Cancer Biomarkers - Volume 27, issue 4

Authors: Zhang, Jingwei | Kong, Xia | Shi, Qizhu | Zhao, Bin

Article Type: Research Article

Abstract: BACKGROUND: MicroRNAs (miRNAs) have been reported to serve as potential biomarkers in various cancer and play important roles in tumor progression. OBJECTIVE: The aim of this study was to investigate the prognostic significance and functional role of miR-383-5p in breast cancer. METHODS: The expression levels of miR-383-5p in breast cancer tissues and cell lines were measured using quantitative real-time PCR analysis. Kaplan-Meier curve and Cox regression analysis were used to explore the prognostic significance of miR-383-5p in breast cancer. The CCK-8 assay was used to assess cell proliferation ability. Transwell assays were …used to assess cell migration and invasion abilities of breast cancer cells. RESULTS: The expression of miR-383-5p was significantly downregulated in breast cancer tissues and cell lines, compared with that in normal tissues and normal epithelial MCF-10A cells, respectively. The expression of miR-383-5p was associated with differentiation, lymph node metastasis, and TNM stage. Patients with low miR-383-5p expression had shorter overall survival than those with high miR-383-5p expression. Overexpression of miR-383-5p significantly inhibited cell proliferation, migration, and invasion, while downregulation of miR-383-5p promoted cell proliferation, migration, and invasion in vitro . LDHA was a direct target of miR-383-5p. CONCLUSIONS: Taken together, miR-383-5p was downregulated in breast cancer tissues and cell lines, and overexpression of miR-383-5p inhibited cell proliferation, migration, and invasion in breast cancer cells by targeting LDHA. Based on our findings, miR-383-5p may be a prognostic biomarker and therapeutic target for breast cancer. Show more

Keywords: miR-383-5p, breast cancer, prognosis, proliferation, migration, invasion

DOI: 10.3233/CBM-190704

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 423-432, 2020

Authors: Lei, Ren | Feng, Liuchun | Hong, Deng

Article Type: Research Article

Abstract: Faced with the increasing colorectal cancer (CRC) cases, the interrogation of pivotal molecules in CRC appears to be vitally important. Long non-coding RNAs (lncRNAs) are well-known regulators of gene expression at transcriptional, post-transcriptional or epigenetic level, among which the competing endogenous RNA (ceRNA) network is a common way that lncRNAs exert their properties. The current study aimed to provide a new insight into improving the outcomes of CRC patients. Our study detected that ELFN1-AS1 expression was elevated in CRC tissues and cells, and ELFN1-AS1 upregulation was correlated with poor prognosis of CRC sufferers. Besides, it was viewed that …ELFN1-AS1 knockdown impeded the proliferation and migration abilities as well as activated the apoptosis ability of CRC cells. In subsequence, mechanism assays also displayed that ELFN1-AS1 targeted miR-4644 to augment TRIM44 level. Finally, rescue experiments confirmed that TRIM44 took part in the ELFN1-AS1 -medatied promotional influences on CRC cells proliferation and migration. In conclusion, ELFN1-AS1 exerted pro-proliferation, anti-apoptosis and pro-migration functions on CRC cells by acting as a sponge of miR-4644 to increase TRIM44 expression at mRNA and protein level, providing an additional molecule responsible for the carcinogenesis and progression for CRC. Show more

Keywords: Colorectal cancer (CRC), ELFN1-AS1, miR-4644, TRIM44

DOI: 10.3233/CBM-190559

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 433-443, 2020

Authors: Yang, Chuanjia | Xu, Weixue | Gong, Jian | Liu, Zhen | Cui, Dongxu

Article Type: Research Article

Abstract: To characterize the somatic alterations of papillary thyroid carcinomas (PTC) in Chinese patients, we performed the next-generation-sequencing (NGS) study of the tumor-normal pairs of DNA and RNA samples extracted from 16 Chinese PTC patients. The whole genome sequencing (WGS) and transcriptome sequencing (RNA-seq) were conducted for 6 patients who were either current or former smokers and the whole exome sequencing (WES) and RNA-seq were conducted for another 10 patients who were never smokers. The NGS data were analyzed to identify somatic alteration events that may underlie PTC in Chinese patients. We identified a number of PTC driver genes harboring somatic …driver mutations with significant functional impact such as COL11A1, TP53, PLXNA4, UBA1, AHNAK, CSMD2 and TTLL5 etc. Significant driver pathways underlying PTC were found, namely, the metabolic pathway, the pathway in cancer, the olfactory transduction pathway and the calcium signaling pathway. In addition, this study revealed genes with significant somatic copy number aberrations and corresponding somatic gene expression changes in PTC tumors, the most promising ones being BRD9, TRIP13, FZD3, and TFDP1 etc. We also identified several structural variants of PTCs, especially the novel in-frame fusion proteins such as TRNAU1AP-RCC1, RAB3GAP1-R3HDM1, and ENAH-ZSWIM5. Our study provided a list of novel PTC candidate genes with somatic alterations that may function as biomarkers for PTC in Chinese patients. The follow-up mechanism studies may be conducted based on the findings from this study. Show more

Keywords: Papillary thyroid carcinoma (PTC), whole genome sequencing, transcriptome sequencing, somatic alteration

DOI: 10.3233/CBM-191200

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 445-460, 2020

Authors: Wu, Jiao | Li, Yi-Tian | Tian, Xiao-Ting | Liu, Yu-Si | Wu, Mo-Li | Li, Pei-Nan | Liu, Jia

Article Type: Research Article

Abstract: BACKGROUNDS: Anaplastic thyroid cancer/ATC is highly lethal malignancy without reliable chemotherapeutic drug. Resveratrol possesses anti-ATC activities but encounters resistance in some cases due to certain unknown reason(s). OBJECTIVE: Because signal transducer and activator of transcription/STAT3 signaling is critical for ATC cell survival and the main molecular target of resveratrol, its roles in determining the fates of resveratrol-treated ATC cells were investigated here. METHODS: Human THJ-11T, THJ-16 and THJ-21T ATC cell lines were treated by 100 μ M resveratrol and their growth, statuses of STAT3 signaling and STAT3-related gene expression were examined. …The relevance of STAT3 activation with resveratrol resistance was elucidated using STAT selective inhibitor AG490. Leukemia inhibitory factor/LIF expression and phosphorylated-STAT3/p-STAT3 nuclear translocation in ATC tissues were immunohistochemically analyzed. RESULTS: Resveratrol inhibited proliferation, p-STAT3 nuclear translocation as well as LIF and STAT3 expression of THJ-16T and THJ-21T but not THJ-21T cells which showed LIF upregulation and more frequent p-STAT3 nuclear translocation. AG490 significantly prevent p-STAT3 nuclear translocation, and reversed the resveratrol tolerance of THJ-11T cells. Immonohistochemical staining revealed 14.3% (4/28) of LIF and 3.6% (1/28) of p-STAT3 detection in noncancerous ATC-surrounding tissues, which increased to 89.5% (17/19) and 52.6% (10/19) respectively among ATC specimens. The correlative analysis indicated the relevance of LIF expression and STAT3 activation (r = 0.825; P < 0.01). CONCLUSIONS: The status of STAT3 activation and LIF expression are closely correlated with the therapeutic effect of resveratrol on ATCs. Frequent LIF upregulation and STAT3 activation are the unfavorable factors of ATCs and the potential targets of anti-ATC therapy. Show more

Keywords: Anaplastic thyroid cancer, STAT3 signaling, resveratrol, drug resistance

DOI: 10.3233/CBM-191010

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 461-469, 2020

Authors: Yu, Ting | Gong, Li | Li, Wei | Zuo, Qianfei | Cai, Dongping | Mao, Hui | Wang, Lina | Lin, Jie | Xiao, Bin

Article Type: Research Article

Abstract: BACKGROUND: Gastric cancer is one of the leading causes of death worldwide. MicroRNA-30a (miR-30a) has been demonstrated to be involved in several types of cancer development. OBJECTIVE: We aimed to identify the molecular mechanism of miR-30a in gastric cancer. METHODS: We investigated the expression of miR-30a in gastric cancer tissues by qRT-PCR. The role of miR-30a on the metastasis and proliferation of gastric cancer was evaluated by cell migration assay, CCK-8 assay and tumor peritoneal dissemination model. The target of miR-30a in gastric cancer was identified. RESULTS: We discovered that miR-30a was significantly …downregulated in gastric cancer tissues compared with adjacent nonmalignant tissues. The expression of miR-30a was inversely correlated with progression of gastric cancer. Gain- and loss-of function revealed that miR-30a acted as a potent tumor suppressor in gastric cancer. Re-expressed miR-30a inhibited gastric cancer cells migration, knock down miR-30a have the opposite effects. Furthermore, overexpression of miR-30a suppressed tumor peritoneal dissemination in vivo . We identified that fibroblast activation protein α (FAPα ) was a direct target of miR-30a. The relative expression of FAPα was significantly higher in gastric cancer tissues compared with adjacent nonmalignant tissues. Inhibition of FAPα could recapitulate the effects of miR-30a, and overexpression of FAPα could abrogate the effect of miR-30a. CONCLUSION: MiR-30a inhibited gastric cancer metastasis by targeting FAPα , suggesting that miR-30a may function as a novel tumor suppressor in gastric cancer. Show more

Keywords: microRNA-30a, FAPα, gastric cancer, proliferation, metastasis

DOI: 10.3233/CBM-190314

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 471-484, 2020

Authors: Zhang, Weijia | Su, Xiaoyan | Li, Shuang | Liu, Zhen | Wang, Qian | Zeng, Hai

Article Type: Research Article

Abstract: BACKGROUND: Ovarian cancer (OC) is one of the most common malignancy worldwide. Emerging evidences have demonstrated that microRNAs (miRNAs) play an important role in regulating the initiation and development of OC. OBJECTIVE: The present study was to explore the clinical significance of serum exosomal miR-484 in OC. METHODS: A total of 113 OC patients and 60 healthy volunteers were enrolled in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure serum exosomal miR-484 levels in blood samples. RESULTS: Our results showed that serum exosomal miR-484 levels were …significantly lower in OC patients. Serum exosomal miR-484 was able to discriminate OC cases from controls, with an area under the receiver-operating characteristics (ROC) curve (AUC) of 0.821. Combination of serum exosomal miR-484 with CA-125 showed an elevated AUC of 0.912 in identifying OC patients from controls. Moreover, decreased serum exosomal miR-484 expression was significantly associated with aggressive clinical variables as well as shorter overall survival and progression-free survival. The OC patients with simultaneously low serum exosomal miR-484 expression and high serum CA-125 levels tended to suffer the worst clinical outcomes. The multivariate analysis confirmed that low serum exosomal miR-484 level was an independent indicator. CONCLUSIONS: Collectively, serum exosomal miR-484 could serve as a reliable and non-invasive marker for predicting the prognosis of OC. Show more

Keywords: Ovarian cancer, miR-484, serum exosomes, biomarker, prognosis

DOI: 10.3233/CBM-191123

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 485-491, 2020

Authors: Cai, Xianguo | Zhang, Xianjun | Mo, Licai | Zhu, Jialiang | Yu, Hongyuan

Article Type: Research Article

Abstract: Long non-coding RNAs (lncRNAs) are implicated in the development of carcinomas, containing renal carcinoma. The competing endogenous RNA (ceRNA) network is well-known in modulating the pathological and physiological processes of tumors. Still and all, the function role of oncogenic lncRNA PCGEM1 prostate-specific transcript (PCGEM1) in renal carcinoma was undefined till now. This paper aimed to figure out the role and mechanism of PCGEM1 in renal carcinoma. In this study, PCGEM1 was observed to be lifted in renal carcinoma cells. Loss-of-function experiments displayed that silencing of PCGEM1 repressed cell proliferation and migration, and activated apoptosis in renal carcinoma. FISH assay and …subcellular fractionation assay indicated that PCGEM1 was largely located in the cytoplasm. As demonstrated, PCGEM1 interacted with microRNA433-3p (miR-433-3p). Subsequently, luciferase reporter and RIP experiments together with qRT-PCR certified that PCGEM1 and fibroblast growth factor 2 (FGF2) functioned as ceRNA for miR-433-3p, leading to the upregulation of FGF2 expression. Finally, rescue assays exhibited that FGF2 overexpression rescued the inhibited cell progression caused by PCGEM1 downregulation. MiR-433-3p inhibitor could reverse the cell growth and migration caused by PCGEM1 downregulation. The present research investigated the molecular mechanism underlying PCGEM1 in renal carcinoma, exposing a PCGEM1-mediated therapy for the treatment of patients with renal carcinoma. Show more

Keywords: Renal carcinoma, ceRNA, PCGEM1, FGF2, miR-433-3p

DOI: 10.3233/CBM-190669

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 493-504, 2020

Authors: Kong, Junjie | Shen, Shu | Zhang, Zifei | Wang, Wentao

Article Type: Research Article

Abstract: BACKGROUND: Cholangiocarcinoma (CCA) is the most common biliary malignancy worldwide. However, the molecular mechanisms of its tumorigenesis and progression are still largely unclear. OBJECTIVE: This study aimed to explore the hub genes and pathways associated with CCA prognosis by coexpression analysis. METHODS: A coexpression network complex was constructed using the top 20% most variant genes in the GSE89748 dataset to find modules associated with prognosis related clinical trait-histology. The hub genes in the clinically significant modules were defined as candidates if they were common in both the coexpression network and protein-protein interaction (PPI) network. …Afterwards, survival analysis, expression level analysis and a series of bioinformatic analysis were used to validate the hub genes. RESULTS: Twenty-five modules were obtained, and the cyan, light cyan and red modules regarded as closely associated with histology were selected. Subsequently, combining the PPI network complexes and coexpression networks, we screened 20 candidates. After expression and survival analysis, 10 real hub genes (LIMA1, HDAC1, ITGA3, ACTR3, GSK3B, ITGA2, THOC2, PTGES3, HEATR1 and ILF2) were finally identified. Additionally, functional enrichment analysis revealed that the hub genes were mainly enriched in cell cycle-related pathways. CONCLUSIONS: Overall, this study identified 10 hub genes and cell cycle-related pathways were closely related to CCA development, progression and prognosis, which may contribute to CCA diagnosis and treatment. Show more

Keywords: Cholangiocarcinoma, bioinformatics analysis, weighted gene coexpression network analysis (WGCNA), prognosis

DOI: 10.3233/CBM-190038

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 505-517, 2020

Authors: Deng, Mingming | Zhang, Zhe | Liu, Bofang | Lv, Qingjie | Hou, Kezuo | Che, Xiaofang | Qu, Xiujuan | Liu, Yunpeng | Zhang, Ye | Hu, Xuejun

Article Type: Research Article

Abstract: BACKGROUND: Occludin/ELL domain containing 1 (OCEL1) is a novel discovered protein with its molecular functions remaining unknown and its role in lung cancer has not been directly explored. OBJECTIVES: This study focused on the role of OCEL1 in the progression and prognosis of non-small cell lung cancer (NSCLC). METHODS: A public database and tissue samples (80 NSCLC tissue samples and paired normal lung samples) were used to compare differences in OCEL1 expression and investigate its relationship with clinical characteristics and prognosis. RESULTS: Compared to adjacent normal lung tissue samples, OCEL1 …expression was significantly down-regulated in tumor tissues. In addition, there was a negative correlation between OCEL1 and Ki67 expression levels. Low OCEL1 expression was significantly associated with lymph node metastasis, higher TNM stage, and poor prognosis. Importantly, multivariate analysis identified OCEL1 expression as an independent predictor for unfavorable NSCLC prognosis. CONCLUSIONS: These results indicated that OCEL1 protein may serve as a novel prognostic biomarker in NSCLC. Show more

Keywords: OCEL1, NSCLC, prognosis, immunohistochemistry

DOI: 10.3233/CBM-191268

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 519-524, 2020

Authors: Geng, Hua | Li, Shixiong | Guo, Yixian | Yan, Fang | Han, Yuebin | Xu, Meilin | Cui, Yanzhi

Article Type: Research Article

Abstract: BACKGROUND: Lung adenocarcinoma is the most common type of lung cancer, and it is one of the most aggressive and rapidly fatal tumor types. OBJECTIVE: To identify a signature mutation genes for prognostic prediction of lung adenocarcinoma. METHODS: Four hundred and sixty-two lung adenocarcinoma cases were screened out and downloaded from TCGA database. Mutation data of 18 targeted genes were detected by MuTect. LASSO-COX model was used to screen gene loci, and then a prognosis model was established. Afterwards, 40 clinical patients of lung adenocarcinoma were collected to verify the mutation features and …the predictive function of the above prognostic model. The mutations of above 18 genes were sequenced with targeted next generation sequencing (NGS) and analyzed with GATK and MuTect. RESULTS: TP53 (282, 32.38%), NF1 (82, 9.41%) and EGFR (80, 9.18%) were the top 3 most frequent mutation genes. A total of 7 variables were screened out after lasso-COX analysis (tumor stage, age, diagnostic type, SMARCA4, GNAS, PTCH2, TSC2). SMARCA4 , GNAS and TSC2 were a gene mutation signature to predict a poor prognosis. CONCLUSIONS: We established a prognostic model for lung adenocarcinoma, and further concluded that SMARCA4 , GNAS and TSC2 were a gene signature which plays a prognostic role. Show more

Keywords: Lung adenocarcinoma, gene mutation signature, prognosis, a risk model

DOI: 10.3233/CBM-191204

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 525-532, 2020

Authors: Zhou, Wei | Chang, Aoshuang | Zhao, Houyu | Ye, Huiping | Li, Dairong | Zhuo, Xianlu

Article Type: Research Article

Abstract: BACKGROUND: Metastasis often leads to poor prognosis in nasopharyngeal carcinoma (NPC) patients. Evidence has indicated the important roles of microRNA (miRNA) in cancer metastasis. The aim of this study was to identify and verify the key miRNAs that might be involved in the development of NPC metastasis. METHODS: Microarray data were obtained and analyzed to screen the differentially expressed miRNAs (DEMs) between NPC tissues with metastasis and those without metastasis. The target genes of the DEMs were predicted and their functions were annotated. Then, candidate hub genes were screened out through protein-protein interaction analysis, and the …key miRNAs were identified. Afterwards, the expression levels of the key miRNAs were assessed by qRT-PCR based on an in vitro model. RESULTS: A total of 22 DEMs were screened out, and 616 target genes were predicted. Gene Ontology (GO) and pathway enrichment analysis showed that the target genes may be enriched in a diversity of GO terms and signaling pathways. Among them, eleven hub genes were identified, such as PTEN, KAT2B, CCND1, STAT3, and MAP3K5. Moreover, a five-miRNA profile (miR-106b, miR-17, miR-20b, miR-18a and miR-93) was identified and their expression levels were tested to be up-regulated in high-metastatic NPC cells relative to low-metastatic ones. CONCLUSION: The present study revealed that five miRNAs (miR-106b, miR-17, miR-20b, miR-18a and miR-93) and several hub genes such as PTEN, KAT2B, CCND1, STAT3, and MAP3K5, might play critical roles in the development of NPC metastasis. Future investigations are needed to confirm the results. Show more

Keywords: Nasopharyngeal carcinoma, metastasis, microRNA, microarray, qRT-PCR

DOI: 10.3233/CBM-190601

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 533-539, 2020

Authors: Fu, Tao | Ji, Xin | Bu, Zhaode | Zhang, Ji | Wu, Xiaojiang | Zong, Xianglong | Fan, Biao | Jia, Ziyu | Ji, Jiafu

Article Type: Research Article

Abstract: BACKGROUND: Gastric cancer is the third leading cause of cancer-related deaths worldwide. OBJECTIVE: The present study aims to identify key long non-coding RNAs (lncRNAs) and their potential roles in the pathogenesis of gastric adenocarcinoma. METHODS: The lncRNA and mRNA expression profile between gastric adenocarcinoma and adjacent non-tumor tissues were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between gastric adenocarcinoma and adjacent non-tumor tissues were identified after bioinformatics analysis. DElncRNA-DEmRNA co-expression network and DElncRNA-nearby DEmRNA interaction network were constructed, respectively. Functional annotation for DEmRNAs interacted with DElncRNAs …was performed. Receiver operating characteristic (ROC) analysis of selected DElncRNAs was conducted. RESULTS: Based on TCGA, the mRNA and lncRNA expression profiles of 375 gastric adenocarcinoma and 32 adjacent non-tumor tissues were downloaded. A total of 1502 DEmRNAs and 928 DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues were identified. HOXC-AS3 might involve with gastric adenocarcinoma by regulating a set of HOX genes (HOXC8, HOXC9, HOXC10, HOXC11, HOXC12 and HOXC13) with cis-effect. AC115619.1-APOA4/APOB and AP006216.2-APOA1/APOA4 integrations might play roles in gastric adenocarcinoma through regulating pathways of Fat digestion and absorption and Vitamin digestion and absorption. Six lncRNAs including (HOTAIR, C20orf166-AS1, PGM5-AS1, HOXC-AS3, HOXC-AS2 and AC012531.1) have excellent diagnostic value for gastric adenocarcinoma. CONCLUSIONS: This study identifies key lncRNAs in gastric adenocarcinoma which provides clues for exploring the pathogenesis and developing potential biomarkers for gastric adenocarcinoma. Show more

Keywords: Gastric adenocarcinoma, The Cancer Genome Atlas (TCGA), long non-coding RNAs (lncRNAs), mRNA, biomarker

DOI: 10.3233/CBM-192389

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 541-553, 2020

Authors: Pirim, Dilek

Article Type: Research Article

Abstract: BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths and mining the molecular factors underlying CRC pathogenesis is imperative for alleviating the disease burden. OBJECTIVE: To highlight key molecular pathways, prioritize hub genes and their regulators related to CRC. METHODS: Data sets of TCGA-COAD and GTEx were used to identify differentially expressed genes (DEGs) and their functional enrichments in pathways and biological processes were analyzed using bioinformatics tools. Protein-protein interaction network was constructed and hub genes were identified using Cytoscape. Ingenuity Pathway Analysis was used to analyze the relations …of the hub genes with diseases and canonical pathways. Key regulators targeting the hub genes such as TFs, miRNAs and their interactions were identified using in silico tools. RESULTS: AURKA , CDK1 , MYC , CDH1 , CCNB1 , CDC20 , UBE2C , PLK1 , KIF11 , and CCNA2 were prioritized as hub genes based on their topological properties. Enrichment analyses emphasized the roles of DEGs and hub genes in the cell cycle process. Interactions of the hub genes with TFs and miRNAs suggested TP53, EZH2 and KLF4 as being promising candidate biomarkers for CRC. CONCLUSIONS: Our results provide in silico evidence for candidate biomolecules that may have strong biomarker potential for CRC-related translational strategies. Show more

Keywords: Colorectal cancer, microRNA, transcription factors, in silico tools, bioinformatics, Ingenuity Pathway Analysis

DOI: 10.3233/CBM-191263

Citation: Cancer Biomarkers, vol. 27, no. 4, pp. 555-568, 2020