[Show abstract][Hide abstract] ABSTRACT: The main purpose of this study is to investigate the interactions between Lin28 and Her2 in gastric cancer. Lin28 and Her2 expression were evaluated in surgically resected samples of 298 gastric cancer patients using immunohistochemical staining. The correlations between Lin28/Her2 expression and clinical variables were retrospectively analyzed. The mRNA level of LIN28 and HER2 was detected by reverse-transcriptase polymerase chain reaction. Among all gastric cancer patients, 33.9 % (101/298) were determined as Her2-positive, and 43.0 % (128/298) were defined as Lin28-positive. Lin28 was significantly associated with Her2, advanced tumor stage, lesion size, and Ki67 level (p < 0.05 for each). Kaplan-Meier analysis illustrated that both Lin28 and Her2 are poor prognostic factors in gastric cancer; Lin28(+)/Her2(+) patients have the poorest survival (median survival = 17 months, p < 0.01). Multivariate Cox analysis showed that Lin28 is a significant prognostic factor (hazard ratio (HR) = 1.79, 95 % confidence interval (CI) 1.23-2.62). Further stratification analysis indicated that Lin28 may be a prognostic factor in chemotherapy. In vitro data on MKN-28 and MKN-45 cells showed that Lin28 can upregulate Her2 expression at translational level. Both Lin28 and Her2 are poor prognostic factors in gastric cancer. Lin28 may regulate Her2 post-transcriptionally in gastric cancer cells, which indicates it might be a potential target in the treatment of gastric cancer.
[Show abstract][Hide abstract] ABSTRACT: Chemotherapy resistance is one of the major obstacles limiting the success of cancer drug treatment. Among the mechanisms of resistance to chemotherapy treatment, there are those closely related to P-Glycoprotein, multidrug resistance-related protein, glutathione S-transferase pi and topoisomerase-II. Lin28 is a highly conserved RNA-binding protein, it consists of a cold shock domain and retroviral-type (CCHC) zinc finger motifs. In previous preclinical and clinical studies, positive Lin28 expression in cancer cells was correlated with decreased sensitivity to chemotherapy. And Lin28 could mediate cancer chemotherapy resistance via regulation of miR107 and Let-7 MiRNA. This article reviews current knowledge on predictive value of Lin28 in response to chemotherapy. Better understanding of its role may facilitate patient's selection of therapeutic regimen and lead to optimal clinical outcome.
[Show abstract][Hide abstract] ABSTRACT: Current endocrine therapies for females with estrogen receptor-positive breast cancer have facilitated substantial improvements in outcomes. The effectiveness of endocrine therapy is limited by either initial de novo resistance or acquired endocrine resistance. Multiple mechanisms responsible for endocrine resistance have been proposed, including deregulation of various components of the estrogen receptor (ER) pathway, alterations in cell cycle and cell survival signaling molecules, and the activation of escape pathways. Dysregulation of miRNA expression has been associated with experimental and clinical endocrine therapy resistance. miRNAs are pivotal to understanding the complex biological mechanism of endocrine resistance, and may serve as novel candidate predictive and prognostic surrogates and therapeutic targets. This review focuses on current progress concerning the roles of miRNAs in endocrine resistance, and discusses the challenges and opportunities for implementing miRNA-based assays and treatment for patients with endocrine-resistant breast cancer.
[Show abstract][Hide abstract] ABSTRACT: The relationship between estrogen receptor (ER)α and patient prognosis has been identified in gastric cancer; however, the definite role of ERα in gastric cancer remains to be fully elucidated. The aim of the present in vitro study was to investigate the impact of ERα on cell proliferation, migration and invasion in gastric cancer cell lines. We investigated the biological effect of ERα overexpression on gastric carcinoma cells. An MKN28 gastric cancer cell line stably overexpressing ERα was established. The effect of ERα overexpression on cell growth was assessed by evaluating cell survival, colony formation, cell cycle progression and apoptosis. Cell migration and invasion were detected by Transwell migration/invasion assays. The protein levels of several potentially involved genes were determined by western blotting to elucidate the underlying molecular mechanisms. The Student's t-test was used to determine the statistical differences between various experimental and control groups, and one-way ANOVA test was used to determine the difference between three or more groups. The results showed that ERα overexpression significantly inhibited cell growth and proliferation, blocked cell entry into the G1/G0 phase and promoted cell apoptosis. In addition, ERα reduced the motility and invasion of gastric cancer cells. These phenotypes may partly be explained by a decrease in β-catenin expression caused by ERα overexpression. ERα overexpression effectively inhibited cell growth and cancer progression by suppressing β-catenin in gastric cancer, identifying ERα as a promising target with therapeutic potential for development of new approaches to treat gastric cancer.
[Show abstract][Hide abstract] ABSTRACT: Resistance to radiation therapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to breast tumorigenesis; however, the relationship between Lin28 and radioresistance remains unknown. In this study, we investigated the association of Lin28 with radiation resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines. The results showed that the expression level of Lin28 was closely associated with resistance to radiation treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to radiation than MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which have low-level Lin28 expression. Transfection with Lin28 siRNA significantly led to an increase of sensitivity to radiation. By contrast, stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to radiation treatment. Stable expression of Lin28 also significantly inhibited radiation-induced apoptosis. Moreover, further studies have shown that caspases, H2A.X and Let-7 miRNA were the molecular targets of Lin28. Stable expression of Lin28 and treatment with radiation induced H2AX expression, while inhibited p21 and γ-H2A.X. Overexpression of Let-7 enhanced the sensitivities to radiation in breast cancer cells. Taken together, these results indicate that Lin28 might be one mechanism underlying radiation resistance, and Lin28 could be a potential target for overcoming radiation resistance in breast cancer.
PLoS ONE 06/2013; 8(6):e67373. DOI:10.1371/journal.pone.0067373 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate the expression of Lin28 in gastric carcinoma and to assess its clinical significance. The expression level of Lin28 was assessed by reverse-transcriptase polymerase chain reaction in 10 surgically resected gastric carcinoma and corresponding normal tissues, and by immunohistochemical staining in surgically resected gastric carcinoma tissues of 229 patients, including 215 curative resection patients and 14 palliative resection patients. The expression level of Lin28 mRNA in gastric carcinoma tissues and corresponding normal tissues had no statistically significant difference. In curative resection patients, Lin28 protein expression was positive in 99 of 215 (46.0 %) gastric carcinoma tissues. In palliative resection patients, Lin28 protein expression was positive in 4 of 14 (28.6 %) gastric carcinoma tissues. In R0 patients, Lin28 protein positive expression was correlated with poor outcome (P = 0.017). In multivariate analysis, the Lin28 protein positive expression was a significant independent prognostic factor for overall survival (P = 0.024; HR, 1,768; 95 % CI 1.077-2.903). Our results indicate that Lin28 was expressed in both gastric carcinoma and corresponding normal tissues. Lin28 protein positive expression served as an independent prognostic factor.
Medical Oncology 03/2013; 30(1):382. DOI:10.1007/s12032-012-0382-x · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Estrogen receptor α36 (ERα36) is believed to mediate membrane-initiated effects of estrogen signaling, and promote cell growth and resistance to tamoxifen treatment. However, few studies are available regarding ERα36 expression in gastric cancer. In the present study, we evaluated the expression of ERα36, as well as estrogen receptor α66 (ERα66), in gastric cancer and its correlation with clinicopathological parameters. Real-time polymerase chain reaction (PCR) was applied to detect the expression of ERα66 and ERα36 mRNA in 45 pairs of samples of gastric cancer tissues and matched normal tissues. The ΔΔCT method was used to evaluate the relative quantity of target mRNA expression. Among the 45 pairs of samples of gastric cancer tissues and matched normal tissues adjacent to the tumor, the ERα36 mRNA levels in normal tissues were significantly higher than those observed in gastric cancer tissues (p=0.040). Additionally, the expression of ERα66 mRNA levels between gastric cancer tissues and matched normal tissues had no statistically significant difference. We confirmed that ERα36 mRNA was expressed in the four gastric cancer cell lines, and ERα66 mRNA was expressed in two of the four gastric cancer cell lines. According to the tissue and cell findings, it was suggested that the expression level of ERα36 is greater than that of ERα66 in gastric cancer. In conclusion, the expression of ERα66 and ERα36 in gastric cancer tissues and cells was confirmed in this study. A decreased expression of ERα36 mRNA in gastric cancer tissues may be one of the factors affecting tumorigenesis in gastric cancer patients.
[Show abstract][Hide abstract] ABSTRACT: Previous studies suggested that estrogen receptor alpha (ERα) plays an important role in the chemoresistance of breast cancers. However, large random trials failed to demonstrate any benefit of the concurrent estrogen antagonist tamoxifen on the chemotherapy efficacy. Thus, in the present study, the importance of the role of ERα in the chemoresistance of breast cancer cells was investigated.
The ERα-transfected Bcap37 cells and natural ERα-positive T47D breast cancer cells were treated using chemotherapeutic agents with or without 17-beta estradiol (E2) pretreatment. Their viabilities were assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. The dead cell rates were determined using propidium iodide dye exclusion tests, and the expression levels of Bcl-2 and Bax were detected through Western blot analysis. The effects of E2 on the growth of breast cancer cells were also determined via cell growth curve and cell cycle analysis.
ERα activation by E2 increased the sensitivity of natural ERα-positive T47D breast cancer cells to chemotherapeutic agents. However, the increase in ERα expression in ERα-negative Bcap37 breast cancer cells also significantly increased their resistance. These phenomena cannot be explained by asserting that ERα mediated the chemoresistance of breast cancer cells by regulating the expression of Bcl-2 and Bax. Our findings show that ERα activation upregulated the expression of Bcl-2 in natural ERα-positive T47D breast cancer cells, whereas ERα activation by E2 downregulated and upregulated the Bcl-2 and Bax expression levels, respectively, in ERα-transfected Bcap37 cells. This phenomenon was due to the influence of ERα on the growth of breast cancer cells. Specifically, ERα activation enhanced the growth of natural ERα-positive breast cancer cells and thus increased their sensitivity to chemotherapeutic agents. However, ERα activation also inhibited the growth of ERα-transfected Bcap37 cells and increased the resistance of cancer cells to chemotherapeutic agents. Chemoresistance of ERα-transfected Bcap37 cells was only due to the specific growth inhibition by E2, which is not applicable to common ERα-positive breast cancer cells.
Although ERα was associated with chemoresistance of breast cancers, ERα itself did not mediate this resistance process.
Journal of Experimental & Clinical Cancer Research 05/2012; 31(1):42. DOI:10.1186/1756-9966-31-42 · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/Aims: Although malignant ulcers have been documented in gastric cancer, the specific relationship between ulcer size and lymph node stages in gastric cancer remains uncertain. The aim of this study was to investigate the relationship between ulcer size and lymph node stages in gastric cancer patients. Methodology: The diameter of the malignancy ulcer was measured, the patients were divided into three groups based on the presence of ulcer and its median size: U0 no ulcer; U1 ulcer size 0-3cm, U2 the ulcer size >3cm. Univariate and multivariate analyses were perfromed. Results: The distribution of lymph node stages differed significantly between U0 and U1+U2 (p<0.001), and the similar difference was present between U1 and U2 (p<0.001). In all patients, the presence of ulcer correlated with lymph node stages (pN- vs. pN+). In ulcerative gastric cancer patients the stage pN2-3 was more common in patients with U2 (14.1%, 19/135) than in U1 (6.4%, 12/188; p< 0.001). A logistic regression model revealed that lymph node metastases were associated with presence of malignant ulcer (p=0.002), and the ulcer size still emerges as a significant variable ulcer size in ulcerative cancer (p=0.022). Conclusions: For gastric cancer patients, the presence of ulcer and ulcer size might be a potential biomarker of lymph node metastasis.