Cancer Biomarkers - Volume 26, issue 3

Authors: Huang, Ge | Huang, Qing | Xie, Zilu | Zhou, Huihui | Cao, Jiangbo | Shi, Long | Yang, Mingwei

Article Type: Research Article

Abstract: BACKGROUND: Lung squamous cell carcinoma (LUSC) is malignant disease with poor therapeutic response and unfavourable prognosis. OBJECTIVE: This study aims to develop a long non-coding RNA (lncRNA) signature for survival prediction in patients with LUSC. METHODS: We obtained lncRNA expression profiles of 493 LUSC cases from The Cancer Genome Atlas, and randomly divided the samples into a training set (n = 296) and a testing set (n = 197). Univariate Cox regression and random survival forest algorithm were performed to select optimum survival-related …lncRNAs. RESULTS: A lncRNA-focused risk score model was then constructed for prognosis prediction in the training set and further validated in the testing set and the entire set. Finally, bioinformatics analysis was carried out to explore the potential signaling pathways associated with the prognostic lncRNAs. A set of 9 lncRNAs were found to be strongly correlated with overall survival of LUSC patients. These 9 lncRNAs were integrated into a prognostic signature, which could separate patients into high- and low-risk groups with significantly different survival times in the training set (median: 30.5 vs. 80.5 months, log-rank P < 0.001). This signature was also confirmed in the testing set and the entire set. Besides, the prognostic value of the 9-lncRNA signature was independent of clinical features and maintained stable in stratified analyses. Functional enrichment study suggested that the 9 lncRNAs may be mainly involved in metabolism-related pathways, phosphatidylinositol signaling system, p53 signaling pathway, and notch signaling pathway. CONCLUSIONS: Our study demonstrated the potential clinical implication of the 9-lncRNA signature for survival prediction of LUSC patients. Show more

Keywords: Biomarker, long non-coding RNA, lung squamous cell carcinoma, prognosis

DOI: 10.3233/CBM-182275

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 239-247, 2019

Authors: Ye, Tianyi | Yao, Hongwen | Xu, Yang | Zhao, Xiaohang | Lu, Haizhen | Zhang, Rong

Article Type: Research Article

Abstract: Neoadjuvant chemotherapy (NACT) followed by radical surgical hysterectomy and pelvic lymph node dissection is considered an effective method to treat patients with bulky stage IB–IIA cervical cancer, but not all patients benefit from NACT. Apoptotic proteins play important roles in the progression of chemotherapy, and second mitochondria-derived activator of caspase (Smac) may have a cooperative relationship with Omi/HtrA2, leading to carcinogenesis and chemotherapy resistance. Chemosensitivity is an important prognostic factor for cervical cancer patients. The aim of this study was to evaluate the significance of Smac, survivin, X-linked inhibitor-of-apoptosis protein (XIAP), and Omi/HtrA2 expression in predicting the response to neoadjuvant …chemotherapy and the prognostic significance of te expression of these proteins in cervical cancer patients. Our findings showed that low expression levels of survivin and high expression levels of Omi/HtrA2 in chemotherapy-responsive cervical carcinoma patients significantly increased chemosensitivity. Show more

Keywords: Cervical carcinoma, chemosensitivity, apoptotic proteins, IHC

DOI: 10.3233/CBM-182165

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 249-259, 2019

Authors: Feng, Fan | Zhang, Dongjing | Han, Fangkai | Zhang, Xingtao | Duan, Tengfei | Zhang, Xiuwen

Article Type: Research Article

Abstract: The triple negative breast cancer (TNBC) accounts for 15% to 20% of the total number of breast cancer diagnosed. A number of clinical studies have shown that TNBC has a high risk of early recurrence and distant metastasis, and a low rate of disease free survival and total survival. The premise of TNBC deterioration was abnormal proliferation and migration of tumor cells, and this study firstly showed that GATS gene could promote proliferation of MDA-MB-231 breast cancer cells. Through lentiviral expression system, the GATS gene was konckdown by shGATS lentivirus infection in the MDA-MB-231 cells, and the …result indicated it could remarkably decrease the ability of cell proliferation and migration. Real-time PCR, western blot and immunofluorescence experiments showed the expressions of protein LC3, and p-Akt in shGATS cell group were lower than the shCtrl group. Therefore, we suggest the GATS could promote the MDA-MB-231 cell proliferation, migration and clonogenicity through cell autophagy by the PI3K/Akt pathway, which paved the way for further study the function of GATS in TNBC, and GATS may potentially be a target for gene therapy against triple negative breast cancer. Show more

Keywords: Triple negative breast cancer, cell proliferation, autophagy, PI3K/Akt signal pathway

DOI: 10.3233/CBM-181681

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 261-269, 2019

Authors: Salvianti, Francesca | Massi, Daniela | De Giorgi, Vincenzo | Gori, Alessia | Pazzagli, Mario | Pinzani, Pamela

Article Type: Research Article

Abstract: BACKGROUND: Circulating tumor cells (CTCs) and circulating cell free DNA (ccfDNA) represent a liquid biopsy of a tumor allowing real time disease monitoring especially in advanced stages of cancer, but their analysis is technically challenging. OBJECTIVE: We aimed to demonstrate the feasibility of two different technical approaches to detect the BRAFV600E mutation in the liquid biopsy of 20 metastatic melanoma patients by using both the enriched CTC fraction and circulating ccfDNA from the same blood sample. METHODS: We detected CTCs by a filtration method in 20 metastatic melanoma patients and detected the BRAFV600E …variant on CTCs and ccfDNA by an allele-specific qPCR assay; the mutated samples were confirmed by ICE-COLD PCR followed by Sanger sequencing. RESULTS: We found CTCs in 70% of the samples, and identified the BRAFV600E variant on CTCs. We correlated the results with those obtained on ccfDNA from the same blood draw. We found some discordant results between CTCs and ccfDNA. CONCLUSIONS: Our results underline the importance of investigating both CTCs and ccfDNA in a liquid biopsy approach to melanoma patients. Show more

Keywords: Liquid biopsy, BRAFV600E mutation, melanoma, circulating tumor cells (CTCs), circulating cell-free DNA (ccfDNA)

DOI: 10.3233/CBM-181647

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 271-279, 2019

Authors: Liu, Anwei | Xue, Yongping | Liu, Fei | Tan, Haoyuan | Xiong, Qiao | Zeng, Shuxiong | Zhang, Zhensheng | Gao, Xu | Sun, Yinghao | Xu, Chuanliang

Article Type: Research Article

Abstract: BACKGROUND: Urothelial carcinoma of the bladder is a heterogeneous disease for which reliable prognostic molecular biomarkers have not been established. OBJECTIVE: To investigate the prognostic value of tumor-associated trypsin inhibitor (TATI) expression combined with p53 expression in bladder cancer patients who have undergone radical cystectomy. METHODS: Tissue microarrays from 110 patients were analyzed immunohistochemically for TATI and p53 protein expression. Complete clinical-pathological information and follow-up data were collected. Univariable Kaplan-Meier analysis and log-rank test were performed to assess the association between TATI and p53 expression patterns with clinical outcomes. Cox’s proportional hazard analysis …was performed to identify potential independent risk factors for predicting disease progression and evaluate the prognostic value of combining the expression of TATI and p53 on progression-free survival (PFS) and overall survival (OS). RESULTS: TATI expression was positively correlated with favorable differentiation of bladder cancer, and lower tumor stage. p53 expression was positively related to tumor stage, tumor grade, and lymph-node invasion. Univariate Kaplan-Meier analysis revealed significant differences between TATI-positive vs. TATI-negative and p53-positive vs. p53-negative patients, regarding PFS. Multivariate analysis showed that both TATI and p53 expression were independent factors for predicting disease progression. CONCLUSION: TATI expression patterns could enhance the prognostic value of p53 overexpression on progression. Show more

Keywords: Bladder cancer, TATI, p53, progression, prognostic value, combined expression

DOI: 10.3233/CBM-182143

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 281-289, 2019

Authors: Mitchell, Andrew | Hasanali, Sarrah L. | Morera, Daley S. | Baskar, Rohitha | Wang, Xin | Khan, Rahil | Talukder, Asif | Li, Charles S. | Manoharan, Meenakkshy | Jordan, Andre R. | Wang, Jiaojiao | Bollag, Roni J. | Singh, Nagendra | Albo, Daniel | Ghosh, Santu | Lokeshwar, Vinata B.

Article Type: Research Article

Abstract: BACKGROUND: Differential expression of chemokines/chemokine receptors in colorectal cancer (CRC) may enable molecular characterization of patients’ tumors for predicting clinical outcome. OBJECTIVE: To evaluate the prognostic ability of these molecules in a CRC cohort and the CRC TCGA-dataset. METHODS: Chemokine (CXCL-12α , CXCL-12β , IL-17A, CXCL-8, GM-CSF) and chemokine receptor (CXCR-4, CXCR-7) transcripts were analyzed by RT-qPCR in 76 CRC specimens (normal: 27, tumor: 49; clinical cohort). RNA-Seq data was analyzed from the TCGA-dataset (n = 375). Transcript levels were correlated with outcome; analyses: …univariate, multivariable, Kaplan-Meier. RESULTS: In the clinical cohort, chemokine/chemokine receptor levels were elevated 3-10-fold in CRC specimens (P ⩽ 0.004) and were higher in patients who developed metastasis (P = 0.03 – < 0.0001). CXCR-4, CXCR-7, CXCL-12α , CXCL-8, IL-17 and GM-CSF levels predicted metastasis (P ⩽ 0.0421) and/or overall survival (OS; P ⩽ 0.0373). The CXCR-4+ CXCR-7+ CXCL-12 marker (CXCR-4/7+ CXCL-12 (α /b) signature) stratified patients into risk for metastasis (P = 0.0014; OR, 2.72) and OS (P = 0.0442; OR, 2.7); sensitivity: 86.67%, specificity: 97.06%. In the TCGA-dataset, the CXCR-4/7+ CXCL-12 signature predicted metastasis (P = 0.011; OR, 2.72) and OS (P = 0.0006; OR: 4.04). In both datasets, the signature was an independent predictor of clinical outcome. CONCLUSIONS: Results of 451 specimens from both cohorts reveal that the CXCR-4/7+ CXCL-12 signature potentially predicts outcome in CRC patients and may allow earlier intervention. Show more

Keywords: CXCL-12, CXCR-7, CXCR-4, CXCL-8, colorectal cancer

DOI: 10.3233/CBM-190210

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 291-301, 2019

Authors: Wu, You-Jun | Hu, Zi-Long | Hu, Shi-Dong | Li, Yu-Xuan | Xing, Xiao-Wei | Yang, Yu | Du, Xiao-Hui

Article Type: Research Article

Abstract: Glutamate dehydrogenase (GDH) is a key enzyme in glutaminolysis and can regulate allosteric functions. Immunohistochemical study found that GDH expressed in gastric cancer cell cytoplasm and membrane, and a few located in the nucleus, ranging from light yellow to tan to sepia. According to the analysis by Kaplan Meier survival curve and the Log-Rank test, the median survival of GDH high expression in patients was 51.7 months with 95% confidence intervals (CI) was 41.138–55.262. The expression level of GDH was significantly reduced after silencing GDH gene in gastric cancer cells and tissues. Further, after silencing GDH gene, gastric cancer cell …migration and invasion ability were decreased significantly. Protein expression of. In addition, tumor growth was significantly reduced after silencing GDH gene. In vivo and in vitro experiments suggest that GDH can decrease gastric cancer cell migration and invasion, thus inhibiting tumor growth. Show more

Keywords: Glutamate dehydrogenase, notch signaling pathways, gastric cancer cell, invasion, migration

DOI: 10.3233/CBM-190022

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 303-312, 2019

Authors: Huang, Kaibin | Qu, Hongyue | Zhang, Xiaoni | Huang, Tanxiao | Sun, Xiao | He, Wan | Li, Mingwei | Lin, Liewen | Xu, Mingyan | Chen, Shifu | Xia, Ligang

Article Type: Research Article

Abstract: BACKGROUND: Circulating tumor DNA (ctDNA) has been recognized as a promising biomarker for colorectal cancer (CRC) early diagnosis and postoperative monitoring. However, we hypothesize that the clinical value of ctDNA sequencing may differ for colon cancer (CC) and rectal cancer (RC). METHODS: Forty-three patients with primary CRC were prospectively enrolled. Tumor tissue samples, paired preoperative plasma samples and a series of postoperative plasma samples were obtained. Mutations in each sample were identified and compared. RESULTS: For 73.0% patients, at least one concordant mutation was detected in both tumor tissue DNA and paired preoperative …ctDNA. The mutation concordance rate were higher in CC patients compared to RC patients (92.3% vs 45.5%; p = 0.004). For early stage patients, the mutation concordance rate was 72.7%. The recurrence rate was 33.3% for patients with postoperative ctDNA positive mutations, and 3.4% for patients with negative ctDNA (HR 10.767; 95% CI 1.1–103.8; p = 0.040). CONCLUSION: Liquid biopsy via ctDNA sequencing has great potential for the early detection and postoperative monitoring of CRC. The DNA of CC tissues is more likely to be released into blood than the DNA of RC tissues. This should be considered when diagnosing CRC patients with ctDNA sequencing technology. Show more

Keywords: Circulating tumor DNA, colorectal cancer, early diagnosis, predicting recurrence, next generation sequencing

DOI: 10.3233/CBM-190257

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 313-322, 2019

Authors: Li, Juncheng | Zou, Xiaoming

Article Type: Research Article

Abstract: PURPOSE: MicroRNAs (miRNAs) have been reported to be involved in tumorigenesis. The aim of this study was to investigate the functional role and prognostic value of miR-652 in gastric cancer (GC). METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression levels of miR-652 in human GC tissue samples and GC cell lines. The Kaplan-Meier survival curves and Cox regression analysis were performed to measure the prognostic value of miR-652 in GC. The tumor cell proliferation capacity was estimated by MTT assay, and cell migration and invasion were assessed by Transwell assays. The …luciferase reporter assay was performed to confirm the target gene of miR-652. RESULTS: MiR-652 was significantly elevated in GC tissues and cell lines (all P < 0.001). And the expression level of miR-652 was significantly associated with TNM stage and lymph node metastasis (all P < 0.05). GC patients with high expression of miR-652 had a shorter overall survival rate than those with low miR-652 expression (log-rank P < 0.001). The miR-652 and TNM stage were proven to be independent prognostic predictors for the GC patients. Overexpressing miR-652 could enhance cell proliferation, migration and invasion (all P < 0.01). RORA was proved to be the target gene of miR-652. CONCLUSION: MiR-652 functions as an oncogene in GC and promotes tumor progression via targeting RORA. MiR-652 might be a novel predictive marker for the poor prognosis of GC patients. Show more

Keywords: MicroRNA-652, prognosis, progression, gastric cancer

DOI: 10.3233/CBM-190361

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 323-331, 2019

Authors: Paganelli, Alessia | Garbarino, Federico | Toto, Paola | Martino, Giuseppe Di | D’Urbano, Marika | Auriemma, Matteo | Giovanni, Pamela Di | Panarese, Fabrizio | Staniscia, Tommaso | Amerio, Paolo | Paganelli, Roberto

Article Type: Research Article

Abstract: BACKGROUND: To date, serological markers to monitor melanoma progression and response to therapy are lacking. In this context cytokines appear to be promising biomarkers of the disease. OBJECTIVE: To compare cytokine and chemokine levels in melanoma patients and in healthy controls and to assess possible variations according to melanoma stage. METHODS: Serum chemokine and cytokine levels were determined by ELISA in 34 patients diagnosed histologically of malignant melanoma. Seven healthy volunteers were used as controls. RESULTS: We found a subset of cytokines (CCL3, CCL4, IFN-γ and IL-10) …to be significantly higher in melanoma patients than in control group, thus confirming the importance of the inflammation in cancer. While CCL3 increased with tumor progression, IFN-γ and IL-10 showed higher levels in stage I patients. Moreover, we noticed a direct correlation between CCL3 level and the presence of ulceration in the primary tumor; on the contrary, CCL4, IL-10 and IFN-γ were lowered down in patients with ulcerated melanoma. CONCLUSIONS: These results expand and confirm observations made in other studies focusing on a more limited number of molecules. This extended panel of cytokines examines the potential roles of type2 cytokines (such as IL-4) and many chemokines (mainly CCL3) as biomarkers in melanoma progression. Show more

Keywords: Cytokines, chemokines, melanoma, biomarkers, cancer immunology

DOI: 10.3233/CBM-190370

Citation: Cancer Biomarkers, vol. 26, no. 3, pp. 333-342, 2019