Cancer Biomarkers - Volume 21, issue 3

Authors: Xiao, Hua | Liu, Wen | Zhao, Zhenzhen | Zhang, Yan | Song, Yingying | Luo, Bing

Article Type: Research Article

Abstract: BACKGROUND: Gap junction protein beta 2 gene (GJB2) encodes one of connexins- Connexin 26 (Cx26), which mainly expressed in epithelial cells. Cx26 is usually considered a channel to exchange information between cells, which plays a critical role in tumor cell proliferation. OBJECTIVE: We investigated GJB2 rs2274084 polymorphism in three types of tumors, including nasophoryngeal carcinoma (NPC), gastric cancer (GC) and lymphoma. METHODS: Proteinase K digestion and phenolchloroform purification and QIAamp DNA FFPE tissue kit was used for DNA extraction. The genotype of GJB2 gene rs2274084 was detected through Sequenom MassARRAY SNP technique. The …Chi-square test and Fisher’s exact test were used to compare the differences between two groups. RESULTS: The genotype frequency of GJB2 gene rs2274084 was significantly different between EBV-positive NPC and normal control (P < 0.05). However, for EBV-associated gastric cancer (EBVaGC), EBV-negative gastric cancer (EBVnGC) and lymphoma, no significant differences were found in comparison with the normal control. CONCLUSIONS: The mutation rate of TT genotype was a risk factor to the occurrence of EBV-positive NPC. Show more

Keywords: SNP, GJB2, Connexin 26, EBV, NPC

DOI: 10.3233/CBM-170078

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 499-504, 2018

Authors: Hogendorf, Piotr | Durczyński, Adam | Skulimowski, Aleksander | Kumor, Anna | Poznańska, Grażyna | Strzelczyk, Janusz

Article Type: Research Article

Abstract: BACKGROUND: Pancreatic cancer (PDAC) will have been the second leading cancer-related death in the United States by 2020, according to current estimation. Its late manifestation and the lack of good early detection methods are the cause of extremely low survival rates. Therefore, there is an urgent need to develop highly sensitive and specific marker. GDF-15, a member of TGFbeta family, has recently emerged as a protein playing an important role in carcinogenesis of various neoplasms. OBJECTIVE: Our aim was to assess the potential of GDF-15, IL-17, IL-23 serum concentration, and the panel of PDAC markers in …differentiating pancreatic adenocarcinoma from chronic pancreatitis. METHODS: Sixty-three consecutive patients operated on due to pancreatobiliary lesions were enrolled in this study. Levels of CEA, CA125 and Ca19-9 were assessed using standard laboratory protocols. A sample of serum was collected prior to the surgery via central line. Levels of GDF-15, Il-17, Il-23 were measured using a ELISA kit. After standard pathological examination of specimens obtained on surgery, patients were divided into 2 groups: 42 patients with pancreatic adenocarcinoma and 21 patients with focal chronic pancreatitis. RESULTS: Mean GDF-15 concentration in patients with CP vs PDAC was 2247.95 (± 179.27) vs 7694.58 (± 1878.94) [pg/mL] respectively (p = 0.011). Mean concentration of Il-17, Il-23, Ca19-9, Ca125, Ca15-3, CEA in patients with CP and PDAC was 862.36 (± 30.84) vs 841.83 (± 33.94) p = 0.833; 127.85 (± 5.87) vs 127.51 (± 9.74) p = 0.175; 34.95 (± 23.34) vs 266.62 (±  49.7) p = 0.001; 13.4 (± 1.6) vs 39.27 (± 6.85) p = 0.005; 18.4 (± 1.48) vs 20.2 (± 1.38) p = 0.416; 1.96 (± 0.38) vs 5.93 (± 1.74) p = 0.004 respectively. In order to compare these markers with the routinely used ones, ROC curve was built. CA19-9 with clinically used cut-off point of ⩾ 36 IU/mL has specificity of 90.5% and sensitivity of 57.14%. At the same time GDF-15 with the optimal cut-off point of 2.7 ng/mL has specificity of 76.19% and sensitivity of 73.8%. Although in our research group CA19-9 has an excellent specificity, its usefulness is hampered by its low sensitivity. On the other hand, GDF-15 parameters are well-balanced making it a more useful biomarker of PDAC. CONCLUSIONS: In conclusion, GDF-15 is more accurate than Ca19-9 in differentiating pancreatic mass due to chronic pancreatitis from pancreatic adenocarcinoma. Interleukin 17 and 23 cannot be considered as PDAC biomarkers. GDF-15 concentration in serum should be further investigated in order to assess their usefulness in pancreatic adenocarcinoma diagnosis. Show more

Keywords: Pancreatic cancer, pancreatic adenocarcinoma, focal chronic pancreatitis, cancer biomarker, GDF-15, Il-17, Il-23, Ca19-9, Ca15-3, Ca125, CEA, panel of biomarkers

DOI: 10.3233/CBM-170203

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 505-511, 2018

Authors: Yu, Benxia | Gao, Wei | Zhou, Hui | Miao, Xia | Chang, Yuan | Wang, Liping | Xu, Miao | Ni, Guangzhen

Article Type: Research Article

Abstract: BACKGROUND AND OBJECTIVE: Propofol, an intravenous anesthetic agent, has been found to inhibit growth of breast cancer cells. However, the mechanisms underlying the antitumor are not known. A recent report has found that propofol could significantly downregulate miR-24 expression in the human malignant cancers. In breast cancer cells, overexpression of miR-24 promotes cell proliferation and inhibits cell apoptosis by downregulation of p27. The miR-24 has been reported to be overexpressed in breast cancer and breast cancer cell lines. In the present study, we hypothesized that propofol induces apoptosis of breast cancer cells by miR-24/p27 signal pathway. METHODS: …Breast cancer MDA-MB-435 cells were exposed to propofol (10 μ M) for 6 hr and cell death was assessed using TUNEL staining, Flow cytometry and cleaved caspase-3 expression. microRNA-24 (miR-24) expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). miR-24 was overexpressed using a miR-24 mimic. P27 was knocked down using a small interfering RNA. p27 and cleaved caspase-3 expression was assessed by Western blot. RESULTS: MDA-MB-435 exposed to propofol showed a significant increase in apoptotic cells, followed by the downregulation of miR-24, upregulation of p27 expression and cleaved caspase-3 expression. Targeting p27 inhibits propofol-induced cell apoptosis; miR-24 overexpression decreased propofol-induced cell apoptosis, cleaved caspase-3 and p27 expression. CONCLUSIONS: Propofol induces cell death in MDA-MB-435 cells via inactivation of miR-24/p27 signal pathway. Show more

Keywords: Propofol, breast cancer, miR-24, p27

DOI: 10.3233/CBM-170234

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 513-519, 2018

Authors: Li, Qicai | Song, Shirong | Ni, Guangzhen | Li, Yu | Wang, Xiaohui

Article Type: Research Article

Abstract: OBJECTIVE: Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of osteosarcoma (OS); Previous study has reported that miR-542-3p was significantly upregulated in osteosarcoma tissues and miR-542-3p may be as an oncogene in osteosarcoma pathogenesis. In our study, we investigated the circulating miR-542-3p and its clinical relevance in osteosarcoma. METHODS: Serum MiR-542-3p levels were determined by quantitative real-time PCR assays (qRT-PCR) in 76 patients with OS and 76 healthy volunteers. Patient survival analyses were …performed by Kaplan-Meier analyses and Cox regression models. All statistical tests were two-sided. RESULTS: It was observed that the serum levels of miR-542-3p was significantly higher in patients with OS compared with the control groups (P < 0.01). High serum of miR-542-3p was significantly associated with advanced tumor stage and shorter survival (P < 0.01). ROC curve analysis calculated the ideal miR-542-3p cut-off value of 0.84 in prediction of OS, with a sensitivity of 53.8%, specificity of 93.6%, positive predictive value of 87.3% and negative predictive value of 63.7%. CONCLUSIONS: The results showed that serum miR-542-3p levels could serve as a non-invasive blood biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients. Show more

Keywords: Osteosarcoma, biomarker, prognosis, miR-542-3p

DOI: 10.3233/CBM-170255

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 521-526, 2018

Authors: Bao, Jie | Zhou, Chenjie | Zhang, Jiaqing | Mo, Jiaqiang | Ye, Qing | He, Junming | Diao, Jingfang

Article Type: Research Article

Abstract: BACKGROUND: The long non-coding RNA FOXD2-AS1 is highly expressed in non-small cell lung cancer and promotes malignant progression. However, the role of FOXD2-AS1 in esophageal squamous cell carcinoma (ESCC) is still unclear. OBJECTIVE: In this study, we examined the relationships between the expression level of FOXD2-AS1 and the outcome of ESCC patients. METHODS: Expression of FOXD2-AS1 was evaluated in cancer tissue and adjacent non-tumor tissue samples from 147 ESCC patients who received radical surgical resection using qRT-PCR. The correlations between the expression level of FOXD2-AS1 and patients’ overall (OS) and disease free survival …(DFS) were analyzed. RESULTS: FOXD2-AS1 expression was upregulated in ESCC tissue than that in adjacent non-tumor tissue samples (P < 0.001). Kaplan-Meier analysis showed that high FOXD2-AS1 expression was correlated with poor prognosis in ESCC patients. Patients with a high level of FOXD2-AS1 had a shorter OS and DFS than those with a low level of FOXD2-AS1 (P = 0.005 and 0.0001, respectively). On multivariate analysis, the hazard ratio of FOXD2-AS1 expression was 1.66 (95% CI = 1.04–2.64, P = 0.033) for OS and 2.68 (95% CI = 1.49–4.82, P = 0.001) for DFS. CONCLUSIONS: Overall, our results provided convinced evidence that FOXD2-AS1 may serve as a predictive marker for ESCC patients’ survival. Show more

Keywords: Long non-coding RNA, FOXD2-AS1, survival, esophageal squamous cell carcinoma

DOI: 10.3233/CBM-170260

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 527-533, 2018

Authors: Xiong, Jie | Xiong, Ke | Bing, Zhitong

Article Type: Research Article

Abstract: BACKGROUND: Accumulating evidence shows that clinical factors alone are not adequate for predicting the survival of patients with urothelial bladder cancer (UBC), and many genes have been found to be associated with UBC prognosis. PURPOSE: The objective of this study is to develop a signature which integrates clinical and molecular information to predict the overall survival of UBC patients more accurate. MATERIALS AND METHODS: We integrated messenger RNA (mRNA) and microRNA (miRNA) expression profiles and the corresponding clinical data of 402 UBC patients and 19 normal controls from The Cancer Genome Atlas. Univariate …Cox regression followed by a multiple testing correction and an elastic net-regulated Cox regression were adopted to identify a prognostic signature. RESULTS: We generated an integrated clinical-RNA signature which consisting of 3 clinical variables, 3 protective mRNAs, 7 risky mRNAs, 2 protective miRNAs and 1 risky miRNA. The area under the receiver operating characteristic curve of the integrated clinical-RNA signature was 0.802, larger than that of the clinical-alone signature (0.709) or the RNA-alone signature (0.726). UBC patients in the high-risk group had a significantly shorter overall survival time compared with patients in the low-risk group (clinical-RNA signature, hazard ratio = 2.441). CONCLUSIONS: Our conclusions that we have identified an integrated clinical-RNA signature that was superior to the traditional clinical-alone signature for ascertaining the overall survival prognosis of patients with UBC. These findings provide some novel genes for tumor molecular biologist to further study their functions and mechanisms in UBC tumorigenesis and malignance, and may be useful for effective clinical risk management of UBC patients. Show more

Keywords: Urothelial bladder cancer, clinical, RNA, signature, prognosis

DOI: 10.3233/CBM-170314

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 535-546, 2018

Authors: Guo, Xiangjun | Shi, Jiaxin | Wen, Yan | Li, Mengmeng | Li, Qin | Li, Xiaomei | Li, Jiashu

Article Type: Research Article

Abstract: BACKGROUND: High-mobility group A2 (HMGA2) has been investigated to be associated with tumorigenesis; however, the expression pattern and clinical significance of HMGA2 in non-small cell lung cancer (NSCLC) remains poorly understood. The purpose of this study is to examine the expression of HMGA2 and to analyze its relationships with respect to clinico-pathological features and patient survival in NSCLC. METHODS: The expression level of HMGA2 was examined by Western blot and immunohistochemistry in NSCLC cells and tissues. The relationship between HMGA2 expression and survival of NSCLC patients was calculated by a Kaplan-Meier method and the evaluation of …risk factor was determined by the multiple regression analysis. RESULTS: NSCLC tissues exhibited a higher expression level of HMGA2 compared to normal tissues (p < 0.05) and the expression level of HMGA2 was significantly associated with poor differentiation of NSCLC (p < 0.05), lymph node metastasis (p < 0.05) and advanced clinical stage (p < 0.05). Besides, HMGA2 was also confirmed to be elevated in NSCLC cells by Western blot. Moreover, increased expression of HMGA2 correlated with decreased survival of NSCLC patients (p < 0.05). CONCLUSIONS: HMGA2 was highly expressed in NSCLC tissues and cells and its overexpression was correlated with low-grade differentiation, lymph node metastasis, advanced clinical stage and poor survival time of NSCLC, which suggested that it could serve as a potential molecular marker and prognostic index for NSCLC. Show more

Keywords: Non-small cell lung cancer, NSCLC, high-mobility group A2, HMGA2, expression, prognosis

DOI: 10.3233/CBM-170401

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 547-555, 2018

Authors: Guan, Zhen-Biao | Cao, Yu-Shu | Li, Yi | Tong, Wan-Ning | Zhuo, An-Shan

Article Type: Research Article

Abstract: BACKGROUND: The aim in this study was to explore the role of long non-coding RNA GHET1 in development of non small cell lung cancer (NSCLC). METHODS: LncRNA GHET1 expression levels were analyzed by qRT-PCR in tumor tissues and adjacent normal tissues in NSCLC. Measuring the cell proliferation and invasion abilities by CCK8, cell colony formation and transwell invasion assays. Relative protein expression was analyzed by western blot assays. RESULTS: Expression of lncRNA GHET1 was notably higher in NSCLC tissues compared with adjacent normal tissues by using qRT-PCR analyses. Higher lncRNA GHET1 expression associated …with lymph node metastasis, TNM stage and showed poor outcome in NSCLC patients. Knockdown of lncRNA GHET1 suppressed cell proliferation and invasion capacity and Epithelial-Mesenchymal Transition (EMT) phenomenon of NSCLC cells. Moreover, we demonstrated that knockdown of lncRNA GHET1 suppresses LATS1/YAP pathway signaling pathway by downregulating YAP1 expression in NSCLC cells. CONCLUSIONS: GHET1 predicted a poor outcome and acted as a tumor-promoting gene in NSCLC. Thus, inhibition of GHET1 may be a potential target of NSCLC treatment. Show more

Keywords: Non small cell lung cancer, long non-coding RNA, GHET1, cell proliferation, cell invasion

DOI: 10.3233/CBM-170431

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 557-563, 2018

Authors: Duan, Shujie

Article Type: Research Article

Abstract: OBJECTIVE: To explore the influence of Beclin-1 on vasculogenic mimicry (VM) induced by hypoxia in glioma. METHODS: CD34-PAS staining was carried out to observe VM formation, and immunohistochemistry was used to determine the expression levels of Beclin-1, HIF-1α , VEGF and MMP2 in 105 patients with primary glioma. Human glioma U87MG cells were divided into Normoxia, Hypoxia, Hypoxia + NC siRNA and Hypoxia + Beclin-1 siRNA groups. Cobalt chloride (CoCl 2 ) was used to stimulate hypoxic conditions, and a VM tube formation assay …was used to detect VM formation. Wound healing and Transwell invasion assays were used to detect the invasive and migratory abilities of U87MG cells, respectively. Fluorescent LC3 puncta analysis was performed to examine the status of autophagic flux. Expression levels of Beclin-1 and VM-related molecules were determined using real-time quantitative-polymerase chain reaction (RT-qPCR) and western blotting. RESULTS: There were 34 VM-positive cases and 71 VM-negative cases among 105 glioma patients, and VM formation was correlated with pathological grade and the expression of Beclin-1, HIF-1α , VEGF and MMP2. Positive relations were found between Beclin-1 and the expression of HIF-1α , VEGF and MMP2. Under hypoxic conditions, significant increases in the total length of tubes, migration rate, invasion cell number and expression of VM-related molecules were found in U87MG cells. Silencing Beclin-1 markedly decreased hypoxia-induced VM formation and the invasive and migratory abilities, together with the expression of VM-related molecules, in U87MG cells and significantly inhibited the autophagic flux. CONCLUSION: Silencing Beclin-1 can attenuate hypoxia-induced VM formation and the metastatic ability of U87MG cells and is a potential target for VM inhibition in glioma. Show more

Keywords: Beclin-1, glioma, vasculogenic mimicry, siRNA

DOI: 10.3233/CBM-170444

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 565-574, 2018

Authors: Zhang, Hai-Feng | Li, Wei | Han, Yi-Di

Article Type: Research Article

Abstract: BACKGROUND: Recent findings have identified thousands of long non-coding RNAs (lncRNAs) and reveal that lncRNAs play crucial roles in the regulation of tumor development and progression. However, the clinical significance and potentially functional value of LINC00261 in hepatocellular carcinoma (HCC) remain unknown. METHODS: Expression of LINC00261 was detected by qRT-PCR in HCC tissues and adjacent normal tissues. Kaplan-Meier analysis was used to assess the relationship between LINC00261 expression and the overall survival (OS) time. Cell proliferation and invasion were evaluated using MTT assay, cell colony formation assay and transwell assay. The protein expression was determined by …western blot analysis. RESULTS: In present study, we confirmed that LINC00261 was frequently lower in HCC tissues compared to adjacent normal tissues. Decreased LINC00261 expression associated with lager tumor size, TNM stage (III-IV) and poor overall survival time of HCC patients. The functional assays demonstrated that overexpression of LINC00261 in HCC cells inhibited cell proliferation, cell colony formation, cell invasion and EMT process in vitro . Moreover, we also demonstrated that upregulation of LINC00261 significantly inhibited Notch signaling by downregulating Notch1 and Hes-1 expression in HCC cells. CONCLUSION: These results indicated that LINC00261 may be a potential target of HCC treatment. Show more

Keywords: Hepatocellular carcinoma, long non-coding RNA, LINC00261, Notch1, Hes-1

DOI: 10.3233/CBM-170471

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 575-582, 2018

Authors: Chai, Annie Wai Yeeng | Cheung, Arthur Kwok Leung | Dai, Wei | Ko, Josephine Mun Yee | Lee, Nikki Pui Yue | Chan, Kin Tak | Law, Simon Ying-Kit | Lung, Maria Li

Article Type: Research Article

Abstract: BACKGROUND: Nidogen-2 (NID2), a secretory basement membrane protein, has been implicated as a potential biomarker in ovarian cancer and hepatocellular carcinoma. OBJECTIVE: In this study, we aimed to investigate the utility of detecting serum NID2 levels for identification of esophageal squamous cell carcinoma (ESCC) patients and prediction of poor survival outcome. METHODS: Using an in-house NID2 enzyme-linked immunosorbent assay (ELISA), serum samples from 101 ESCC patients and 50 healthy controls were screened for their NID2 levels. RESULTS: The serum NID2 levels in ESCC patients (median 24.4 μ g/L) …are significantly higher (p = 4.3e-09) than that of the healthy controls (median 15.85 μ g/L). The receiver operating characteristic (ROC) curve demonstrated an area under the curve of 0.756. At the threshold of 17.95 μ g/L, the sensitivity and specificity achieved are 0.76 and 0.63, respectively. Kaplan-Meier survival analysis revealed that patients with high serum NID2 levels (⩾ 32.6 μ g/L) have significantly higher risk of death (HR = 1.984, 95% CI: 1.175–3.349; log-rank p-value = 0.012) compared to those with low serum NID2 levels (< 20.0 μ g/L). CONCLUSIONS: In conclusion, we show that detecting the elevation of serum NID2 levels has potential diagnostic and prognostic value for ESCC patients. Show more

Keywords: Nidogen-2, enzyme-linked immunosorbent assay, esophageal squamous cell carcinoma, serum biomarker, extracellular matrix protein

DOI: 10.3233/CBM-170484

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 583-590, 2018

Authors: Forcella, Matilde | Mozzi, Alessandra | Stefanini, Federico M. | Riva, Alice | Epistolio, Samantha | Molinari, Francesca | Merlo, Elisabetta | Monti, Eugenio | Fusi, Paola | Frattini, Milo

Article Type: Research Article

Abstract: BACKGROUND: Aberrant sialylation is a characteristic feature associated with cancer. The four types of mammalian sialidases identified to date have been shown to behave in different manners during carcinogenesis. While NEU1, NEU2 and NEU4 have been observed to oppose malignant phenotypes, the membrane-bound sialidase NEU3 was revealed to promote cancer progression. OBJECTIVES: With the aim of improving the knowledge about sialidases deregulation in various cancer types, we investigated the amount of NEU1, NEU3 and NEU4 transcripts in paired normal and tumor tissues from 170 patients with 11 cancer types. METHODS: mRNA was extracted …from patients’ tissue specimens and retrotranscribed into cDNA, which was quantified by Real-Time PCR. RESULTS: We found NEU1 and NEU3 to be up regulated, while NEU4 was down regulated in most cancer types. In particular, colorectal cancer tissues showed the highest increase in NEU3 expression. Both NEU1 and NEU3 showed a strong up-regulation in ovarian cancer. CONCLUSIONS: Our data show that human sialidases are expressed at different levels in healthy tissues and are strongly deregulated in tumors. Moreover, sialidases expression in our European cohort showed significant differences from Asian populations. Some of these peculiar features open potential applications of sialidases in cancer diagnosis and therapy. Show more

Keywords: Sialome, sialidase expression, cancer progression, diagnosis and therapy

DOI: 10.3233/CBM-170548

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 591-601, 2018

Authors: Ricco, Gabriele | Cavallone, Daniela | Cosma, Chiara | Caviglia, Gian Paolo | Oliveri, Filippo | Biasiolo, Alessandra | Abate, Maria Lorena | Plebani, Mario | Smedile, Antonina | Bonino, Ferruccio | Pontisso, Patrizia | Brunetto, Maurizia Rossana

Article Type: Research Article

Abstract: BACKGROUND: The role of serum biomarkers in the surveillance of hepatocellular carcinoma (HCC) is controversial. OBJECTIVE: We assessed the diagnostic performances of alpha-fetoprotein (AFP) and protein-induced by vitamin-K-absence/antagonist-II (PIVKA-II) in 388 cirrhotic patients with chronic liver disease (CLD). METHODS: Biomarkers were quantified by automated chemiluminescent-enzyme-immunoassays (Fujirebio, Tokyo, Japan) at HCC diagnosis in 258 patients (204 males; median age 66.9 years) and in 130 cirrhotics without HCC (104 males; median-age 60.6 years). CLD etiology in HCC/non-HCC was CHB in 48/35, CHC in 126/56 and Non-Viral in 84/39. RESULTS: Overall AUROC values …for AFP and PIVKA-II were 0.698 (95%CI = 0.642–0.753, P < 0.001) and 0.780 (95%CI = 0.730–0.831, P < 0.001). AFP/PIVKA-II AUROC (95%CI) were: 0.822 (0.728–0.915)/0.833 (0.739–0.926) in CHB, 0.648 (0.560–0.736)/0.732 (0.650–0.814) in CHC; 0.640 (0.540–0.740)/0.806 (0.722–0.889) in Non-Viral-CLD. AFP/PIVKA-II diagnostic accuracy was 40.5–59.8%/62.7–73.5% and combining both markers 78.2% for CHB, 77% for Non-Viral-CLD and 75% for CHC. AFP correlated with ALT in HCC patients with CHC (ρ = 0.463/P < 0.001) and Non-Viral CLD (ρ = 0.359/P = 0.047), but not in CHB (treated with antivirals). PIVKA-II correlated with tumour size independently of CLD-etiology (P < 0.001) and AFP in CHB patients only (P = 0.007). CONCLUSION: The diagnostic performance of AFP and PIVKA-II is significantly influenced by the etiology and activity of CLD; their combination provides a better diagnostic accuracy. Show more

Keywords: Alpha-fetoprotein, protein induced by vitamin K absence/antagonist-II, HCC, chronic liver disease

DOI: 10.3233/CBM-170551

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 603-612, 2018

Authors: Zhao, Bin | Lu, Yu-Lin | Yang, Yong | Hu, Li-Bing | Bai, Yu | Li, Rui-Qian | Zhang, Guo-Ying | Li, Jun | Bi, Cheng-Wei | Yang, Li-Bo | Hu, Chen | Lei, Yong-Hong | Wang, Qi-Lin | Liu, Zhi-Min

Article Type: Research Article

Abstract: Long non-coding RNAs (lncRNAs) were playing critical roles in tumorigenesis. However, in prostate cancer, the roles and mechanisms of lncRNAs especially ANRIL were largely unknown. We investigated the effects of ANRIL on the proliferation and migration of prostate cancer cells using CCK-8 assay and Transwell migration assay. Real-time PCR and western blotting assays were used to analyze the levels of ANRIL, let-7a, TGF-β 1, p-Smad2 and p-Smad7. Our results showed that ANRIL was significantly overexpressed in prostate cancer tissues compared with corresponding normal tissues. Knockdown of ANRIL significantly inhibited the proliferation and migration of prostate cancer LNCap, PC3 …and DU145 cells. Knockdown of ANRIL significantly decreased the levels of TGF-β 1 and p-Smad2, and increased the level of p-Smad7 in prostate cancer LNCap cells. We further found that knockdown of ANRIL significantly enhanced the expression of let-7a, and rescue experiment found that let-7a inhibitor recovered the suppressive effects of ANRIL silencing on the proliferation and migration of prostate cancer LNCap, PC3 and DU145 cells. And let-7a inhibitor recovered the suppressive effects of ANRIL silencing on the activity of TGF-β 1/Smad signaling pathway in prostate cancer LNCap cells. Taken together, our findings indicated that overexpression of lncRNA ANRIL promoted the proliferation and migration of prostate cancer cells via regulating let-7a/TGF-β 1/Smad signaling pathway. Show more

Keywords: lncRNA ANRIL, prostate cancer, let-7a, TGF-β1/Smad signaling pathway

DOI: 10.3233/CBM-170683

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 613-620, 2018

Authors: Pirouzpanah, Saeed | Taleban, Forough-Azam | Mehdipour, Parvin | Sabour, Siamak | Atri, Morteza

Article Type: Research Article

Abstract: BACKGROUND: The option of endocrine therapy in breast cancer remains conventionally promising. OBJECTIVE : We aimed to investigate how accurately the pattern of hypermethylation at estrogen receptor (ESR ) and progesterone receptor (PgR ) genes may associate with relative expression and protein status of ER, PR and the combinative phenotype of ER/PR. METHODS : In this consecutive case-series, we enrolled 139 primary diagnosed breast cancer. Methylation specific PCR was used to assess the methylation status (individual test). Tumor mRNA expression levels were evaluated using real-time RT-PCR. Immunohistochemistry data was used to present hormonal receptor status …of a tumor (as test reference). RESULTS : Methylation at ESR1 was comparably frequent in ER-breast tumors (83.0%, P < 0.001; sensitivity = 83.0%, specificity = 65.2% and diagnostic odds ratio, DOR = 12.0) and strongly correlated with ER-/PR- conditions (Cramer’s V = 0.44, P < 0.001). Methylated PgRb promoter frequently was observed in tumors recognised as ER- or negative ER/PR (77.1%, P < 0.01). Assessment of DNA methylation of ESR1 harbouring methylation at PgRb was a case significantly suggested to be able to detect the lack of ER/PR expressions (55.6%, P < 0.01; sensitivity = 80.6%, specificity = 68.7% and DOR = 8.7). However, methylated PgRb was quite acceptable determinant to contribute with methylated ESR1 to rank tumors as ER-/PR- (64.4%, P < 0.01; sensitivity = 78.0%, specificity = 62.5% and DOR = 6.0). CONCLUSIONS : Despite the methylation status of ESR1 showed preponderant contribution to tumoral phenotypes of ER- and ER-/PR-, the hypermethylation of PgRb seem another epigenetic signalling variable actively associate with methylated ESR1 to show lack of ER+/PR+ tumors in breast cancer. Show more

Keywords: Breast cancer, hypermethylation, estrogen receptor, progestrone receptor

DOI: 10.3233/CBM-170697

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 621-638, 2018

Authors: Ma, Xingcong | Zhao, Xiaoyao | Yan, Wanjun | Yang, Jun | Zhao, Xixi | Zhang, Hong | Hui, Yuxin | Zhang, Shuqun

Article Type: Research Article

Abstract: BACKGROUND: Inhibition of lymphocytes infiltration and activity may impair antitumor immune response and limit treatment responsiveness. Wnt/β -catenin pathway has been suggested to contribute to immune evasion in tumor by suppressing the function of immune cells and excluding T cell infiltration. However, the effects of Wnt/β -catenin on TILs recruitment remain controversial. OBJECTIVE: We aimed to investigate whether intratumoral Wnt/β -catenin signaling could affect the lymphocyte infiltration in breast cancer. METHODS: The distribution of stromal TILs, CD8 + and FOXP3 + …TIL subsets, and the expression of β -catenin were separately assessed on consecutive sections of 96 breast cancer specimens. RESULTS: Both stromal infiltrated TILs and β -catenin expression were upregulated in hormone receptor negative HER2-enriched and TNBC subtypes. Furthermore, high levels of stromal TILs as well as CD8 + or FOXP3 + TIL subsets were associated with β -catenin overexpression by breast cancer, respectively. CONCLUSIONS: For the first time, we demonstrated that rather than excluding lymphocytes infiltration as reported in mela-noma, high levels of TILs were associated with β -catenin overexpression in BC. Wnt/β -catenin signaling may play a critical role in BC immunity, particularly in HER2-enriched and triple negative BC, and may serve as a potential target for regulating immune infiltrates in breast cancer. Show more

Keywords: Tumor infiltrating lymphocytes, Wnt/β-catenin signaling, CD8+ TILs, FOXP3+ TILs, breast cancer

DOI: 10.3233/CBM-170708

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 639-650, 2018

Authors: Zhang, Chun | Yang, Xi | Qi, Quan | Gao, Yuhai | Wei, Qiang | Han, Shuwen

Article Type: Research Article

Abstract: BACKGROUND: Chronic hepatitis C (CHC) is a contagious liver disease that results from infection with the hepatitis C virus (HCV). The most serious consequence of CHC is HCV-related hepatocellular carcinoma (HCC). OBJECTIVE: To illustrate the clinical significance of lncRNA HEIH expression in serum and exosomes in the development of HCV-related HCC. METHODS: Thirty-five CHC, twenty-two HCV-induced cirrhosis and ten HCV-related HCC patients in Huzhou Central Hospital from January 2016 to September 2016 were recruited in the present study. Basic patient information, clinical serological indicators, and clinical imaging data were investigated and analyzed. Serum …samples were collected from patients after receiving informed consent. Exosomes were extracted from the serum, and electron microscopy was used to observe the ultrastructure of exosomes. Quantitative PCR was used to detect lncRNA HEIH gene expression in serum and exosomes. RESULTS: The changes in the ALT, GGT, HDL, INR, Alb and AFP levels in the patients with HCV-induced cirrhosis and HCV-related HCC were statistically significant. In patients with HCV-related HCC, lncRNA-HEIH expression in serum and exosomes was increased, but the ratio of lncRNA-HEIH expression in serum versus exosomes was decreased compared to patients with CHC. Show more

Keywords: Chronic hepatitis C, cirrhosis, hepatocellular carcinoma, HEIH, exosome

DOI: 10.3233/CBM-170727

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 651-659, 2018

Authors: Chen, Yu-Hua | Zhou, Bi-Yun | Wu, Guo-Cai | Liao, De-Quan | Li, Jing | Liang, Si-Si | Wu, Xian-Jin | Xu, Jun-Fa | Chen, Yong-Hua | Di, Xiao-Qing | Lin, Qiong-Yan

Article Type: Retraction

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

Keywords: Exogenous interleukin-37, human lung adenocarcinoma A549 cells, biological characteristic, chemotaxis and regulatory T cells

DOI: 10.3233/CBM-170732

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 661-673, 2018

Authors: Fu, Shuang | Liu, Li | Zhang, Xin | Liu, Zhi-Ping | Wang, Rui-Tao

Article Type: Research Article

Abstract: BACKGROUND: Laryngeal cancer is one of the most common malignancies in the head and neck. Activated platelets play a critical role in cancer development and progression. Altered mean platelet volume (MPV) and platelet distribution width (PDW) have been found in various types of cancer. The purpose of the current study was to investigate the association of platelet indices with laryngeal cancer. STUDY DESIGN: The study included 216 patients with laryngeal cancer, 189 subjects with benign laryngeal disease, and 213 control subjects between January 2015 and December 2015. All participants’ clinical and laboratory characteristics at initial diagnosis …were collected. RESULT: MPV was significantly lower and PDW was markedly higher in laryngeal cancer patients compared with control subjects and patients with benign laryngeal disease. A significant correlation between MPV and lymph node metastasis was found. The prevalence of laryngeal cancer increased as MPV quartiles decreased and PDW quartiles increased. Furthermore, MPV and PDW were independent risk factors for distinguishing laryngeal cancer from benign laryngeal disease. CONCLUSIONS: The patients with laryngeal cancer have reduced MPV and increased PDW compared to the subjects without laryngeal cancer. In addition, MPV and PDW play different roles in laryngeal cancer from benign laryngeal disease. Show more

Keywords: Laryngeal cancer, mean platelet volume, platelet distribution width, diagnosis

DOI: 10.3233/CBM-170751

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 675-680, 2018

Authors: Wang, Pingan | Guo, Lingyu | Li, Kaipeng | Ning, Shanglei | Shi, Weichen | Liu, Zhaochen | Chen, Yuxin

Article Type: Research Article

Abstract: BACKGROUND: This research was aimed to study the expression of Serine/arginine rich splicing factor 2 (SRSF2) in tissues of hepatocellular carcinoma, and explore the relationship between the expression and the clinic pathological and prognosis of human hepatocellular carcinoma (HCC). METHODS: One hundred and fifty-three pairs HCC tissues and adjacent normal tissue were collected from January 2010 to March 2013. The expression of SRSF2 gene was detected by immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction (PCR), and the relationship between the expression and the clinic pathological and prognosis of HCC being analyzed. RESULTS: …In 153 cases of hepatocellular carcinoma, SRSF2 was highly expressed in 93 cases, low expression of 60 cases, immunohistochemistry score (6.50 ± 2.82), which was significantly higher than that in adjacent normal tissues (2.94 ± 1.23) (P < 0.05). The expression of SRSF2 in HCC was not associated with gender (χ 2 = 0.014, P = 0.906), age (χ 2 = 0.007, P = 0.931), tumor size (χ 2 = 3.566, P = 0.059) and T stage (χ 2 = 2.708, P = 0.100), and was significantly correlated with tumor differentiation (χ 2 = 9.687, P = 0.007), lymph node metastasis (χ 2 = 4.827, P = 0.028), distal metastasis (χ 2 = 9.235, P = 0.002), tumor, node, metastasis (TNM) stage (χ 2 = 3.978, P = 0.046), portal vein invasion and serum alpha-fetoprotein (χ 2 = 14.919, P = 0.000). The expression of SRSF2 protein in hepatocellular carcinoma was positively correlated (r = 0.704, P < 0.05) with serum alpha-fetoprotein through Pearson analysis. The survival rates of SRSF2 overexpressing hepatocellular carcinoma were 74.19%, 44.09%, 26.88%, 24.73% and 21.51% at 1 year, 2 years, 3 years, 4 years and 5 years respectively, which were lower than those of SRSF2 low expression group (93.33%, 71.67%, 56.67%, 51.67% and 50.00%). CONCLUSION: SRSF2 is highly expressed in hepatocellular carcinoma and its expression increases with the degree of tumor differentiation and TNM staging. It is related to lymph node metastasis and metastasis of tumor cells, and is positively related to serum alpha fetoprotein content, and affects the postoperative survival time of HCC patients. Show more

Keywords: SRSF2, hepatocellular carcinoma, immunohistochemistry, clinical pathology

DOI: 10.3233/CBM-170770

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 681-687, 2018

Authors: Ding, Dongbing | Yao, Yao | Yang, Changming | Zhang, Songbai

Article Type: Research Article

Abstract: The aim of present study was to investigate the clinical significances of mannose receptor (MR) and CD163 in colorectal cancer (CRC). Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were utilized for this analysis. Preoperative serum MR and CD163 levels ranged from 0.153 to 0.804 μ g/ml (median = 0.359 μ g/ml) and from 0.319 to 1.314 μ g/ml (median = 0.685 μ g/ml) in CRC patients respectively. Strikingly, preoperative serum levels of MR and CD163 were significantly increased in CRC patients than in healthy individuals (P …< 0.0001). ROC analyses suggested that the optimum diagnostic cut-offs for serum MR and CD163 were 0.3485 μ g/ml (AUC 0.7205, sensitivity 54.82%, and specificity 80.46%) and 0.6111 μ g/ml (AUC 0.7463, sensitivity 62.65%, and specificity 80.46%) respectively. Detection of serum MR and CD163 together obviously enhanced the diagnostic accuracy (AUC 0.7968, sensitivity 69.28%, and specificity 77.01%). Then, preoperative serum MR and CD163 levels correlated significantly with serum CEA, CA19-9 and CA72-4 concentrations in CRC patients (P < 0.05). High MR and CD163 expression in serum was associated significantly with shorter overall survival (P < 0.05) and demonstrated as adversely prognostic factors (P < 0.05). Further, expression of MR and CD163 in CRC tissues was significantly higher than that in para-cancer tissues (P < 0.001). High expression of MR and CD163 in CRC tissues also correlated significantly with shorter overall survival (P < 0.05). MR and CD163 expression in serum or CRC tissues all correlated positively with the degree of lymphatic metastasis (P < 0.0001). In conclusion, MR and CD163 may be novel biomarkers for CRC patients. Show more

Keywords: Mannose receptor, CD163, marker, colorectal cancer

DOI: 10.3233/CBM-170796

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 689-700, 2018

Authors: Wang, Cheng-Yang | Ding, Huan-Zhang | Tang, Xiao | Li, Ze-Geng

Article Type: Research Article

Abstract: OBJECTIVE: The present study investigates the differences in immune function, hemorheological alterations and prognostic evaluation in colorectal cancer (CRC) patients with different traditional Chinese medicine (TCM) syndromes. METHODS: A total of 128 patients, diagnosed as stage II and III of CRC, were recruited. They were assigned into three TCM syndromes: deficiency syndrome, excess syndrome, and syndrome of intermingled deficiency and excess, and another 53 healthy individuals were selected as the control. Flow cytometry was used to determine the peripheral blood lymphocyte subsets (the levels of CD + 3 , CD …+ 4 , CD + 8 , NK cells, and the ratios of CD + 4 /CD + 8 , Th1/Th2 and Tc1/Tc2). Whole blood viscosity (WBV), plasma viscosity (PV), hematocrit (Hct), erythrocyte sedimentation rate (ESR), plasma fibrinogen concentration (PFC) were measured using a fully-automatic blood rheological instrument. The univariate analysis and Cox regression analysis were conducted to evaluate the prognosis of CRC patients with different TCM syndromes. RESULTS: Compared with healthy individuals, CRC patients with three different syndromes had lower levels of CD + 3 , CD + 4 , NK cells, and ratios of CD + 4 /CD + 8 , Th1/Th2 and Tc1/Tc2, but higher level of CD + 8 , WBV, PV, Hct, ESR and PFC. Besides, patients with excess syndrome showed the highest levels of CD3 + , CD4 + and NK cells, and ratios of CD + 4 /CD + 8 , Th1/Th2 and Tc1/Tc2, but the lowest level of CD + 8 among three syndromes, and those with deficiency syndrome showed an opposite trend. Compared with patients with excess syndrome, those with deficiency syndrome showed decreased WBV, PV, Hct, ESR and PFC. The pathological type, surgical approach, tumor node metastasis (TNM) stage, liver metastasis, TCM treatment time and different TCM syndromes were independent factors of prognostic survival in CRC patients except perioperative blood transfusion volume. CONCLUSIONS: Taken together, we conclude that patients with TCM deficiency syndrome has lower immune function and poorer prognosis while patients with TCM excess syndrome has higher immune function and better prognosis of CRC. Show more

Keywords: Colorectal cancer, traditional Chinese medicine syndrome, immune function, hemorheological alteration, prognosis

DOI: 10.3233/CBM-170805

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 701-710, 2018

Authors: Lu, Hong-Jie | Yan, Jing | Jin, Pei-Ying | Zheng, Gui-Hong | Qin, Su-Ming | Wu, Dong-Mei | Lu, Jun | Zheng, Yuan-Lin

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF has been watermarked ``RETRACTION''. The retraction notice is available at http://doi.org/10.3233/CBM229005.

Keywords: MicroRNA-152, CTSL, gastrointestinal stromal tumor, proliferation, migration, invasion, apoptosis

DOI: 10.3233/CBM-170809

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 711-722, 2018

Authors: Wang, Hui-Ju | Wang, Liang | Song, Shu-Shu | He, Xiang-Lei | Pan, Hong-Ying | Hu, Zhi-Ming | Mou, Xiao-Zhou

Article Type: Research Article

Abstract: BACKGROUND AND AIM: Hypercalcemia is a potentially fatal and not rare complication of hepatocellular carcinoma (HCC), and its underlying mechanism remains unclear. Parathyroid hormone (PTH) is the most important regulator of the concentrations of calcium and phosphate in blood; parathyroid hormone-related protein (PTHrP) was the most frequent cause of humoral hypercalcemia of malignancy; parathyroid hormone 1 receptor (PTH1R) is the common receptor for PTH and PTHrP. The aim of this study is to investigate the expression of PTH, PTHrP, and PTH1R in HCC tissues, and their relationship with clinical pathological characters in HCC. METHODS: First, a …meta-analysis based on online Oncomine Expression Array database was conducted to compare the different mRNA expression of PTH1R, PTH and PTHrP between hepatocellular carcinoma and normal tissues. Then, the protein expression level of differentially expressed gene was examined by immunohistochemistry staining in 223 HCC tissues and 102 non-tumorous liver tissues controls. The relationship between the protein expression and clinicopathological parameters was analyzed by χ 2 test, and overall survival analysis was performed using Kaplan-Meier survival analysis. RESULTS: PTH1R mRNA expression was significantly lower in HCC tissues compared with normal tissues, while the expression of PTH and PTHrP showed no significant difference between HCC tissues and normal tissues. High PTH1R protein expression was found in 90/102 cases of adjacent non-tumorous liver tissues, and in 91 of 223 cases of HCC tissues. PTH1R expression was significantly related to tumor size, Edmondson Grade, AFP, and overall survival. CONCLUSIONS: PTH1R may be the major cause of hypercalcemia in HCC, and the decreased PTH1R expression was a poor prognosis in HCC. Show more

Keywords: PTH1R, PTH, PTHrP, hepatocellular carcinoma

DOI: 10.3233/CBM-170823

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 723-730, 2018

Authors: Petrini, Iacopo | Lencioni, Monica | Vasile, Enrico | Fornaro, Lorenzo | Belluomini, Lorenzo | Pasquini, Giulia | Ginocchi, Laura | Caparello, Chiara | Musettini, Gianna | Vivaldi, Caterina | Caponi, Sara | Ricci, Sergio | Proietti, Agenese | Fontanini, Gabriella | Naccarato, Antonio Giuseppe | Nardini, Vincenzo | Santi, Stefano | Falcone, Alfredo

Article Type: Research Article

Abstract: PURPOSE: The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho-mTOR in resected stage II–III adenocarcinomas. METHODS: Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated. Antibodies anti-HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded slides. Using FISH, HER2 amplification was …evaluated in cases with an intermediate (+ 2) staining. RESULTS: EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p = 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p = 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was not a prognostic factor by itself (p = 0.234). AKT1 and EGFR overexpression was mutually exclusive and patients with EGFR or AKT1 overexpression experienced a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p = 0.005). CONCLUSIONS: EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers. Show more

Keywords: Gastric cancer, gastro-esophageal junction cancer, EGFR, AKT1, MET

DOI: 10.3233/CBM-170865

Citation: Cancer Biomarkers, vol. 21, no. 3, pp. 731-741, 2018