkers - Volume 29, issue 4

Authors: Abhishek, Amar | Ansari, Nasreen Ghaji | Singh, Vishwajeet | Sinha, Rahul Janak | Mishra, Prabhakar | Mishra, Abhishek

Article Type: Research Article

Abstract: BACKGROUND: The etiology of prostate cancer (PCa) is multi-factorial including environmental and genetic factors. Present study evaluates the association between level of pesticides, stress level and CYP1A1 gene polymorphism with PCa patients. METHODS: A case control study was conducted with 102 PCa patients and age match symptomatic (n = 107) and asymptomatic benign prostatic hyperplasia (BPH, n = 70) patients. Pesticide level was characterized by Gas Chromatography. The oxidative stress and scavenging mechanisms were determined by biochemical method. Two polymorphisms of CYP1A1 gene, rs4646903 and rs1048943, …were analyzed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism and allele specific PCR method. RESULTS: Higher level of pesticide namely beta-hexachlorocyclohexane (β -HCH), Malathion, Chlorpyrifos and Fenvalerate were found in PCa group (all p value: < 0.05). Kruskal Wallis H test depicted that level of β -HCH and Malathion significantly correlated with higher grade of PCa (all p < 0.05). The PCa Patients with simultaneously low antioxidant activity and high stress level tended to suffer worst clinical outcomes. Dominant model of rs4646903 and rs1048943 suggested that substitution is associated with a higher risk of PCa (OR: 2.2, CI: 1.6–3.8, p : 0.009 and OR: 1.95, CI: 1.1–3.4, p : 0.026; respectively) and this risk was also influenced by smoking and pesticide exposure. CONCLUSION: Environmental and genetic factors are reported to raise risk; person with high level of these pesticides especially in high risk genotype might be more susceptible to PCa. Show more

Keywords: Prostate cancer, pesticides, polymorphism, CYP1A1, gas chromatography

DOI: 10.3233/CBM-190636

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 429-440, 2020

Authors: Yang, Qian | Kong, Shan | Zheng, Ming | Hong, Yuelan | Sun, Jing | Ming, Xiaotian | Gu, Yingqiu | Shen, Xianjuan | Ju, Shaoqing

Article Type: Research Article

Abstract: BACKGROUND: Long intergenic non-coding RNA (lincRNA) belongs to a special type of RNA that is unable to encode proteins but has been proved to play a role in gene regulation and differentially expressed in various malignant tumors. OBJECTIVE: In this study, we aimed to identify whether lincRNA LINC00173 was differentially expressed in non-small-cell lung cancer (NSCLC) and whether it could serve as a potential diagnostic biomarker. METHODS: The quantification real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of LINC00173 in serum and cultured cells. For large sample analysis, the …lncRNA expression matrix in TCGA database were generated via R software. To evaluate the diagnostic performance of serum LINC00173, the receiver operating characteristic (ROC) curve was used. RESULTS: The qRT-PCR analysis showed that the serum LINC00173 expression level in 108 NSCLC patients was higher than that in 91 healthy donors and 55 patients with benign pulmonary disease (BPD). And the area under the curve (AUC) of serum LINC00173 was 0.809 for the diagnosis of NSCLC (95% CI: 0.750–0.868, p < 0.001), 0.670 for BPD (95% CI: 0.584–0.756, P < 0.001), and 0.730 for small-cell lung cancer (SCLC, 95% CI: 0.636–0.825, P < 0.001). Besides, we established a diagnostic model of combined detection of LINC00173, CEA and Cyfra21-1, and found that combined detection of these indicators significantly improved the diagnostic efficiency. Analysis of the Clinicopathological parameters showed that high LINC00173 expression was correlated with histological typing of tumor, tumor metastasis and serum Cyfra21-1 levels. In addition, serum LINC00173 expression decreased in patients who received chemotherapy and rebound in recurrent NSCLC patients. CONCLUSION: Serum LINC00173 may prove to be a potential non-invasive auxiliary diagnostic biomarker for NSCLC patients. Show more

Keywords: Non-small-cell lung cancer, LINC00173, biomarker, diagnosis

DOI: 10.3233/CBM-201616

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 441-451, 2020

Authors: Wang, Changming | Piao, Chiyuan | Liu, Junlong | Zhang, Zhe | Zhu, Yuyan | Kong, Chuize

Article Type: Research Article

Abstract: OBJECTIVE: Sirtuins family are defined as class III histone deacetylases (HDACs). Recently, mammalian silent information regulator two 4 (SIRT4) has been reported to be a tumor suppressor gene in multiple cancers. The objective of the present study was to explore the potential role of SIRT4 in clear cell renal cell carcinoma (ccRCC). METHODS: We estimated SIRT4 expression levels in ccRCC and its adjacent non-neoplastic tissue by Western blotting (WB), quantitative real-time polymerase chain reaction (qRT-PCR) and bioinformatics data, the clinical and survival data were also collected and analyzed. In vitro study, ccRCC cell lines were …transfected with SIRT4-siRNA or lentivirus to downregulate or overexpress the expression level of SIRT4. Then, the proliferation capacity of tumor cell was assessed by 5-Ethynyl-2’-deoxyuridine (EDU) assay, cell migration and invasion capacity were assessed by Transwell assays. RESULTS: Our results indicated that the expression level of SIRT4 in ccRCC was significantly lower than the corresponding normal tissues (P < 0.001). Meanwhile, bioinformatics data and the result of WB showed that low SIRT4 expression level was obviously involved with poor overall survival and advanced tumor stage in ccRCC patients. Biological experiments demonstrated that overexpression of SIRT4 significantly reduced the proliferation, migration and invasion ability of ccRCC cells. Conversely, downregulation of SIRT4 enhanced the proliferation, migration and invasion ability of ccRCC cells. CONCLUSIONS: These findings support that SIRT4 acts as a tumor suppressor in ccRCC and might be a novel biomarker and new therapeutic target for ccRCC. Show more

Keywords: ccRCC, SIRT4, tumor suppressor, proliferation, migration, invasion

DOI: 10.3233/CBM-191253

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 453-462, 2020

Authors: Sun, Hui | Chen, Yi | Fang, Yue-Yu | Cui, Ting-Yun | Qiao, Xue | Jiang, Chun-Yu | Lu, Zhi-Bin

Article Type: Research Article

Abstract: BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common cancer worldwide. Circular RNAs (circRNAs) are recently identified as important gene regulators with critical roles in cancer biology. In this study, we focus on the effect of circ_0000376 targeting miR-384 on malignant phenotypes of NSCLC cells. METHODS: Circ_0000376 and miR-384 expression in NSCLC tissue samples were measured using qRT-PCR. The association between pathological parameters and the circ_0000376 expression was analyzed as well. Human NSCLC cell lines A549 and NCI-H460 were used as cell models. CCK-8 and BrdU assay were used to assess the effect of circ_0000376 …on NSCLC cell line proliferation and drug sensitivity. Transwell assay was conducted to detect the effect of circ_0000376 on migration and invasion. Further, luciferase reporter assay was employed to validate the targeting of miR-384 by circ_0000376. RESULTS: Circ_0000376 expression in NSCLC clinical samples was up-regulated and this was linked to unfavorable pathological parameters. Circ_0000376 markedly accelerated the proliferation and metastasis, and enhanced chemoresistance of NSCLC cells. Mechanically, circ_0000376 overexpression could bind with miR-384 and repress its expression. CONCLUSIONS: Circ_0000376 is a newly discovered oncogenic circRNA in NSCLC, and can be potentially regarded as a diagnostic biomarker and therapy target. Show more

Keywords: Circ_0000376, miR-384, NSCLC, biomarker

DOI: 10.3233/CBM-190912

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 463-473, 2020

Authors: Meng, Fanlu | Zhang, Linlin | Ren, Yaoyao | Ma, Qing

Article Type: Research Article

Abstract: Previous studies have suggested potential signature genes for lung cancer, however, due to factors such as sequencing platform, control, data selection and filtration conditions, the results of lung cancer-related gene expression analysis are quite different. Here, we performed a meta-analysis on existing lung cancer gene expression results to identify Meta-signature genes without noise. In this study, functional enrichment, protein-protein interaction network, the DAVID, String, TfactS, and transcription factor binding were performed based on the gene expression profiles of lung adenocarcinoma and non-small cell lung cancer deposited in the GEO database. As a result, a total of 574 differentially expressed genes …(DEGs) affecting the pathogenesis of lung cancer were identified (207 up-regulated expression and 367 down-regulated expression in lung cancer tissues). A total of 5,093 interactions existed among the 507 (88.3%) proteins, and 10 Meta-signatures were identified: AURKA , CCNB1 , KIF11 , CCNA2 , TOP2A , CENPF , KIF2C , TPX2 , HMMR , and MAD2L1 . The potential biological functions of Meta-signature DEGs were revealed. In summary, this study identified key genes involved in the process of lung cancer. Our results would help the developing of novel biomarkers for lung cancer. Show more

Keywords: Lung cancer, DEG, PPI-interaction, biomarkers, AURKA, CCNB1

DOI: 10.3233/CBM-200110

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 475-482, 2020

Authors: Wu, Hanwei | Liu, Yuchen | Duan, Hongfang | Fan, Xiaoqin | Wang, Yujie | Song, Jian | Han, Jinghong | Yang, Ming | Lu, Lu | Nie, Guohui

Article Type: Research Article

Abstract: BACKGROUND: Circular RNAs (circRNAs) are endogenous RNAs that have a covalent closed cycle configuration. circRNAs have been found to be differentially expressed in many human cancers. Therefore, circRNAs may be ideal biomarkers for the diagnosis and treatment of cancer. However, we know very little about the function of circRNAs in nasopharyngeal carcinoma (NPC). The purpose of this study was to evaluate the circRNA expression profiles in NPC. METHODS: We utilized high-throughput RNA sequencing (RNA-Seq) to evaluate the circRNA expression profile in NPC A total of 13,561 unique circRNA candidates were detected. Selection of aberrantly expressed circRNAs …was carried out using a q -value of < 0.001 with a fold change of > 2.0 or < 0.5. We carried out Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses to identify the biological functions of differentially expressed circRNAs. Moreover, bioinformatics analyses were implemented to predict the effects between circRNAs and cancer-related microRNAs (miRNAs), and we used Cytoscape to build a cancer-related circRNA-miRNA target gene map. Finally, to verify dysregulated circRNAs, quantitative real-time PCR was utilized. RESULTS: In NPC tissues, we found that 73 circRNAs were downregulated and 59 were upregulated. The top 12 candidate circRNAs were selected from several vital NPC pathways such as the human papillomavirus and Epstein-Barr virus infection signaling pathways (hsa05165 and hsa05169 , respectively), Hepatitis B (hsa05161 ), and the Ras signaling pathway (hsa04014 ). A network map of circRNA-miRNA interactions of 12 differentially expressed circRNAs was built. Hsa_circ_0007637 expression distinguished NPC tissues from paired healthy tissues and NPC cell lines (HNE1 6-10B, 5-8F, CNE-2, and so on) from a normal epithelial (NP460) cell line. CONCLUSIONS: In this study, we investigated the profiles of differentially expressed circRNAs in NPC, and our results show that hsa_circ_0007637 may be a biomarker for NPC and play a role in its development. This observation-based research identified dysregulated circRNAs in NPC, which may assist in the development of biomarkers for this disease. Further studies on the mechanisms and functions of these circRNAs may promote our understanding of NPC tumorigenesis. Show more

Keywords: CircRNAs, RNA-Seq, NPC, Hsa_circ_0007637

DOI: 10.3233/CBM-201731

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 483-492, 2020

Authors: Song, Jia-Yi | Li, Xiao-Ping | Qin, Xiu-Jiao | Zhang, Jing-Dong | Zhao, Jian-Yu | Wang, Rui

Article Type: Research Article

Abstract: Growing evidence has underscored long non-coding RNAs (lncRNAs) serving as potential biomarkers for cancer prognosis. However, systematic tracking of a lncRNA signature for prognosis prediction in non-small cell lung cancer (NSCLC) has not been accomplished yet. Here, comprehensive analysis with differential gene expression analysis, univariate and multivariate Cox regression analysis based on The Cancer Genome Atlas (TCGA) database was performed to identify the lncRNA signature for prediction of the overall survival of NSCLC patients. A risk-score model based on a 14-lncRNA signature was identified, which could classify patients into high-risk and low-risk groups and show poor and improved outcomes, respectively. …The receiver operating characteristic (ROC) curve revealed that the risk-score model has good performance with high AUC value. Multivariate Cox’s regression model and stratified analysis indicated that the risk-score was independent of other clinicopathological prognostic factors. Furthermore, the risk-score model was competent for the prediction of metastasis-free survival in NSCLC patients. Moreover, the risk-score model was applicable for prediction of the overall survival in the other 30 caner types of TCGA. Our study highlighted the significant implications of lncRNAs as prognostic predictors in NSCLC. We hope the lncRNA signature could contribute to personalized therapy decisions in the future. Show more

Keywords: Non-small cell lung cancer, long non-coding RNAs, overall survival, prognostic signature

DOI: 10.3233/CBM-190505

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 493-508, 2020

Authors: Khalil, Athar | Nemer, Georges

Article Type: Research Article

Abstract: Glioblastoma is the most common type of malignant brain tumors and the most feared cancer among adults. The poor prognosis among patients affected with this type of cancer is associated with its high-invasiveness and the lack of successful therapies. A comprehensive understanding for the early molecular mechanisms in glioblastoma would definitely enhance the diagnosis and the treatment strategies. Deregulated expression of key genes that are known to be involved in early neurogenesis could be the instigator of brain tumorigenesis. Ras Like Without CAAX 1 (RIT1 ) gene that encodes an unusual “orphan” GTPase protein belongs to this category of critical …genes that are known to be involved in controlling sequential proliferation and differentiation of adult hippocampal neural progenitor cells. In this study, we surveyed RIT1 gene expression by in-silico approaches to determine its spatio-temporal pattern in glioblastoma. Our results revealed a significant and progressive upregulation of RIT1 mRNA levels in various publicly available datasets. RIT1 expression ranked among the top upregulated genes in glioblastoma cohorts and it correlated with poor overall survival. Genetic and epigenetic analysis of RIT1 didn’t reveal any significant aberration that could underlie its deregulated expression. Yet, our results highlighted the possibility of its activity to be transcriptionally controlled by STAT3, one of the main players in the onset of glioblastoma. In conclusion, our study presented for the first time a potential oncogenic role for RIT1 in glioblastoma. Knowing that the RAS superfamily of proteins has created an evolution in the cancer field, RIT1 should be added to this list through further investigations on its possible usage as a biomarker and therapeutic target in glioblastoma. Show more

Keywords: RIT1, glioblastoma, bioinformatics, STAT3, clinical data

DOI: 10.3233/CBM-191264

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 509-519, 2020

Authors: Yin, Yong | Yang, Keke | Li, Juanjuan | Da, Peng | Zhang, Zhenxin | Qiu, Xiaoxia

Article Type: Research Article

Abstract: OBJECTIVE: To assess the expression levels of IFITM1 in human tissue samples and laryngeal squamous cell carcinoma (LSCC) cells, and to explore the potential mechanisms of IFITM1 in LSCC progression. METHODS: Quantitative PCR and immunohistochemical (IHC) assays were performed to detect IFITM1 expression in 62 LSCC tissues and corresponding normal tissues. We further detected the effects of IFITM1 on the proliferation, migration and invasion of LSCC cells and NF-κ B signaling pathway through colony formation assay, wound healing assay and transwell assay, respectively. RESULTS: We demonstrated the possible involvement of IFITM1 …in the progression of LSCC. We found the upregulated expression of IFITM1 in human LSCC tissues and cells, and analyzed the correlations between IFITM1 expression and osteopontin. Our data further confirmed that IFITM1 affected cell proliferation, migration, and invasion of LSCC cells via the regulation of NF-κ B signaling pathway. CONCLUSIONS: We investigated the potential involvement of IFITM1 in the progression of LSCC, and therefore confirmed that IFITM1 was a potential therapeutic target for LSCC. Show more

Keywords: Laryngeal squamous cell carcinoma, interferon-induced transmembrane protein 1 (IFITM1), proliferation, migration, osteopontin, NF-κB signaling pathway, therapeutic target

DOI: 10.3233/CBM-201435

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 521-529, 2020

Authors: He, Xiaowen | Ma, Jun | Zhang, Mingming | Cui, Jianhua | Yang, Hao

Article Type: Research Article

Abstract: Colorectal cancer (CRC) remains one of the most commonly diagnosed malignancies worldwide. Circular RNAs (circRNAs) are being found to play crucial roles in human cancer, including CRC. The purpose of this study was to explore the function and mechanism of circ_0007031 on CRC progression and 5-fluorouracil (5-FU) resistance. The levels of circ_0007031, ATP-binding cassette subfamily C member 5 (ABCC5) and miR-133b were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Cell survival and proliferation were detected by the 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Cell colony formation was evaluated using a standard colony formation assay. Transwell assays were performed to …determine cell migration and invasion. Targeted correlations among circ_0007031, miR-133b and ABCC5 were verified by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pulldown assays. Animal experiments were performed to observe the role of circ_0007031 in vivo . Our data indicated that circ_0007031 up-regulation was associated with CRC resistance to 5-FU. Circ_0007031 knockdown repressed CRC cell proliferation, migration and invasion and enhanced 5-FU sensitivity. Circ_0007031 directly interacted with miR-133b. Moreover, circ_0007031 knockdown regulated CRC cell progression and 5-FU sensitivity by miR-133b. ABCC5 was a direct target of miR-133b, and circ_0007031 mediated ABCC5 expression via acting as a miR-133b sponge. Furthermore, miR-133b overexpression regulated CRC cell progression and sensitivity to 5-FU by down-regulating ABCC5. Additionally, circ_0007031 knockdown suppressed tumor growth in vivo . Our current work had led to the identification of circ_0007031 knockdown that repressed CRC cell malignant progression and enhanced 5-FU sensitivity via regulating ABCC5 expression by sponging miR-133b. Show more

Keywords: CRC, 5-FU, circ_0007031, miR-133b, ABCC5

DOI: 10.3233/CBM-200023

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 531-542, 2020

Authors: Krishna, Akhilesh | Singh, Vineeta | Singh, Shraddha | Kumar, Sachil | Kumar, Vijay | Mehrotra, Divya | Singh, Uma Shankar | Mahdi, Abbas Ali

Article Type: Research Article

Abstract: BACKGROUND: Histone deacetylases (HDACs) are considered as an essential regulator of cellular proliferation, differentiation, and apoptosis. The HDAC2 enzyme of Class I HDACs plays an important role in tumor progression of human malignancies. OBJECTIVE: The aim of the present study was to analyze the HDAC2 gene expression in pre-oral cancer and oral squamous cell carcinoma (OSCC), and its association with clinico-pathological features. METHODS: The HDAC2 protein expression was analyzed through the immunohistochemistry and western blot techniques in 82 oral pre-malignant, 90 OSCC, and 16 normal control tissues. qRT-PCR was used to quantify the …mRNA fold change in all groups. RESULTS: The HDAC2 protein and mRNA levels were significantly higher in OSCC and pre-oral cancer groups compared to the controls. Immunostaining of HDAC2 protein was enhanced in 84.4% of OSCC and 67.1% of pre-cancerous tissue sections (p < 0.01). The mean protein level was analyzed as 1.96 ± 0.44 in oral carcinoma, 1.61 ± 0.39 in pre-cancer and 0.96 ± 0.10 in control tissues. In addition, HDAC2 mean protein level was associated with histological differentiation (OR = 25, p < 0.05) and tumor-node-metastasis (TNM) stages (OR = 6.2, p < 0.05) of OSCC patients. CONCLUSIONS: The upregulated HDAC2 gene in pre-cancer and OSCC tissues indicates its crucial role in the transformation of pre-malignant to malignant carcinoma. It could be a potential cancer biomarker of prognosis and targeted therapy in OSCC. Show more

Keywords: Histone deacetylases, HDAC2 protein, OSCC, oral pre-cancer, oral cancer

DOI: 10.3233/CBM-190729

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 543-552, 2020

Authors: Zahran, Asmaa M. | Riad, Khalid F. | Elsayh, Khalid I. | Elmasry, Heba M. | Rayan, Amal

Article Type: Research Article

Abstract: BACKGROUND AND AIM: There is a limited data at the moment regarding the clinical value of inflammatory indices and malnutrition markers in children with acute leukemias. We have examined the usefulness of prognostic nutritional index (PNI), Glasgow prognostic score (GPS), Prognostic Index (PI), monocyte to lymphocyte (MLR), neutrophil to lymphocyte (NLR), and platelet to lymphocyte (PLR) ratios to stratify patients as regards the response to induction therapy correlating them to different prognostic factors. PATIENTS AND METHODS: Children with acute leukemia and without microbial-induced inflammation at the time of diagnosis were prospectively recruited. Preliminary total and differential …CBC, c-reactive protein (CRP), serum albumin (ALB) were used to calculate different inflammatory indicators including NLR, MLR, PLR, PNI, GPS, and PI. RESULTS: Higher PNI was significantly more associated to children who achieved remission as compared to those without remission (p < 0.0001). Patients without remission had GPS 1 or 2 compared to GPS 0 or 1 in those who entered remission (p = 0.001). NLR was significantly lower in patients in remission than in those without remission (p = 0.005). Similarly, complete remission was significantly associated to MLR ⩽ 0.45 as compared to MLR > 0.45 (p < 0.0001). CONCLUSION: Pretreatment PNI, GPS, CRP, serum albumin, NLR, MLR, and PLR are remission promising prognostic markers in pediatric acute leukemias, which deserve to be further investigated in large-scale studies. Show more

Keywords: Prognostic nutritional index, Glasgow prognostic score, prognostic index, monocyte to lymphocyte, neutrophil to lymphocyte, platelet to lymphocyte ratios, AML, ALL

DOI: 10.3233/CBM-201790

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 553-564, 2020

Article Type: Other

DOI: 10.3233/CBM-200906

Citation: Cancer Biomarkers, vol. 29, no. 4, pp. 565-, 2020