Cancer Biomarkers - Volume 21, issue 1

Authors: Hou, Li | Hou, Xiaofei | Wang, Lijing | Li, Zenghui | Xin, Beibei | Chen, Jing | Gao, Xiaofei | Mu, Haixia

Article Type: Research Article

Abstract: BACKGROUND: The study was aimed at investigating the role of PD98059 on impairing the cisplatin-resistance of ovarian cancer cells and figuring out the potential mechanism. MATERIAL AND METHODS: Treated with low dose of cisplatin (DDP), DDP-resistant ovarian cancer cells were built and named as SKOV-3/DDP. The cell viabilities of ovarian cancer cell line SKOV-3 and SKOV-3/DDP were detected using MTT assay. Wound healing assay and flow cytometry were performed to detect the migratory ability and cell cycle variation of the two cells and assess the sensibility to DDP in the two cell lines. However, cotreated with DDP …and PD98059, cell viability, migration and cell cycle of SKOV-3/DDP were determined again. The DDP-resistance varied a lot and the potential mechanism was studied via western blot assay. RESULTS: Both treated with DDP, SKOV-3/DDP showed an intense resistance than SKOV-3 including stronger cell viability, larger migration area and less G1/G0 arrest, which confirmed the successfully established DDP-resistant cell line. The phosphorylation of ERK and the activation of epithelial mesenchymal transition (EMT) process contributes to the enhanced resistance. PD98059, a MEK inhibitor, suppresses the ERK pathway and the EMT process of SKOV-3/DDP. Co-treated by DDP and PD98059, cell proliferation and migratory area decreased, meantime more cell were arrested in G0/G1 phase compared to simple treatment of DDP or PD98059. CONCLUSION: PD98059 efficiently impairs the DDP-resistance of ovarian cancer cells via downregulating the ERK pathway and the EMT process. Show more

Keywords: Ovarian cancer, cisplatin resistance, epithelial mesenchymal transition, ERK pathway

DOI: 10.3233/CBM-170644

Citation: Cancer Biomarkers, vol. 21, no. 1, pp. 187-194, 2018

Authors: Hu, Xiao-Yan | Liu, Zhe | Zhang, Kai-Lin | Feng, Jing | Liu, Xiao-Fang | Wang, Ling-Yun | Wang, Zi-Wei

Article Type: Research Article

Abstract: N-myc downstream regulated gene 2 (NDRG2) is frequently down-regulated in various cancers and functions as a candidate tumor suppressor gene. NDRG2 has been shown to be SUMOylated on the lysine 333 residue, which promoted its ubiquitination and sequentially degradation by the SUMO-targeted ubiquitin E3 ligase RNF4. However, how to regulated NDRG2 deSUMOylation process remains largely unknown. Here, we report that Sentrin/SUMO specific protease (SENP2) was down-regulated in clinic gastric cancer samples and possessed a tumor-suppressive role in gastric cancer. At the molecular level, we found that SENP2 interacts with NDRG2 and mediates the de-SUMOylation process of NDRG2. Overexpression of SENP2 …stabilized NDRG2, whereas silencing SENP2 caused rapid NDRG2 SUMOylation and degradation, indicating SENP2 antagonizes NDRG2 ubiquitination and degradation, thereby promoting the stability and function of this protein. Thus, our study reveals that SENP2 acts as a tumor suppressor which is deregulated in gastric cancer and the specific de-SUMOylation activity of SENP2 for NDRG2 is critical for it stabilization as well as gastric cancer cells proliferation. Show more

Keywords: SENP2, NDRG2, gastric cancer, SUMOylation

DOI: 10.3233/CBM-170651

Citation: Cancer Biomarkers, vol. 21, no. 1, pp. 195-201, 2018

Authors: Sun, Jiachun | Wang, Dengkui | Li, Xiangming | Yan, Junqiang | Yuan, Xiaozhi | Wang, Wei

Article Type: Research Article

Abstract: OBJECTIVE: Glioma-associated oncogene homolog 1 (Gli1 ) in Hedgehog signal pathway regulates Cyclin D1 expression, cell cycle or proliferation modulation. Esophageal cancer patients had significantly elevated Gli1 expression, which is related with survival and prognosis. It has been demonstrated that the level of miR-150 was decreased in esophageal cancer patients compared to normal control. As a complementary relationship exists between miR-150 and 3’-UTR of Gli1 , this study investigated if miR-150 played a role in regulating Gli1 expression, and proliferation or cell cycle of esophageal cancer cells. PATIENTS AND METHODS: Esophageal squamous cell carcinoma (ESCC) …patients from our hospital were recruited to collect tumor and adjacent tissues for miR-150 and Gli1 expression. Esophageal carcinoma cell line EC9706 and normal esophageal epithelial cell line HEEC were compared for expression of miR-150, Gli1 and Cyclin D1 . Dual luciferase reporter gene assay examined the targeted relationship between miR-150 and 3’-UTR of Gli1 . In vitro cultured EC9706 cells were treated with miR-150 mimic, si-Gli1 or the combination of miR-150 mimic and si-Gli1, respectively, to check their gene expression, cell cycle and proliferation. RESULTS: ESCC tissues had significantly higher Gli1 expression and lower miR-150 expression. EC9706 cell also had higher Gli1 expression than that in HEEC, whilst miR-150 was down-regulated. Via targeting 3’-UTR of Gli1 gene, miR-150 inhibited its expression. Transfection of miR-150 mimic, si-Gli1 or the combination of miR-150 mimic and si-Gli1, respectively, remarkably decreased expression of Gli1 and Cyclin D1 expression in EC9706 cells, whose cell cycle arresting at G0/G1 phase was enhanced with weakened proliferation. CONCLUSIONS: MiR-150 can induce G0/G1 cell cycle arresting and weaken proliferation of esophageal carcinoma cells via targeted inhibition on Gli1 and downstream expression of Cyclin D1 . Show more

Keywords: MicroRNA-150, Gli1, Cyclin D1, cell proliferation, cell cycle, esophageal carcinoma

DOI: 10.3233/CBM-170658

Citation: Cancer Biomarkers, vol. 21, no. 1, pp. 203-210, 2018

Authors: Yang, Ching-Yao | Lin, Mong-Wei | Chang, Yih-Leong | Wu, Chen-Tu

Article Type: Research Article

Abstract: BACKGROUND: Globo H is a tumor-associated carbohydrate antigen exclusively expressed in cancer cells rather than normal tissue. Globo H has been found on many cancers of epithelial origins, and become an attractive target for cancer vaccine. OBJECTIVES: We aimed to study the expression of Globo H in non-small cell lung cancer (NSCLC) patients, and correlated its expression with common driver mutations, clinical outcomes, and status of immune checkpoint, programmed death-ligand 1 (PD-L1). METHODS: The study enrolled 228 patients with surgically resected stage I NSCLC, including 139 patients with adenocarcinoma (ADC) and 89 patients …with squamous cell carcinoma (SqCC). Using immunohistochemistry, tumors with moderate to strong membranous staining in ⩾ 1% tumor cells per section were scored as positive Globo H expression. Driver mutations including EGFR, KRAS, BRAF were detected by direct sequencing, while ALK, PI3KCA, FGFR1 and PD-L1 expression was detected by immunohistochemical (IHC) staining. RESULTS: Positive Globo H expression was detected in 88 of the 228 (38.6%) patients. These included 51 of 139 (36.7%) patients with ADC and 37 of 89 (41.6%) patients with SqCC. Positive Globo H expression was significantly associated with EGFR mutation and PD-L1 expression in the ADC group, and PI3KCA overexpression in the SqCC group. The survival analysis showed that Globo H expression was not an independent prognostic factor in stage I NSCLC. CONCLUSIONS: Globo H expression was correlated with specific driver mutations in ADC and SqCC NSCLC tumors, as well as PD-L1 status. Immunotherapy targeting Globo H may have potential application in lung cancer treatment. Show more

Keywords: Cancer vaccine, Globo H, immunotherapy, non-small cell lung cancer, tumor-associated carbohydrate antigen

DOI: 10.3233/CBM-170660

Citation: Cancer Biomarkers, vol. 21, no. 1, pp. 211-220, 2018

Authors: Huang, Tonghai | Wang, Guangsuo | Yang, Lin | Peng, Bin | Wen, Yuxin | Ding, Guanggui | Wang, Zheng

Article Type: Research Article

Abstract: BACKGROUND: Non-small cell lung cancer (NSCLC) is the main type of lung cancer. While miR-186 is significantly reduced in lung cancer tissues and cells, its role in NSCLC has not been completely elucidated. MATERIAL AND METHODS: We used qRT-PCR and western blot methods to investigate the levels of miR-186 and YY1 in 21 pairs of NSCLC tissues. Dual luciferase reporter gene assays were performed to detect whether miR-186 directly targets YY1 . Next, the roles of miR-186 and its target gene (YY1 ) in determining the proliferation, apoptosis and migration capabilities of selected cell lines (A549 and HCC827) …were investigated by using miR-186 mimics or YY1 siRNA. RESULTS: Our results showed that miR-186 was downregulated and YYI was upregulated in NSCLC tissue, and miR-186 expression was negatively associated with YY1. Similarly, miR-186 was also downregulated and YY1 expression also was upregulated in both A549 and HCC827 cells; furthermore, miR-186 was found to directly target YY1 . Cell proliferation, invasion, and migration, as well as apoptosis induction were more strongly inhibited by YY1 siRNA than by miR-186. CONCLUSION: Our results suggest that miR-186 and its target gene (YY1 ) could possibly serve as new prognostic biomarkers and therapeutic targets for treating NSCLC in humans. Show more

Keywords: miR-186, YY1, cell proliferation, apoptosis, migration and invasion, non-small cell lung cancer

DOI: 10.3233/CBM-170670

Citation: Cancer Biomarkers, vol. 21, no. 1, pp. 221-228, 2018

Authors: Feferman, Leo | Deaton, Ryan | Bhattacharyya, Sumit | Xie, Hui | Gann, Peter H. | Melamed, Jonathan | Tobacman, Joanne K.

Article Type: Research Article

Abstract: BACKGROUND: Arylsulfatase B (ARSB) removes the 4-sulfate group from chondroitin 4-sulfate (C4S) and dermatan sulfate and is required for their degradation. Prior work showed that ARSB immunohistochemical scores were lower in malignant prostate tissue, and were associated with higher Gleason scores and recurrence. OBJECTIVE: This study aims to confirm that ARSB immunostaining of prostate tissue obtained at the time of radical prostatectomy is prognostic for prostate cancer recurrence. METHODS: Intensity and distribution of ARSB immunostaining were digitally analyzed in a large, well-annotated, prostate cancer tissue microarray (TMA). Scores were calculated for stroma and epithelium and compared …for 191 cases, including 36 recurrences, defined as PSA > 0.2 ng/ml. RESULTS: Epithelial scores were significantly lower in the recurrences (p = 0.010), and among subgroups with age > 60, initial PSA > 6 ng/ml, or Gleason grade = 7. ARSB score did not improve the prediction of recurrence in multifactorial analysis. CONCLUSIONS: Study findings validate previous findings and provide further evidence that lower ARSB is associated with prostate cancer recurrence. Additional studies are required to assess if there are specific cutoff values that may help predict recurrence. Show more

Keywords: Sulfatase, chondroitin sulfate, versican, immunohistochemistry, glycosaminoglycans, N-acetylgalactosamine-4-sulfatase

DOI: 10.3233/CBM-170680

Citation: Cancer Biomarkers, vol. 21, no. 1, pp. 229-234, 2018

Authors: Bakhti, Seyedeh Zahra | Latifi-Navid, Saeid | Zahri, Saber | Bakhti, Fatemeh Sadat | Hajavi, Naser | Yazdanbod, Abbas

Article Type: Research Article

Abstract: BACKGROUND: Although the most extensive studies revealed the role of H. pylori VacA and CagA toxins in the development of gastric adenocarcinoma, the magnitude of this association and the correlations of vacA mosaicism and cagA status with cardia gastric adenocarcinoma (CGA) still remain controversial. OBJECTIVE: We aimed to examine the linkage of H. pylori highly cytotoxic genotypes to CGA in Iranian populations as a model. METHODS: A total of 601 Iranian patients were enrolled. Biopsies were cultured, genotyped, and anatomically and histologically classified. RESULTS: The vacA …c1 genotype, but not cagA status, showed a strong association with the risk of both CGA and non-cardia adenocarcinoma (NCGA), whether the controls were non-tumors, as those with either non-atrophic gastritis or peptic ulcerations, (the OR (95%CI) was 14.11 (4.91–40.52) and 9.59 (4.06–22.65), respectively) or those with NAG (the OR (95%CI) was 10.71 (3.49–32.82) and 8.11 (3.26–20.16), respectively). The vacA c1/cagA + genotype was significantly associated with an increased risk of NCGA, whether the controls were non-tumors or those with NAG; the adjusted risk was 4.706 (1.41–15.67) and 4.85 (1.42–16.51), respectively. CONCLUSIONS: The H. pylori vacA c1 genotype, but not cagA status, might be the first important bacterial biomarker for predicting the cardia adenocarcinoma risk in male patients aged ⩾ 55 in Iran. Show more

Keywords: Helicobacter pylori, vacA c, cagA, cardia gastric adenocarcinoma, diffuse-type gastric adenocarcinoma, intestinal-type gastric adenocarcinoma

DOI: 10.3233/CBM-170701

Citation: Cancer Biomarkers, vol. 21, no. 1, pp. 235-246, 2018

Authors: Sun, Yun-Peng | Wang, Xuan | Gao, Yong-Sheng | Zhao, Song | Bai, Yang

Article Type: Research Article

Abstract: In large autopsy series, the estimated frequency of primary tumors of the heart ranges from 0.0017% to 0.33%. Approximately 25% of primary cardiac tumors are malignant, and nearly 20% of these are sarcomas. To date, a completely feasible surgical resection remains the major treatment measure of cardiac sarcoma, especially for recurrent focal cardiac sarcoma and the recurrence of a restrictive metastasis. Although characteristically medical treatments are recommended, there is no consistent opinion for adjuvant radiotherapy and chemotherapy following an operation. Since these tumors usually undergo extensive spread by the time that the diagnosis is established, the prognosis of cardiac sarcoma remains poor. …In this report, we described a case who underwent initial cardiac tumor resection, and was confirmed to be a pleomorphic undifferentiated sarcoma based on pathological findings. However, the patient complicated with cerebral infarction and subsequent brain metastasis sarcoma after the initial surgery, which was confirmed by brain tissue pathology. During the course of therapy, the patient underwent three surgical operations and refused to accept any chemotherapy and radiotherapy intervention. To the best of our knowledge, this is the first case report describing a primary cardiac sarcoma complicated with cerebral infarction and brain metastasis. The management of primary cardiac sarcoma is also discussed. Show more

Keywords: Primary cardiac sarcoma, cerebral infarction, brain metastasis

DOI: 10.3233/CBM-170448

Citation: Cancer Biomarkers, vol. 21, no. 1, pp. 247-250, 2018