Quanquan Sun

MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1.

Radioresistance is a major challenge during the treatment of breast cancer. A further understanding of the mechanisms of radioresistance could provide strategies to address this challenge. In our study, we compared the expression of miR‐200c in four distinct breast cancer cell lines: two representative basal cancer cells (MDA‐MB‐231 and BT549) vs. two representative luminal cancer cells (MCF‐7 and BT474). The results revealed practically lower expression of miR‐200c in the two basal cancer cell lines and higher expression of miR‐200c in luminal cancer cells compared to the normal breast epithelial cell line MCF‐10A. Ectopic expression of miR‐200c in MDA‐MB‐231 cells inhibited irradiation‐induced autophagy and sensitized the breast cancer cells to irradiation. We also identified UBQLN1 as a direct functional target of miR‐200c involved in irradiation‐induced autophagy and radioresistance. In 35 human breast cancer tissue samples, we detected an inverse correlation between the expression of miR‐200c vs. UBQLN1 and LC3. These results indicate that the identified miR‐200c/UBQLN1‐mediated autophagy pathway may help to elucidate radioresistance in human breast cancer and might represent a therapeutic strategy.

Meta-analysis of Outcomes Compared between Robotic and Laparoscopic Gastrectomy for Gastric Cancer

This meta-analysis was performed to evaluate and compare the outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for treating gastric cancer. A systematic literature search was carried out using the PubMed database, Web of Knowledge, and the Cochrane Library database to obtain comparative studies assessing the safety and efficiency between RG and LG in May, 2013. Data of interest were analyzed by using of Review Manager version 5.2 software (Cochrane Collaboration). A fixed effects model or random effects model was applied according to heterogeneity. Seven papers reporting results that compared robotic gastrectomy with laparoscopic gastrectomy for gastric cancer were selected for this meta-analysis. Our meta- analysis included 2,235 patients with gastric cancer, of which 1,473 had undergone laparoscopic gastrectomy, and 762 had received robotic gastrectomy. Compared with laparoscopic gastrectomy, robotic gastrectomy was associated with longer operative time but less blood loss. There were no significant difference in terms of hospital stay, total postoperative complication rate, proximal margin, distal margin, numbers of harvested lymph nodes and mortality rate between robotic gastrectomy and laparoscopic gastrectomy. Our meta-analysis showed that robotic gastrectomy is a safe technique for treating gastric cancer that compares favorably with laparoscopic gastrectomy in short term outcomes. However, the long term outcomes between the two techniques need to be further examined.

Mammosphere cells from high-passage MCF7 cell line show variable loss of tumorigenicity and radioresistance.

Mammosphere culture of cancer cell lines is an important approach used for enrichment of stem-like cancer cells (SLCs), but over-subcultured cell lines have been experimentally shown to change properties over time. It remains unclear if mammosphere cells (MSs) derived from high-passage cancer cell lines retain the tumorigenicity and radioresistance seen in MSs from primary or low-passage cell lines. In this study, we report that mammospheres derived from MCF-7 sublines after different passage numbers were consistently enriched for CD44+/CD24(-/low) cells but were not consistently enriched for tumorigenic and radioresistant cells. The tumorigenicity and radioresistance of MSs were associated with their sphere-forming ability, proliferation ability in vitro, and intracellular reactive oxygen species (ROS) levels. The radioresistant MSs showed significant cell cycle arrest in G2/M phase after X-ray irradiation and expressed higher ataxia telangiectasia mutated (ATM) mRNA levels. These results suggest that MSs from high-passage cancer cell lines were not consistently enriched for stem-like cancer cells with higher tumorigenicity and enhanced radioresistance.

MiR-451 increases radiosensitivity of nasopharyngeal carcinoma cells by targeting ras-related protein 14 (RAB14)

Radioresistance severely impedes the treatment of nasopharyngeal carcinoma (NPC). Recent evidence has shown that the abnormal expression of microRNAs (miRNAs) contributes to radiosensitivity. The aim of this study, therefore, was to investigate whether expression of the miRNAs correlated with radiosensitivity in the context of NPC. Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to quantify miR-451 expression in two representative NPC cell lines. The role of miR-451 in NPC radiosensitivity was analyzed using a colony formation assay and an immunofluorescence assay with overexpression of miR-451 in NPC cells. Luciferase reporter assays, RT-PCR, and Western blot were performed to confirm the target of miR-451. High levels of miR-451 expression enhanced radiosensitivity in NPC cells by inhibiting the repair of irradiation-induced double-strand breaks (DSBs) and increasing apoptosis. The results also demonstrated that miR-451 directly targeted ras-related protein 14 (RAB14). Downregulation of RAB14 partially replicated the miR-451-mediated DSBs induced by ionizing radiation (IR). MiR-451 could be a potential target for enhancing radiosensitivity of NPC cells by targeting RAB14.

miR-101 sensitizes human nasopharyngeal carcinoma cells to radiation by targeting stathmin 1

Radioresistance remains a major problem in the treatment of patients suffering from nasopharyngeal carcinoma (NPC). A better understanding of the mechanisms involved in the induction of radioresistance may provide strategies to improve NPC patients’ response to therapy. The present study aimed to investigate the effect of microRNA (miR)-101 on the radioresistance of NPC cells. Analysis of miR-101 expression levels indicated that miR-101 was downregulated in NPC cell lines. Furthermore, ectopic expression of miR-101 suppressed cell proliferation and enhanced radiosensitivity of NPC cells. Stathmin 1 (STMN1) was additionally verified as a direct functional target of miR-101, which was found to be involved in cell viability, radioresistance and radiation-induced autophagy of NPC cells. In conclusions, the results of the present study suggested that the identified miR-101/STMN1 pathway contributed to the elucidation of the mechanisms of radioresistance in human NPC and that it may represent a potential therapeutic target.

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual γ-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR). Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration- and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G2–M cell-cycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. Mol Cancer Ther; 14(2); 429–39. ©2014 AACR.

IGF-1 from Adipose-Derived Mesenchymal Stem Cells Promotes Radioresistance of Breast Cancer Cells

PURPOSE The aim of this study was to investigate effects of adipose-derived mesenchymal stem cells (AMSCs) on radioresistance of breast cancer cells. MATERIALS AND METHODS MTT assays were used to detect any influence of AMSC supernatants on proliferation of breast cancer cells; cell migration assays were used to determine the effect of breast cancer cells on the recruitment of AMSCs; the cell survival fraction post-irradiation was assessed by clonogenic survival assay; γ-H2AX foci number post-irradiation was determined via fluorescence microscopy; and expression of IGF-1R was detected by Western blotting. RESULTS AMSC supernatants promoted proliferation and radioresistance of breast cancer cells. Breast cancer cells could recruit AMSCs, especially after irradiation. IGF-1 derived from AMSCs might be responsible for the radioresistance of breast cancer cells. CONCLUSIONS Our results suggest that AMSCs in the tumor microenvironment may affect the outcome of radiotherapy for breast cancer in vitro.

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.

Protective effect of tanshinone IIA against radiation‑induced ototoxicity in HEI-OC1 cells

Radiotherapy is a highly efficient treatment method for nasopharyngeal carcinoma that is often accompanied by significant ototoxic side-effects. The inner ear hair cells are particularly prone to serious injury following radiotherapy. Tanshinone IIA is a transcription factor inhibitor that is extracted from the traditional herbal medicine, Salvia miltiorrhiza Bunge. The present study investigated the effects of tanshinone IIA treatment on radiation-induced toxicity in the HEI-OC1 hair cell line. Using an MTT assay and flow cytometry, the radiation-induced weakening of the cells was observed to be alleviated when the cells were pre-treated with tanshinone IIA. Radiation exposure promoted p65/nuclear factor (NF)-κB nuclear translocation and activated the p53/p21 pathway, two processes which play a significant role in radiation-induced cell apoptosis. However, pre-treatment of the cells with tanshinone IIA inhibited p65/NF-κB nuclear translocation and p53/p21 pathway activation. These results demonstrate that tanshinone IIA is capable of protecting cochlear cells from radiation-induced injury through the suppression of p65/NF-κB nuclear translocation and the p53/p21 signaling pathway.