信号转导与转录因子3和表皮生长因子受体在宫颈不同病变组织中的表达及其临床意义

目的:探讨信号转导与转录因子3(STAT3)与表皮生长因子受体(EGFR)在宫颈不同病变组织中的表达变化及其临床意义。方法:采用Western blot与免疫组化的方法检测100例上皮内瘤样病变(CIN)组织、60例宫颈癌组织及40例正常宫颈组织中STAT3与EGFR的表达;分析STAT3与EGFR的表达与宫颈癌组织病理特征的关系;对宫颈癌组织中STAT3与EGFR的表达的相关性进行分析。结果:宫颈癌组织以及CIN组织中STAT3、EGFR的表达量和阳性率显著高于正常宫颈组织(P0.05),且宫颈癌组织中STAT3、EGFR的表达量和阳性率高于CIN组织,差异有统计学意义(P0.05);STAT3与EGFR在宫颈癌组织中的染色强度较正常宫颈组织以及CIN组织显著增强;STAT3与EGFR的异常表达与宫颈癌患者的组织学分级、临床分期以及是否发生淋巴结转移有关(P0.05),而与年龄以及病理分型无关(P0.05);宫颈癌组织中STAT3和EGFR表达呈正相关(P0.05)。结论:STAT3与EGFR表达与CIN、宫颈癌的进展紧密相关,且与宫颈癌部分病理特征相关,二者有可能作为宫颈癌诊断及预后的参考指标。     

β-Sitosterol activates Fas signaling in human breast cancer cells

beta-Sitosterol is the most abundant phytosterol. Phytosterols are enriched in legumes, oil seeds and unrefined plant oils as found in foods such as peanut butter, pistachios and sunflower seeds. beta-Sitosterol inhibits the growth of several specific types of tumor cells in vitro and decreases the size and the extent of tumor metastases in vivo. The effects of beta-sitosterol on the extrinsic apoptotic programmed cell death pathway in human breast MCF-7 and MDA-MB-231 adenocarcinoma cells were examined, along with the extent of its incorporation into cellular membranes and its effects on cell growth, expression of Fas receptor pathway proteins, and caspase-8 activity. The results show that beta-sitosterol exposure promotes its enrichment in transformed cell membranes and significantly inhibits tumor cell growth. Concurrently, Fas levels and caspase-8 activity are significantly increased. These actions are specific, as expression of other proteins of the Fas receptor pathway, including Fas ligand, FADD, p-FADD and caspase-8, remain unchanged. These findings support the hypothesis that beta-sitosterol is an effective apoptosis-promoting agent and that incorporation of more phytosterols in the diet may serve a preventive measure for breast cancer.     

G0S2 represses PI3K/mTOR signaling and increases sensitivity to PI3K/mTOR pathway inhibitors in breast cancer

G0/G1 switch gene 2 (G0S2) is a direct retinoic acid target implicated in cancer biology and therapy based on frequent methylation-mediated silencing in diverse solid tumors. We recently reported that low G0S2 expression in breast cancer, particularly estrogen receptor-positive (ER+) breast cancer, correlates with increased rates of recurrence, indicating that G0S2 plays a role in breast cancer progression. However, the function(s) and mechanism(s) of G0S2 tumor suppression remain unclear. In order to determine potential mechanisms of G0S2 anti-oncogenic activity, we performed genome-wide expression analysis that revealed an enrichment of gene signatures related to PI3K/mTOR pathway activation in G0S2 null cells as compared to G0S2 wild-type cells. G0S2 null cells also exhibited a dramatic decreased sensitivity to PI3K/mTOR pathway inhibitors. Conversely, restoring G0S2 expression in human ER+ breast cancer cells decreased basal mTOR signaling and sensitized the cells to pharmacologic mTOR pathway inhibitors. Notably, we provide evidence here that the increase in recurrence seen with low G0S2 expression is especially prominent in patients who have undergone antiestrogen therapy. Further, ER+ breast cancer cells with restored G0S2 expression had a relative increased sensitivity to tamoxifen. These findings reveal that in breast cancer G0S2 functions as a tumor suppressor in part by repressing PI3K/mTOR activity, and that G0S2 enhances therapeutic responses to PI3K/mTOR inhibitors. Recent studies implicate hyperactivation of PI3K/mTOR signaling as promoting resistance to antiestrogen therapies in ER+ breast cancer. Our data establishes G0S2 as opposing this form of antiestrogen resistance. This promotes further investigation of the role of G0S2 as an antineoplastic breast cancer target and a biomarker for recurrence and therapy response.     

GRIM-19 inhibits the STAT3 signaling pathway and sensitizes gastric cancer cells to radiation

Gastric cancer is one of the most common malignancies, and radiation resistance is one of the key obstacles in gastric cancer treatment. In this study, we demonstrate that “genes associated retinoid–IFN induced mortality-19” (GRIM-19) expression was lower in patients with radiotherapy-resistant tumors compared to patients with radiotherapy-sensitive tumors. In order to further investigate the effects of GRIM-19 expression on the radiation response in gastric cancer cells, we established BGC-803 clones stably expressing exogenous GRIM-19. We found that the percentage of apoptotic cells was higher in cells expressing GRIM-19 than untransfected cells post-radiation treatment. Furthermore, caspase-3, -8, and -9 activity was significantly increased in GRIM-19-expressing cells compared to untransfected cells after radiation. Finally, we demonstrate that expression of GRIM-19 in BGC-803 cells suppresses accumulation of STAT3. Collectively, these data show that GRIM-19 expression sensitizes BGC-803 cells to radiation, and this is likely due to suppression of STAT3 accumulation. In summary, our results indicate that GRIM-19 expression might be a useful therapy to enhance apoptosis in gastric cancer cells in response to radiation treatment.