Cancer Biomarkers - Volume 26, issue 1

Authors: Ma, Chuanyu | Miao, Chuanna | Wang, Chenghong | Song, Fuli | Luo, Minglei

Article Type: Research Article

Abstract: BACKGROUD: Gastric cancer (GC) is one of the leading causes of cancer-related death in East Asia and some South American countries, but its mechanism has not been clarified clearly. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1), a co-regulatory molecule of estrogen receptor α (ER α ), is up-regulated in series of cancers such as endometrial carcinoma, ovarian cancer, colorectal cancer, breast cancer, and non-small cell lung cancer. However, PELP1’s role in GC is still obscure, and its aberrant expression in cancers also remains to be explained. METHODS: Immunohistochemical staining and Real-time …PCR were used to compare the expression level of PELP1 in GC tissues and adjacent tissues. Western blot was used to detect the expression of PELP1 in cell lines. Kaplan-meier analysis and chi-square test were applied to evaluate the potential of PELP1 to function as a cancer biomarker. RNA interference was used to inhibit PELP1 expression in GC cells, followed by detecting cell proliferation, apoptosis, migration and invasion. Luciferase assay was conducted to validate whether miR-15 family members can directly target PELP1. RESULTS: In this study, we validated that PELP1 was significantly up-regulated in GC samples and cell lines. It was also demonstrated that the up-regulation of PELP1 was associated with several clinicopathologic features such as tumor diameter (P < 0.001), serum CEA level (P = 0.034), and lymphatic metastasis (P = 0.0009) of GC patients, and its high expression was correlated with shorter disease-free survival and overall survival of the patients. Knockdown of PELP1 remarkably arrested the proliferation， migration and invasion, while promoted apoptosis. We also confirmed that miR-15 family microRNAs, most of which were down-regulated and tumor suppressor in cancers, were posttranscriptional regulators of PELP1. CONCLUSION: In conclusion, we demonstrated that PELP1 was an oncogene of GC associated with patients’ prognosis and miR-15 family members contributed to its aberrant expression in cancers. Show more

Keywords: PELP1, gastric cancer, prognosis, miR-15 family

DOI: 10.3233/CBM-182279

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 1-9, 2019

Authors: Wang, Shan | Li, Fang | Fan, Haixia | Xu, Jiankai | Hu, Zheng

Article Type: Research Article

Abstract: PIWIL2 is a human Argonaute protein, which is guided by small RNAs to its targets, plays a role in germ cell maintenance and has been proposed to be expressed in precancerous stem cells and tumor stem cells. However, the significance of PIWIL2 expression in oral cancer and precancerous lesions has not been investigated. In this study, we analyzed the expression of the stem cell protein PIWIL2 in oral squamous-cell carcinoma (OSCC) and in premalignant oral leukoplakia (OL) with predominant expression in malignant and premalignant tissues. In the evaluated patients, we found that PIWIL2 was associated significantly with OSCC prognosis and …OL. Furthermore, PIWIL2 was found to be expressed in tumor epithelial cells and macrophages in the tumor microenvironment, which are not derived from enlarged lymph nodes. Cytological experiments confirmed that the human squamous cell carcinoma cell line SCC-25, can promote the PIWIL2 and Nanog level in THP-1 cells, which are extensively used to study the modulation of monocytes and macrophages. Our findings showed that PIWIL2 can predict effectively OSCC prognosis and OL with a high risk of OSCC development and substantiate the deduction that cancer stem(-like) cells in oral cancer have the ability to reconstitute the heterogeneity of the bulk tumor and contribute to poor outcome and immunosuppression. Show more

Keywords: PIWIL2, oral cancer, leukoplakia, prognosis, tumor microenvironment

DOI: 10.3233/CBM-182009

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 11-20, 2019

Authors: Wen, Yu | Tan, Xiaoqing | Wu, Xia | Wu, Qin | Qin, Yan | Liang, Miao | Ran, Guangqin | Gu, Huiying | Xie, Rongkai

Article Type: Research Article

Abstract: BACKGROUND: Golgi phosphoprotein 3 (GOLPH3) is a novel oncogene overexpressed in several human cancers, but specific contributions to endometrial carcinoma (EC) have not been examined. The aims of this study were to evaluate the GOLPH3 expression in EC and investigate its functions in EC cell proliferation, migration, and survival. METHODS: The expression levels of GOLPH3 in EC patient samples and EC cell lines (HEC-1A, KLE, RL95-2, and Ishikawa) were examined using qRT-PCR, western blotting and immunohistochemistry. Further, EC cell lines with either ectopic GOLPH3 overexpression or knockdown were established, and the effects on proliferation, apoptosis, invasion, …and migration were investigated in vitro using cell viability and transwell assays and in mice following cell injection. RESULTS: Compared to adjacent non-cancerous tissues, expression of GOLPH3 was significantly upregulated in EC tissues (P < 0.05), and the expression level of GOPLPH3 was related to the grade of the tumor (P < 0.05). The expression of GOLPH3 was also higher in all four EC cell lines than endometrial stromal cells (ESCs) (P < 0.05). Moreover, GOLPH3 expression was greater in EC cell lines with high invasive capacity than in non-invasive EC cells (P < 0.05). Knockdown of GOLPH3 inhibited EC cell proliferation and increased cell apoptosis in vitro . Further, knockdown of GOLPH3 also inhibited EC cell invasion and migration in vitro and in vivo by regulating the epithelial-mesenchymal transition (EMT). Conversely, GOLPH3 overexpression promoted proliferation and migration. CONCLUSIONS: The present study provides evidence that GOLPH3 promotes EMT and metastasis of EC cells and predicts the risk of EC progression, highlighting its potential as a therapeutic target for this malignancy. Show more

Keywords: GOLPH3, endometrial carcinoma, proliferation, invasion, migration, EMT

DOI: 10.3233/CBM-190096

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 21-30, 2019

Authors: Huang, Bo | Tian, Zhan-Fei | Li, Lu-Feng | Fan, Yi | Yin, Hao-Yang | Li, Yan | Mao, Qing | You, Zhong-Lan

Article Type: Research Article

Abstract: BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer and exhibits high morbidity and mortality in the world. We recently identified LHX3 as a preferentially expressed gene with a possible involvement in HCC. OBJECTIVE: To determine the expression, clinical relevance, prognostic significance and functions of LHX3 in HCC. MATERIALS AND METHODS: LHX3 expression was assessed in 190 cancerous and 40 adjacent non-cancerous tissues by PCR, western blot and immunohistochemistry. Associations between LHX3 expression and clinicopathological characteristics of patients were investigated. Correlations between LHX3 expression and overall survival of patients were analyzed by Kaplan-Meier and …Cox-regression methods. Functional roles of LHX3 were evaluated by transwell assays. RESULTS: LHX3 expression is significantly increased in carcinoma tissues, and associated with clinical stage and metastasis of patients. LHX3 expression is much higher in the advanced-stage patients than the early-stage patients, and is sharply increased in metastasic patients. High LHX3 expression is associated with unfavorable overall survival, and is an independent prognostic factor of patients. Moreover, LHX3 is an unfavorable and independent prognostic factor unique to advanced-stage patients. Knockdown expression of LHX3 obviously inhibits tumor cell migration and invasion. CONCLUSION: LHX3 is an advanced-stage prognostic biomarker, and acts as a new potential metastatic oncogene in HCC. Show more

Keywords: LHX3, prognostic biomarker, metastasis, oncogene, hepatocellular carcinoma

DOI: 10.3233/CBM-182257

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 31-39, 2019

Authors: Huang, Enying | Chen, Xiaogang | Yuan, Yuan

Article Type: Research Article

Abstract: OBJECTIVE: This study aimed to explore the correlation of circular RNA itchy E3 ubiquitin protein ligase (circ-ITCH) with pathological features as well as its predictive value on prognosis in prostate cancer patients. METHODS: Three hundred and twenty-four patients with prostate cancer underwent radical prostatectomy were consecutively included in this retrospective study, and patients’ specimens of tumor as well as paired adjacent tissues were collected for detection of circ-ITCH expression. Patients’ baseline characteristics and survival data were obtained from follow-up records, and correlation of circ-ITCH with patients’ pathological features and survival was determined. RESULTS: …Circ-ITCH expression was decreased in tumor tissue compared with paired adjacent tissues (P < 0.001), and it presented with good value in distinguishing tumor tissues from paired adjacent tissues with area under curve (AUC) of 0.812 (95%CI: 0.780–0.845). Circ-ITCH low expression was associated with advanced pathologic T stage (P = 0.002) and high risk of lymph node metastasis (P = 0.047) in prostate cancer patients. As for prognosis, patients with circ-ITCH high expression had longer disease-free survival (DFS) (P < 0.001) and overall survival (OS) (P < 0.001). Additionally, circ-ITCH (high vs. low) independently predicted better survival, while Gleason score (> 7 vs. ⩽ 7) and surgical margin status (positive vs. negative) independently predicted worse survival in prostate patients underwent radical prostatectomy. CONCLUSIONS: Circ-ITCH is downregulated in prostate cancer tissues, and its low expression correlates with advanced pathologic T stage, high lymph mode metastasis risk and poor survival in prostate cancer patients underwent radical prostatectomy. Show more

Keywords: Circ-ITCH, prostate cancer, expression, pathological features, prognosis

DOI: 10.3233/CBM-182111

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 41-50, 2019

Authors: Aryal, Bibek | Yamakuchi, Munekazu | Shimizu, Toshiaki | Kadono, Jun | Furoi, Akira | Gejima, Kentaro | Takenouchi, Kazunori | Komokata, Teruo | Hashiguchi, Teruto | Imoto, Yutaka

Article Type: Research Article

Abstract: BACKGROUND AND AIMS: A striking difference has been observed in structure and functional properties between plasma and platelet von Willebrand factor (VWF). While the existing evidence has revealed a clinical relevance of plasma VWF-Ag in liver regeneration (LR) and different cancers, this study was designed to explore the properties of intra-platelet (IP) and serum VWF-Ag in patients with hepatocellular carcinoma (HCC) undergoing partial hepatectomy. METHODS: A total of 40 patients undergoing partial hepatectomy were prospectively recruited from 3 institutions. VWF-Ag concentrations were evaluated mainly in serum and platelet extracts. Patients were followed-up for postoperative liver dysfunction …and HCC recurrence. RESULTS: We observed a post-resection increase in the concentration of VWF-Ag in serum and platelet. Patients with postoperative liver dysfunction had substantially reduced serum and IP VWF-Ag concentrations. After a 2-year follow-up, patients with higher post-resection serum and IP VWF-Ag concentrations were found to develop early HCC recurrence. Likewise, IP VWF-Ag was able to independently predict post-resection early HCC recurrence. CONCLUSION: This multicenter, prospective, pilot study demonstrates a bivalent property of IP VWF in LR and oncological outcome; low preoperative VWF appeared to have a negative association on post-resection liver dysfunction, whereas, patients with higher post-resection VWF-Ag concentrations were found to have early HCC recurrence. Show more

Keywords: Platelet, von Willebrand Factor, liver regeneration, HCC, HCC recurrence

DOI: 10.3233/CBM-190168

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 51-61, 2019

Authors: Huang, Deshun | Wang, Fuxi | Wu, Wenzhong | Lian, Cuihong | Liu, Enrang

Article Type: Research Article

Abstract: MicroRNAs (miRNAs; miR) have been proven to act as both oncogenes and tumor suppressors. However, the mechanism of action of miR429 in melanoma cells remains to be elusive. The present study aims to explain the functional role and mechanism of miR429 in the pathogenesis of melanoma. In our study, we have demonstrated that has-miRNA429 (miR429) is a tumor suppressor in melanoma cells. Luciferase reporter assays demonstrated that the overexpression of miR429 reduced the transcriptional activity of AKT serine/threonine kinase 1 (AKT1). Furthermore, the results showed that the mRNA and protein expression levels of AKT1 were downregulated in the melanoma cell …lines when miR429 was overexpressed according to qRT-PCR and western bolt, indicating MicroRNA-429 may directly target AKT1 in melanoma. In vivo , overexpression miR-429 could obviously enhance the inhibition effect of tumor size and weight in the nude mice. Taken together, our findings suggest that novel miR429-regulated pathway may serve as new insights into melanoma oncogenesis and metastasis. Show more

Keywords: Melanoma cells, AKT1, miR429

DOI: 10.3233/CBM-190289

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 63-68, 2019

Authors: Zou, Shui-Lan | Chen, Yue-Li | Ge, Zhen-Zhen | Qu, Yan-Yan | Cao, Ying | Kang, Zhi-Xin

Article Type: Research Article

Abstract: Growing evidence have revealed the serum exosomal miRNAs emerged as biomarkers for various cancer types, including colorectal cancer (CRC). Here, we sought to explore the potential clinical significance of serum exosomal miR-150-5p in CRC. A total of 133 CRC patients and 60 healthy volunteers as control group were recruited in this study. Exosomes were isolated from the serum of all the participants. The total RNA was isolated from the exosomes and the serum exosomal miR-150-5p levels were measured by quantitative reverse transcription-polymerase chain reaction. The findings showed that the serum exosomal miR-150-5p levels were significantly reduced in CRC cases compared …with those in the control group. Serum exosomal miR-150-5p levels in post-operative blood samples were greatly upregulated one month after surgical treatment. In addition, decreased serum exosomal miR-150-5p expression was closely correlated with poorly differentiation, positive lymph node metastasis and advanced TNM stage. Moreover, receiver operating characteristic (ROC) curve analysis showed serum exosomal miR-150-5p level had good performance to identify CRC cases from healthy volunteers, and a combination of serum exosomal miR-150-5p and carcinoembryonic antigen (CEA) could improve the diagnostic accuracy with an increased the area under the ROC curve (AUC) value. Furthermore, the survival time of patients with higher serum exosomal miR-150-5p expression was significantly longer than those with lower expression. Serum exosomal miR-150-5p was confirmed as an independent prognostic indicator in CRC. Mechanistically, ZEB1 was identified as a direct downstream target of miR-150-5p. Collectively, serum exosomal miR-150-5p might be a novel noninvasive biomarker for CRC diagnosis and prognosis. Show more

Keywords: Exosomes, miR-150-5p, serum, colorectal cancer, biomarker

DOI: 10.3233/CBM-190156

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 69-77, 2019

Authors: Li, Yi | Zhao, Lily | Zhao, Pei | Liu, Zhenjun

Article Type: Research Article

Abstract: Non-small cell lung cancer (NSCLC) , as the most prevalent type of lung carcinoma with high severity, is of urgent necessity to be investigated for novel therapeutic strategies. Long non-coding RNAs (lncRNAs) are notable for their participation in cancer regulation, and lncRNA long intergenic non-protein coding RNA 641 (LINC00641 ) has been found to have an inhibitory influence on bladder cancer, but its role in NSCLC has not yet been studied. In this research, we launched an investigation into the biological functions and the underlying molecular mechanisms of LINC00641 in NSCLC. At first, downregulation of LINC00641 was …identified in NSCLC cells. Functionally, LINC00641 suppressed cell proliferation and induced cell apoptosis in NSCLC, indicating that LINC00641 exerted tumor-suppressive role in NSCLC. Through mechanism investigation, we determined that LINC00641 acted as a competing endogenous RNA (ceRNA) in NSCLC by sponging miR-424-5p to upregulate phospholipid scramblase (PLSCR4) expression. Further rescue assays indicated that miR-424-5p and PLSCR4 could reverse LINC00641 -mediated cellular processes. Taken together, it is demonstrated in our study that LINC00641 can function as a tumor suppressor in NSCLC via a ceRNA network. Show more

Keywords: LINC00641, miR-424-5p, PLSCR4, NSCLC

DOI: 10.3233/CBM-190142

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 79-91, 2019

Authors: Wang, Yong

Article Type: Research Article

Abstract: OBJECTIVE: The aim of this work was to extensively explore the long non-coding RNA (lncRNA) expression profiles in acute myeloid leukemia (AML) and to propose candidate lncRNAs with predictive value for AML risk. METHODS: The bone marrow mononuclear cell samples from 10 AML patients and 10 age and gender matched controls were obtained and subjected to next-generation RNA sequencing. Then, the top 5 upregulated and top 5 downregulated lncRNAs in AML patients compared with controls were selected for further quantitative polymerase chain reaction (qPCR) validation in 40 AML patients and 40 age and gender matched controls. …The effect of candidate lncRNA RP11-342M1.7 on proliferation and apoptosis in AML cells was further investigated. RESULTS: RNA sequencing observed 216 upregulated and 412 downregulated lncRNAs in AML patients compared with controls. Enrichment analyses exhibited that these differentially expressed lncRNAs were involved in neoplastic signaling pathways such as cAMP and MAPK signaling pathways. In further qPCR validation, lncRNA RP11-342M1.7 and lncRNA CDCA4P3 were upregulated, while lncRNA CES1P1, lncRNA AC008753.6 and lncRNA RP11-573G6.10 were downregulated in AML patients compared with controls. Multivariate logistic regression analysis disclosed that lncRNA RP11-342M1.7, lncRNA CES1P1 and lncRNA AC008753.6 were independent predictive factors for AML risk, and most importantly, the combination of these three lncRNAs was of remarkably good predictive value for AML risk (AUC: 0.901; 95% CI: 0.835–0.966). Besides, lncRNA RP11-342M1.7 was correlated with higher CR while lncRNA AC008753.6 and lncRNA CTD-2562J15.6 were correlated with lower CR. LncRNA RP11-342M1.7 knockdown suppressed cell proliferation by promoting cell apoptosis in AML cells. CONCLUSIONS: This study reveals the comprehensive lncRNAs expression profiles in AML, and proposes candidate lncRNAs that are potential biomarkers for AML risk. Show more

Keywords: AML risk, expression profiles, long non-coding RNA, predictive value, RNA sequencing

DOI: 10.3233/CBM-190215

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 93-108, 2019

Authors: Singh, Preeti | Augustine, Dominic | Rao, Roopa S. | Patil, Shankargouda | Sowmya, Samudrala Venkatesiah | Haragannavar, Vanishri C. | Nambiar, Shwetha

Article Type: Research Article

Abstract: BACKGROUND: The Indian subcontinent has the highest incidence and prevalence of oral squamous cell carcinoma (OSCC). Inflammation and apoptosis are two emerging hall marks of cancer that might play a significant role in tumorigenesis and metastasis. Concurrent expression of proinflammatory cytokine (IL-1β ) and executioner caspase (Caspase-3) in same OSCC tissue samples has not been reported in an Indian population. OBJECTIVES: The present study aimed to evaluate the immunohistochemical expression of IL-1β and Caspase-3 in same OSCC tissue samples with clinicopathological correlation and survival analysis in Indian population. METHODS: …A retrospective study was conducted utilizing 40 formalin fixed paraffin embedded histologically diagnosed cases of OSCC comprising of 20 metastatic OSCC and 20 non-metastatic OSCC. RESULTS: Increased expression of IL-1β and Caspase-3 were observed in metastatic OSCC. Correlation of expression of IL-1β and Caspase-3 with clinicopathological parameters revealed a significant association between these markers and staging, nodal status and site of the lesion. CONCLUSION: Over expression of IL-1β and Caspase-3 was associated with advanced stage and poor survival of the patient. IL-1β overexpression showed significantly lower disease-free survival and disease specific survival as well. Overexpression of IL-1β and Caspase-3 in incisional OSCC biopsies could be considered for predicting metastasis and survival outcome. Show more

Keywords: Caspase-3, Interleukin-1β, mouth neoplasms, biologic behaviour, cumulative survival, survival analysis

DOI: 10.3233/CBM-190149

Citation: Cancer Biomarkers, vol. 26, no. 1, pp. 109-122, 2019