Cancer Biomarkers - Volume 22, issue 2

Authors: Liu, Lin | Meng, Tao | Yang, Xin-Hui | Sayim, Parhat | Lei, Cheng | Jin, Bo | Ge, Lei | Wang, Hai-Jiang

Article Type: Research Article

Abstract: BACKGROUND: LncRNA and microRNA play an important role in the development of human cancers; they can act as a tumor suppressor gene or an oncogene. LncRNA GAS5, originating from the separation from tumor suppressor gene cDNA subtractive library, is considered as an oncogene in several kinds of cancers. The expression of miR-221 affects tumorigenesis, invasion and metastasis in multiple types of human cancers. However, there’s very little information on the role LncRNA GAS5 and miR-221 play in CRC. Therefore, we conducted this study in order to analyze the association of GAS5 and miR-221 with the prognosis of CRC and …preliminary study was done on proliferation, metastasis and invasion of CRC cells. In the present study, we demonstrate the predictive value of long non-coding RNA GAS5 (lncRNA GAS5) and mircoRNA-221 (miR-221) in the prognosis of colorectal cancer (CRC) and their effects on CRC cell proliferation, migration and invasion. METHODS: One hundred and fifty-eight cases with CRC patients and 173 cases of healthy subjects that with no abnormalities, who’ve been diagnosed through colonoscopy between January 2012 and January 2014 were selected for the study. After the clinicopathological data of the subjects, tissue, plasma and exosomes were collected, lncRNA GAS5 and miR-221 expressions in tissues, plasma and exosomes were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The diagnostic values of lncRNA GAS5 and miR-221 expression in tissues, plasma and exosomes in patients with CRC were analyzed using receiver operating characteristic curve (ROC). Lentiviral vector was constructed for the overexpression of lncRNA GAS5, and SW480 cell line was used for the transfection of the experiment and assigned into an empty vector and GAS5 groups. The cell proliferation, migration and invasion were tested using a cell counting kit-8 assay and Transwell assay respectively. RESULTS: The results revealed that LncRNA GAS5 was upregulated while the miR-221 was downregulated in the tissues, plasma and exosomes of patients with CRC. The results of ROC showed that the expressions of both lncRNA GAS5 and miR-221 in the tissues, plasma and exosomes had diagnostic value in CRC. While the LncRNA GAS5 expression in tissues, plasma and exosomes were associated with the tumor node metastasis (TNM) stage, Dukes stage, lymph node metastasis (LNM), local recurrence rate and distant metastasis rate, the MiR-221 expression in tissues, plasma and exosomes were associated with tumor size, TNM stage, Dukes stage, LNM, local recurrence rate and distant metastasis rate. LncRNA GAS5 and miR-221 expression in tissues, plasma and exosomes were found to be independent prognostic factors for CRC. Following the overexpression of GAS5, the GAS5 expressions was up-regulated and miR-221 expression was down-regulated; the rate of cell proliferation, migration and invasion were decreased. Show more

DOI: 10.3233/CBM-171011

Citation: Cancer Biomarkers, vol. 22, no. 2, pp. 283-299, 2018

Authors: Guo, Tao | Zhao, Shilei | Li, Zhuoshi | Li, Fengzhou | Li, Jinxiu | Gu, Chundong

Article Type: Research Article

Abstract: BACKGROUND: Patients with small (⩽ 2 cm) invasive lung adenocarcinoma are at high risk of poor prognosis and disease recurrence after complete surgical resection. Therefore, identification of high-risk individuals from these patients emerges as an urgent problem. Elevated MACC1 expression predicts a poor prognosis in multiple types of cancer that are independent of TNM staging. This study investigated the prognostic value of MACC1 expression in patients with small invasive lung adenocarcinoma. OBJECTIVE: The current study aimed to evaluate the relationship between MACC1 expression in patients’ tumor tissue and prognosis in small invasive lung …adenocarcinoma. METHODS: The records of 131 patients with small invasive lung adenocarcinoma who underwent complete surgical resection were reviewed. The MACC1 expression was detected by immunohistochemical staining in all specimens. Meanwhile, western blot and real-time quantitative PCR were used to examine the expression level of MACC1 in human lung adenocarcinoma cell lines. The effect of clinicopathological risk factors on patients’ survival was analyzed using the Kaplan-Meier approach and multivariable Cox models. RESULTS: Elevated MACC1 expression was observed in 53 (40.5%) specimens, and in A549, H358, H460 and H322 lung adenocarcinoma cell lines. MACC1 overexpression was associated with differentiation (P = 0.005) and blood vessel invasion (P = 0.001). Compared with low MACC1 expression, elevated MACC1 expression was associated with significantly shorter overall survival (odds ratio = 6.515; 95% confidence interval: 1.382–30.721; P = 0.018) and disease-free survival (odds ratio = 3.270; 95% confidence interval: 1.117–9.569; P = 0.031). Multivariate analyses demonstrated high MACC1 expression is an independent risk factor of worse overall survival (odds ratio = 5.684; 95% confidence interval: 1.145–28.210; P = 0.034) and disease-free survival (odds ratio = 4.667; 95% confidence interval: 1.372–15.877; P = 0.014). CONCLUSION: MACC1 is an independent prognostic marker in patients with small invasive lung adenocarcinoma after complete surgical resection. Differential outcomes are associated with MACC1 expression level. Show more

Keywords: MACC1, lung adenocarcinoma, prognosis

DOI: 10.3233/CBM-171017

Citation: Cancer Biomarkers, vol. 22, no. 2, pp. 301-310, 2018

Authors: Lv, Jia | Yang, Huyin | Wang, Xiaodong | He, Ruixing | Ding, Lianshu | Sun, Xiaoyang

Article Type: Research Article

Abstract: AIMS: To evaluate the prognostic and clinicopathological features of glioma with BRMS1L expression. METHODS: Total 120 glioma samples were obtained as discovery cohort. CGGA, GSE and TCGA datasets were obtained as validation sets. Furthermore, Kaplan-Meier survival and multivariate Cox analysis were used to evaluate the survival distributions. Moreover, the functional role of BRMS1L was also analyzed by transwell assay. RESULTS: In the discovery cohort, decreased BRMS1L expression was significantly associated with high-grade glioma as well as the higher mortality in survival analysis (log-rank test, p < 0.01). And the …three validation cohorts showed the similar results. Furthermore, BRMS1L act as an independent prognostic factor in glioblastoma patients. Additionally, functional assay showed that ectopic of BRMS1L suppressed glioma cells’ invasion. CONCLUSION: BRMS1L plays as an anti-oncogene in GBM and indicates a new potential therapeutic target. Show more

Keywords: Glioma, BRMS1L, prognostic, invasion

DOI: 10.3233/CBM-171019

Citation: Cancer Biomarkers, vol. 22, no. 2, pp. 311-316, 2018

Authors: Molina-Ortiz, Dora | Torres-Zárate, Carmen | Cárdenas-Cardós, Rocío | Palacios-Acosta, José Martin | Hernández-Arrazola, Daniel | Shalkow-Klincovstein, Jaime | Díaz-Díaz, Erick | Vences-Mejía, Araceli

Article Type: Research Article

Abstract: BACKGROUND: Intratumoral up-regulation of genes coding for drug transporters and metabolizing enzymes, such as MDR1 and CYP3A4, after chemotherapy are linked to cancer drug resistance. However their expression in primary soft tissue sarcomas (STS) prior to drug treatment and their role in innate resistance remain unclear. OBJECTIVE: The aim of this study was characterize MDR1 and CYP3A4 expression pattern before to chemotherapy and its clinical implication in pediatric STS. METHODS: In this prospective study we analyzed MDR1 and CYP3A4 mRNA expression in both normal and tumor tissues from 28 newly diagnosed STS pediatric …and then compared with patients’ clinical-pathological data, including chemotherapy response. RESULTS: Our data showed that the expression of the MDR1 gene was significantly higher in malignant tissue than in the normal tissues of patients with STS. In addition, high MDR1 expression was significantly associated with local advances, as well as poor response to treatment. In contrast, CYP3A4 expression level was negligible in both tumoral and non-tumoral tissues. CONCLUSIONS: These results suggest that a significant mRNA level of MDR1 gene was intrinsically present in STS before exposure to chemotherapeutic drugs, suggesting that MDR1 may be important contributors of innate chemoresistance of this tumor type. Show more

Keywords: Soft tissue sarcomas, chemoresistance, MDR1, CYP3A4, mRNA expression level

DOI: 10.3233/CBM-171027

Citation: Cancer Biomarkers, vol. 22, no. 2, pp. 317-324, 2018

Authors: Babińska, Anna | Pȩksa, Rafał | Świa̧tkowska-Stodulska, Renata | Wiśniewski, Piotr | Sworczak, Krzysztof

Article Type: Research Article

Abstract: BACKGROUND: The role of adopokines in adrenal tumors’ hormonal activity remains unclear. Obesity may induce arterial hypertension, disorders of carbohydrate metabolism, and is a risk factor of cardiovascular disease. In patients with subclinical hormone secretion by the adrenal cortex or medulla the risk of metabolic disease is increased. OBJECTIVE: Authors of this retrospective study selected 78 patients with subclinical hormone secretion out of all adrenal incidentaloma patients hospitalized in the Department of Endocrinology and Internal Medicine between 1995 and 2014. METHODS: The analyzed group comprised of 38 subclinical Cushing’s syndrome (SCS), 40 incidentally …discovered pheochromocytoma (PHEO) and 42 patients operated due to an adrenal tumor without pathological hormonal activity. Expression of adiponectin (AdipoR1, AdipoR2) and leptin (Ob-R) receptors in adrenal tumors was assessed in relation to body mass index (BMI) and hormonal activity. RESULTS: We found statistically significant negative correlations between BMI and expression of all examined receptors in SCS patients (AdipoR1: p = 0.032; AdipoR2: p < 0.001; leptin Ob-R: p = 0.001). In PHEOs, BMI correlated negatively only with AdipoR2 (p = 0.014). CONCLUSIONS: Data obtained show that the most significant factor associated with the expression of AdipoR1, AdipoR2 and leptin Ob-R receptors in the adrenal tumor tissue is BMI, not their hormonal activity. Show more

Keywords: AdipoR1, AdipoR2 and Leptin Ob-R receptors, BMI, adrenal tumors

DOI: 10.3233/CBM-171049

Citation: Cancer Biomarkers, vol. 22, no. 2, pp. 325-332, 2018

Authors: Hughes, Nicholas P. | Xu, Lingyun | Nielsen, Carsten H. | Chang, Edwin | Hori, Sharon S. | Natarajan, Arutselvan | Lee, Samantha | Kjær, Andreas | Kani, Kian | Wang, Shan X. | Mallick, Parag | Gambhir, Sanjiv Sam

Article Type: Research Article

Abstract: BACKGROUND AND OBJECTIVE: To monitor therapies targeted to epidermal growth factor receptors (EGFR) in non-small cell lung cancer (NSCLC), we investigated Peroxiredoxin 6 (PRDX6) as a biomarker of response to anti-EGFR agents. METHODS: We studied cells that are sensitive (H3255, HCC827) or resistant (H1975, H460) to gefitinib. PRDX6 was examined with either gefitinib or vehicle treatment using enzyme-linked immunosorbent assays. We created xenograft models from one sensitive (HCC827) and one resistant cell line (H1975) and monitored serum PRDX6 levels during treatment. RESULTS: PRDX6 levels in cell media from sensitive cell lines increased significantly …after gefitinib treatment vs. vehicle, whereas there was no significant difference for resistant lines. PRDX6 accumulation over time correlated positively with gefitinib sensitivity. Serum PRDX6 levels in gefitinib-sensitive xenograft models increased markedly during the first 24 hours of treatment and then decreased dramatically during the following 48 hours. Differences in serum PRDX6 levels between vehicle and gefitinib-treated animals could not be explained by differences in tumor burden. CONCLUSIONS: Our results show that changes in serum PRDX6 during the course of gefitinib treatment of xenograft models provide insight into tumor response and such an approach offers several advantages over imaging-based strategies for monitoring response to anti-EGFR agents. Show more

Keywords: Serum biomarkers, gefitinib, EGFR, NSCLC, proteomics, ELISA

DOI: 10.3233/CBM-171149

Citation: Cancer Biomarkers, vol. 22, no. 2, pp. 333-344, 2018

Authors: Takeshita, Takashi | Yamamoto, Yutaka | Yamamoto-Ibusuki, Mutsuko | Tomiguchi, Mai | Sueta, Aiko | Iwase, Hirotaka

Article Type: Research Article

Abstract: PURPOSE: Plasma and serum cell-free DNA (cfDNA) are useful sources of tumor DNA, but comparative investigations of the tumor mutational status between them are rare. METHODS: we performed droplet digital PCR assay for representative hotspot mutations in metastatic breast cancer (MBC) (ESR1 and PIK3CA ) in serum and plasma cfDNA concurrently extracted from the blood of 33 estrogen receptor-positive MBC patients. RESULTS: ESR1 mutations in plasma cfDNA were found in 7 of the 33 patients; ESR1 mutations in serum cfDNA were detected in only one out of 7 patients with ESR1 mutations in plasma …cfDNA. PIK3CA exon 9 and exon 20 mutations in plasma cfDNA were found in 3 and 7 out of the 33 patients, respectively; PIK3CA exon 9 mutations in serum cfDNA were detected in 2 out of 3 patients with PIK3CA exon 9 mutations in plasma cfDNA; PIK3CA exon 20 mutations in serum cfDNA were detected in 2 out of 7 patients with PIK3CA exon 20 mutations in plasma cfDNA. CONCLUSIONS: Here we show the higher frequency of ESR1 and PIK3CA mutations in the plasma than in the serum in 33 MBC patients; therefore, serum samples should not be considered the preferred source of cfDNA. Show more

Keywords: Metastatic breast cancer, serum cell-free DNA, plasma cell-free DNA, ESR1 mutation, PIK3CA mutation, digital PCR

DOI: 10.3233/CBM-171161

Citation: Cancer Biomarkers, vol. 22, no. 2, pp. 345-350, 2018

Authors: Liberati, Daniela | Marzinotto, Ilaria | Brigatti, Cristina | Dugnani, Erica | Pasquale, Valentina | Reni, Michele | Balzano, Gianpaolo | Falconi, Massimo | Piemonti, Lorenzo | Lampasona, Vito

Article Type: Research Article

Abstract: BACKGROUND: Sensitive and specific biomarkers of Pancreatic Ductal Adenocarcinoma (PDAC) are desperately needed to allow early diagnosis and improve patient’s survival. Ezrin autoantibodies were recently described as present in 93% of PDAC patients and 40% of healthy subjects who later developed PDAC. However, another prospective study failed to replicate these findings. Both studies were based on the use of a solid phase ELISA immunoassay. OBJECTIVE: We aimed at re-evaluating the usefulness of Ezrin autoantibodies as PDAC biomarkers using the Luciferase Immuno Precipitation System (LIPS), an alternative immunoassay format that found successful application for the measurement of …autoantibodies against pancreatic autoantigens. METHODS: We produced a Nanoluciferase™ tagged Ezrin (NLuc-Ezrin). NLuc-Ezrin was then used as antigen in LIPS to test for Ezrin autoantibodies patients affected by PDAC (n = 40), other pancreatic diseases (OPD, n = 50), and healthy controls (n = 60). RESULTS: Overall, binding in liquid phase to Ezrin by serum antibodies was rare and low titer. Furthermore, we did not find statistically significant differences in the prevalence of Ezrin autoantibodies between patients affected by either PDAC or OPD compared to control. CONCLUSIONS: Our results do not confirm the usefulness of Ezrin autoAbs as biomarker of PDAC. Show more

Keywords: PDAC, TAA, biomarker, autoantibody, LIPS

DOI: 10.3233/CBM-181218

Citation: Cancer Biomarkers, vol. 22, no. 2, pp. 351-357, 2018