MUC3A promotes non-small cell lung cancer progression via activating the NFκB pathway and attenuates radiosensitivity

Mucin 3A (MUC3A) is highly expressed in non-small cell lung cancer (NSCLC), but its functions and effects on clinical outcomes are not well understood. Tissue microarray of 92 NSCLC samples indicated that high levels of MUC3A were associated with poor prognosis, advanced staging, and low differentiation. MUC3A knockdown significantly suppressed NSCLC cell proliferation and induced G1/S accumulation via downregulating cell cycle checkpoints. MUC3A knockdown also inhibited tumor growth in vivo and had synergistic effects with radiation. MUC3A knockdown increased radiation-induced DNA double strain breaks and γ-H2AX phosphorylation in NSCLC cells. MUC3A downregulation inhibited the BRCA-1/RAD51 pathway and nucleus translocation of P53 and XCRR6, suggesting that MUC3A promoted DNA damage repair and attenuated radiation sensitivity. MUC3A knockdown also resulted in less nucleus translocation of RELA and P53 in vivo. Immunoprecipitation revealed that MUC3A interacted with RELA and activated the NFκB pathway via promoting RELA phosphorylation and interfering the binding of RELA to IκB. Our studies indicated that MUC3A was a potential oncogene and associated with unfavorable clinical outcomes. NSCLC patients with a high MUC3A level, who should be more frequent follow-up and might benefit less from radiotherapy.     

Telomere length inversely correlates with radiosensitivity in human carcinoma cells with the same tissue background

A relationship between telomeres and radiosensitivity has been established by several studies based on non-mammalian model systems, mouse models, and few human genetic diseases. However, the relationship has not been proven in human carcinoma cells, which have more clinical significance than these other models. The present study aims to determine whether telomere length is related to radiosensitivity in human carcinoma cells, and to examine the influence of tissue or genetic background. Two HEp-2 larynx squamous carcinoma cell lines, eight hepatocellular carcinoma cell lines, and five breast cancer cell lines were used. Telomere length was determined by terminal restriction fragment (TRF) Southern blot analysis and cell survival was measured by a colony-forming assay. Our results indicated that there was a significant negative correlation of telomere length and radiosensitivity in the same tissue-derived cell lines, with or without the same genetic background. Thus, telomere length may be used as a promising tool to predict the radiosensitivity of human carcinomas.     

预测鼻咽癌放射敏感性的CB微核法

本文介绍一种预测鼻咽癌放射敏感性的方法——CB微核法。以该法评介了鼻咽癌细胞株及20例鼻咽癌患者活检标本的放射敏感性,随着剂量增加,微核率也明显增加。CB微核的剂量-效应与克隆法的剂量效应呈高度负相关(r=-0.970)。活检标本微核实验表明,20例中8例反应较高,7例中等,5例反应偏 低;随访表明,反应偏低者中已有2例有复发倾向。由于CB微核法具有简便、快速、正确性较高等优点,适于临床应用。     

Effects of X-irradiation and adriamycin on quiescent and proliferating cells of the seminal vesicle in the castrated mouse

The sensitivity of resting and proliferating cells of the seminal vesicle to X-irradiation and adriamycin has been investigated. Stimulation with testosterone propionate (250 μg/day) was started 11 days after castration in BALB/c mice. X-rays (2.5–7.5 Gy total body irradiation) and intraperitoneal injections of adriamycin (4–16 mg/kg body weight) were administered at various times before or after induction of proliferation by testosterone injection. The DNA contents and the weights of the seminal vesicles were determined at 4 days after the start of stimulation. A D₀ for X-rays of about 10 Gy was found for the seminal vesicle epithelium. For both X-irradiation and adriamycin no significant differences in sensitivity were observed between quiescent (G₀) and proliferating (G₁; S) seminal vesicle cells.     

MET inhibitor PHA-665752 suppresses the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells

Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC), in subsets of patients, radioresistance is still a major problem in the treatment. In this study, we demonstrated that irradiation induced MET overexpression and activation, and the aberrant MET signal mediated by hepatocyte growth factor (HGF) induced radioresistance. We also found that MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells. Further investigation indicated that PHA-665752 suppressed the phosphorylation of the Akt, ERK1/2, and STAT3 proteins in a dose-dependent manner. Our data indicated that the combination of IR with a MET inhibitor, such as PHA-665752, might be a promising therapeutic strategy for NPC.     

Rosiglitazone enhances the radiosensitivity of p53-mutant HT-29 human colorectal cancer cells

Combined-modality treatment has improved the outcome in cases of various solid tumors, and radiosensitizers are used to enhance the radiotherapeutic efficiency. Rosiglitazone, a synthetic ligand of peroxisome proliferator-activated receptors γ used in the treatment of type-2 diabetes, has been shown to reduce tumor growth and metastasis in human cancer cells, and may have the potential to be used as a radiosensitizer in radiotherapy for human colorectal cancer cells. In this study, rosiglitazone treatment significantly reduced the cell viability of p53-wild type HCT116 cells but not p53-mutant HT-29 cells. Interestingly, rosiglitazone pretreatment enhanced radiosensitivity in p53-mutant HT-29 cells but not HCT116 cells, and prolonged radiation-induced G₂/M arrest and enhanced radiation-induced cell growth inhibition in HT-29 cells. Pretreatment with rosiglitazone also suppressed radiation-induced H2AX phosphorylation in response to DNA damage and AKT activation for cell survival; on the contrary, rosiglitazone pretreatment enhanced radiation-induced caspase-8, -9, and -3 activation and PARP cleavage in HT-29 cells. In addition, pretreatment with a pan-caspase inhibitor, zVAD-fmk, attenuated the levels of caspase-3 activation and PARP cleavage in radiation-exposed cancer cells in combination with rosiglitazone pretreatment. Our results provide proof for the first time that rosiglitazone suppresses radiation-induced survival signals and DNA damage response, and enhances the radiation-induced apoptosis signaling cascade. These findings can assist in the development of rosiglitazone as a novel radiosensitizer.     

IGFBP3 and BAG1 enhance radiation-induced apoptosis in squamous esophageal cancer cells

Identification of reliable markers of radiosensitivity and the key molecules that enhance the susceptibility of esophageal cancer cells to anticancer treatments would be highly desirable. To identify molecules that confer radiosensitivity to esophageal squamous carcinoma cells, we assessed the radiosensitivities of the TE-5, TE-9 and TE-12 cloneA1 cell lines. TE-12 cloneA1 cells showed significantly greater susceptibility to radiotherapy at 5 and 10 Gy than either TE-5 or TE-9 cells. Consistent with that finding, 24 h after irradiation (5 Gy), TE-12 cloneA1 cells showed higher levels of caspase 3/7 activity than TE-5 or TE-9 cells. When we used DNA microarrays to compare the gene expression profiles of TE-5 and TE-12 cloneA1 cells, we found that the mRNA and protein expression of insulin-like growth factor binding protein 3 (IGFBP3) and Bcl-2-associated athanogene 1 (BAG1) was five or more times higher in TE-12 cloneA1 cells than TE-5 cells. Conversely, knocking down expression of IGFBP3 and BAG1 mRNA in TE-12 cloneA1 cells using small interfering RNA (siRNA) significantly reduced radiosensitivity. These data suggest that IGFBP3 and BAG1 may be key markers of radiosensitivity that enhance the susceptibility of squamous cell esophageal cancer to radiotherapy. IGFBP3 and BAG1 may thus be useful targets for improved and more individualized treatments for patients with esophageal squamous cell carcinoma.     

塞来昔布对直肠癌HCA-7 细胞放射敏感性的实验研究

目的:观察环氧合酶-2(COX-2)抑制剂塞来昔布对直肠癌HCA-7细胞株的放射敏感性及探讨其机制。方法:采用MTT法检测塞来昔布作用不同时间对直肠癌HCA-7细胞株增殖的影响,计算出塞来昔布的半数抑制浓度IC50;HCA-7细胞克隆形成实验用于检测塞来昔布对HCA-7细胞的放射敏感性,并绘制存活曲线;流式细胞仪(FCM)测定塞来昔布对HCA-7的细胞周期的影响。结果:塞来昔布对HCA-7细胞株的抑制率随时间的延长而升高,48h的IC50是40.19μmol/L;照射组+药物组的SF2、D0、Dq、SER较单纯照射组均有所下降。塞来昔布使HCA-7细胞发生G2和M期阻滞,并抑制S期的比例。结论:塞来昔布能增加直肠癌HCA-7细胞的放射敏感性。