Timeless-Stimulated miR-5188-FOXO1/ß-Catenin-c-Jun Feedback Loop Promotes Stemness via Ubiquitination of ß-Catenin in Breast Cancer.

MicroRNAs (miRNAs) play an essential role in the self-renewal of breast cancer stem cells (BCCs). Our study aimed to clarify the role of proto-oncogene c-Jun-regulated miR-5188 in breast cancer progression and its association with Timeless-mediated cancer stemness. In the present study, we showed that miR-5188 exerted an oncogenic effect by inducing breast cancer stemness, proliferation, metastasis, and chemoresistance in vitro and in vivo. The mechanistic analysis demonstrated that miR-5188 directly targeted FOXO1, which interacted with ß-catenin in the cytoplasm, facilitated ß-catenin degradation, and impaired the nuclear accumulation of ß-catenin, thus stimulating the activation of known Wnt targets, epithelial-mesenchymal transition (EMT) markers, and key regulators of cancer stemness. Moreover, miR-5188 potentiated Wnt/ß-catenin/c-Jun signaling to promote breast cancer progression. Interestingly, c-Jun enhanced miR-5188 transcription to form a positive regulatory loop, and Timeless interacted with Sp1/c-Jun to induce miR-5188 expression by promoting c-Jun-mediated transcription, which further activated miR-5188-FOXO1/ß-catenin-c-Jun loop and facilitated breast cancer progression. Importantly, miR-5188 was upregulated in breast cancer and was positively correlated with poor patient prognosis. This study identifies miR-5188 as a novel oncomiR and provides a new theoretical basis for the clinical use of miR-5188 antagonists in the treatment of breast cancer.

Activation of the IL-17 signalling pathway by the CXCL17-GPR35 axis affects drug resistance and colorectal cancer tumorigenesis.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, and drug resistance following prolonged treatment leads to downregulation of the efficacy of chemotherapy against CRC. CXCL17 is an inflammatory factor that plays a crucial role in tumorigenesis. However, the function of the CXCL17-GPR35 axis in CRC and resistance to chemotherapy is not entirely clear. Bioinformatic analysis was used to identify differentially expressed genes (DEGs) in oxaliplatin (OXA)-resistant CRC tumour tissues compared to OXA-sensitive counterparts. To further determine the function of CXCL17 in taxol-resistant CRC cells (HCT15), proliferation, migration, invasion, cell cycle, and apoptosis were analysed by CCK-8, wound healing, Transwell®, and flow cytometry assays, respectively. In addition, RNA sequencing, western blotting, CCK-8, wound healing, and Transwell® assays were used to further identify and confirm the downstream effects of CXCL17 regulation on taxol resistance. Our study found that CXCL17 and GPR35 were upregulated in OXA-resistant tumour tissues compared to in OXA-sensitive tissues. CXCL17 silencing significantly decreased the viability, migration, and invasion of taxol-resistant CRC cells. CXCL17 silencing arrested taxol-resistant CRC cells in the G2/M phase and promoted apoptosis. The IL-17 signalling pathway is involved in regulation of the CXCL17-GPR35 biological axis in HCT15 cells, and the addition of IL-17A distinctly reversed the decreased proliferation, migration, and the enhanced apoptosis of HCT15 cells upon CXCL17 deletion. In summary, these findings demonstrate that the CXCL17-GPR35 axis and IL-17 signalling pathway are involved in mediating CRC tumorigenesis and drug-resistance. Inhibition of the CXCL17-GPR35 axis and IL-17 may hence be promising therapeutic targets for CRC resistance to OXA.

Cancer-Associated Fibroblasts Promote Radioresistance of Breast Cancer Cells via the HGF/c-Met Signaling Pathway.

PURPOSE: Cancer-associated fibroblasts (CAFs) are an integral part of the tumor microenvironment (TME), which is involved in therapy resistance. This study aimed to investigate the role of CAFs in radiosensitivity of breast cancer cells. METHODS AND MATERIALS: The CAFs were isolated from the breast cancer tissues, and the conditioned medium was collected to culture breast cancer cells. Radiation-induced DNA damage was evaluated by immunofluorescence and western blotting. Cytokine array and enzyme-linked immunosorbent assay were performed to analyze the secretion of cytokines and growth factors. An in vitro clonogenic survival assay and in vivo xenograft mouse model were performed to determine the radiosensitivity of breast cancer cells. Finally, the expression of hepatocyte growth factor (HGF) and c-Met in the breast cancer tissues were detected by immunohistochemistry. RESULTS: The CAFs were found to secrete HGF to activate the c-Met signaling pathway, which induced epithelial-to-mesenchymal transition, growth, and radioresistance of breast cancer cells. Furthermore, radiation was observed to enhance HGF secretion by CAFs and increase c-Met expression in breast cancer cells, which led to HGF/c-Met signaling pathway activation. Moreover, radiation-induced tumor necrosis factor α (TNFα) secretion by breast cancer cells promoted CAF proliferation and HGF secretion. Additionally, HGF and c-Met high expression were associated with worse recurrence-free survival in patients with breast cancer who had received radiation therapy. CONCLUSIONS: The findings revealed that HGF and TNFα are critical for the crosstalk between breast cancer cells and CAFs in the TME and that the HGF/c-Met signaling pathway is a promising therapeutic target for radiosensitizing breast cancer.

FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2-Mediated Alternative Splicing.

Mesenchymal glioblastoma (GBM) is highly resistant to radio-and chemotherapy and correlates with worse survival outcomes in GBM patients; however, the underlying mechanism determining the mesenchymal phenotype remains largely unclear. Herein, it is revealed that FBXO7, a substrate-recognition component of the SCF complex implicated in the pathogenesis of Parkinson's disease, confers mesenchymal properties and chemoresistance in GBM by controlling Rbfox2-mediated alternative splicing. Specifically, FBXO7 ubiquitinates Rbfox2 Lys249 through K63-linked ubiquitin chains upon arginine dimethylation at Arg341 and Arg441 by PRMT5, leading to Rbfox2 stabilization. FBXO7 controls Rbfox2-mediated splicing of mesenchymal genes, including FoxM1, Mta1, and Postn. FBXO7-induced exon Va inclusion of FoxM1 promotes FoxM1 phosphorylation by MEK1 and nuclear translocation, thereby upregulates CD44, CD9, and ID1 levels, resulting in GBM stem cell self-renewal and mesenchymal transformation. Moreover, FBXO7 is stabilized by temozolomide, and FBXO7 depletion sensitizes tumor xenografts in mice to chemotherapy. The findings demonstrate that the FBXO7-Rbfox2 axis-mediated splicing contributes to mesenchymal transformation and tumorigenesis, and targeting FBXO7 represents a potential strategy for GBM treatment.

A Ferroptosis-Related lncRNA Model to Enhance the Predicted Value of Cervical Cancer.

BACKGROUND: Cervical cancer (CC) is a common gynecological malignant tumor. Ferroptosis is a new type of programmed cell death, which plays a crucial part in cancer. However, current knowledge regarding ferroptosis-related long noncoding RNAs (lncRNAs) in CC is still limited. Therefore, our aim is to identify ferroptosis-related lncRNAs, build a steady prediction model, and improve the prediction value of CC. METHODS: We obtained RNA expression and ferroptosis-related gene data of female CC patients from TCGA and FerrDb databases, respectively. Then, the ferroptosis-related lncRNAs were obtained by the limma R package and Cytoscape 3.7.1. We constructed the prediction model by Cox regression analysis. Finally, the prediction model was verified by the median risk score, Kaplan-Meier analysis, the time-dependent receiver operating characteristic (ROC) curve, clinical features, and immunoinfiltration analysis. RESULTS: We acquired 1393 ferroptosis-related lncRNAs. The ferroptosis-related lncRNA signature was obtained by multivariate Cox regression analysis, and the patients were divided into a high-risk group and a low-risk group. The prognosis of the high-risk group was worse than that of the low-risk group. We found that the risk score can be used as an independent prognostic index by multivariate Cox regression analysis. The area under the time-dependent ROC curve reached 0.847 at 1 year, 0.906 at 2 years, 0.807 at 3 years, and 0.724 at 5 years in the training cohort. Principal component analysis showed that the diffusion directions of the two groups were different. Gene set enrichment analysis indicated that lncRNAs of two groups may be involved in tumorigenesis. Further analysis showed that high-risk groups were related to immune-related pathways. Ferroptosis-related lncRNAs are related to the proportion of tumor-infiltrating immune cells in CC. CONCLUSION: We have constructed a ferroptosis-related lncRNA prediction model. The prognostic model had important clinical significance, including improving the predictive value and guiding the individualized treatment of CC patients.

A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma.

Background: Gastric cancer (GC) represents a major global clinical problem with very limited therapeutic options and poor prognosis. Necroptosis, a recently discovered inflammatory form of cell death, has been implicated in carcinogenesis and inducing necroptosis has also been considered as a therapeutic strategy. Objective: We aim to evaluate the role of this pathway in gastric cancer development, prognosis and immune aspects of its tumor microenvironment. Methods and results: In this study, we evaluated the gene expression of 55 necroptosis-related genes (NRGs) that were identified via carrying out a comprehensive review of the medical literature. Necroptosis pathway was deregulated in gastric cancer samples (n=375) as compared to adjacent normal tissues (n=32) obtained from the "The Cancer Genome Atlas (TCGA)". Based on the expression of these NRGs, two molecular subtypes were obtained through consensus clustering that also showed significant prognostic difference. Differentially expressed genes between these two clusters were retrieved and subjected to prognostic evaluation via univariate cox regression analysis and LASSO cox regression analysis. A 13-gene risk signature, termed as necroptosis-related genes prognostic index (NRGPI), was constructed that comprehensively differentiated the gastric cancer patients into high- and low-risk subgroups. The prognostic significance of NRGPI was validated in the GEO cohort (GSE84437: n=408). The NRGPI-high subgroup was characterized by upregulation of 10 genes (CYTL1, PLCL1, CGB5, CNTN1, GRP, APOD, CST6, GPX3, FCN1, SERPINE1) and downregulation of 3 genes (EFNA3, E2F2, SOX14). Further dissection of these two risk groups by differential gene expression analysis indicated involvement of signaling pathways associated with cancer cell progression and immune suppression such as WNT and TGF-ß signaling pathway. Para-inflammation and type-II interferon pathways were activated in NRGPI-high patients with an increased infiltration of Tregs and M2 macrophage indicating an exhausted immune phenotype of the tumor microenvironment. These molecular characteristics were mainly driven by the eight NRGPI oncogenes (CYTL1, PLCL1, CNTN1, GRP, APOD, GPX3, FCN1, SERPINE1) as validated in the gastric cancer cell lines and clinical samples. NRGPI-high patients showed sensitivity to a number of targeted agents, in particular, the tyrosine kinase inhibitors. Conclusions: Necroptosis appears to play a critical role in the development of gastric cancer, prognosis and shaping of its tumor immune microenvironment. NRGPI can be used as a promising prognostic biomarker to identify gastric cancer patients with a cold tumor immune microenvironment and poor prognosis who may response to selected molecular targeted therapy.

2D-3D cascade network for glioma segmentation in multisequence MRI images using multiscale information.

BACKGROUND AND OBJECTIVE: Glioma segmentation is an important procedure for the treatment plan and follow-up evaluation of patients with glioma. UNet-based networks are widely used in medical image segmentation tasks and have achieved state-of-the-art performance. However, context information along the third dimension is ignored in 2D convolutions, whereas difference between z-axis and in-plane resolutions is large in 3D convolutions. Moreover, an original UNet structure cannot capture fine details because of the reduced resolution of feature maps near bottleneck layers. METHODS: To address these issues, a novel 2D-3D cascade network with multiscale information module is proposed for the multiclass segmentation of gliomas in multisequence MRI images. First, a 2D network is applied to fully exploit potential intra-slice features. A variational autoencoder module is incorporated into 2D DenseUNet to regularize a shared encoder, extract useful information, and represent glioma heterogeneity. Second, we integrated 3D DenseUNet with the 2D network in cascade mode to extract useful inter-slice features and alleviate the influence of large difference between z-axis and in-plane resolutions. Moreover, a multiscale information module is used in the 2D and 3D networks to further capture the fine details of gliomas. Finally, the whole 2D-3D cascade network is trained in an end-to-end manner, where the intra-slice and inter-slice features are fused and optimized jointly to take full advantage of 3D image information. RESULTS: Our method is evaluated on publicly available and clinical datasets and achieves competitive performance in these two datasets. CONCLUSIONS: These results indicate that the proposed method may be a useful tool for glioma segmentation.

Impact of Smoking on Response to the First-Line Treatment of Advanced ALK-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis.

Background: The impact of smoking on the efficacy of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) treatment is controversial and has not been systematically explored in the first-line setting. We performed a systematic review based on a pairwise meta-analysis and a Bayesian network meta-analysis (NMA) to address this issue. Methods: PubMed, Embase, Web of Science, Cochrane Library, Clinical-Trials.gov, and other resources were searched until 5 January 2022. Progression-free survival (PFS) was considered the main outcome of interest. Randomized controlled trials with smoking status analysis were included. Cochrane Risk of Bias Tool was performed to assess the risk of bias. Random effects models were adopted conservatively in meta-analysis. The NMA was performed in a Bayesian framework using the "gemtc" version 1.0-1 package of R-4.1.2 software. Results: A total of 2,484 patients from nine studies were eligible for this study, with 1,547 never-smokers (62.3%) and 937 smokers (37.7%). In a pairwise meta-analysis, in the overall population, no significant difference was found between never-smokers and smokers. However, in the subgroup analyses based on crizotinib-controlled studies, anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) derived better PFS in the smoking group over the never-smoking group in the Asian population (HR = 0.17, 95%CI = 0.09-0.31 in the smoking group, HR = 0.39, 95%CI = 0.24-0.65 in the never-smoking group, p = 0.04, low quality of evidence). In NMA, among never-smokers, lorlatinib ranked the highest for PFS (SUCRA = 96.2%), but no significant superiority was found among the new-generation ALK-TKIs except for ceritinib. In smokers, low-dose alectinib performed best (SUCRA = 95.5%) and also demonstrated a significant superiority over ensartinib (HR = 0.23, 95%CI = 0.08-0.68, very low quality of evidence), brigatinib (HR = 0.38, 95%CI = 0.14-0.99, low quality of evidence), ceritinib (HR = 0.24, 95%CI = 0.09-0.66, low quality of evidence), crizotinib (HR = 0.18, 95%CI = 0.08-0.41, moderate quality of evidence), and chemotherapy (HR = 0.11, 95%CI = 0.05-0.28, low quality of evidence). Conclusion: In general, smoking may not affect the treatment efficacy of advanced ALK-positive NSCLC in the first-line setting. However, alectinib may perform better in the smoking Asian population. Moreover, lorlatinib in never-smokers and low-dose alectinib in smokers could be considered optimal first-line therapy for advanced ALK-positive NSCLC. Acceptable limitations of evidence, such as study risk of bias, inconsistency, and imprecision, were present in this NMA.

ESRP1 regulates alternative splicing of CARM1 to sensitize small cell lung cancer cells to chemotherapy by inhibiting TGF-ß/Smad signaling.

Epithelial splicing regulatory protein 1 (ESRP1) is an RNA-binding protein that regulates alternative splicing of mRNA. ESRP1 plays an important role in chemoresistance of various cancers, including breast cancer, colon cancer and non-small cell lung cancer. However, the role of ESRP1 and its mechanism in small cell lung cancer (SCLC) chemoresistance remains unclear. In this study, we found that ESRP1 is significantly downregulated in SCLC chemo-resistant cells compared with chemo-sensitive cells. Moreover, the expression of ESRP1 was significantly lower in SCLC tissues than that in normal adjacent tissues and positively correlated with overall survival. Overexpression of ESRP1 increased SCLC chemosensitivity, and induced cell apoptosis and cell cycle arrest, whereas knockdown of ESRP1 induced the opposite effects. ESRP1 could inhibit the growth of SCLC in vivo. Through mRNA transcriptome sequencing, we found that ESRP1 regulates coactivator-associated arginine methyltransferase 1 (CARM1) to produce two different transcripts CARM1FL and CARM1ΔE15 by alternative splicing. ESRP1 affects the chemoresistance of SCLC by changing the content of different transcripts of CARM1. Furthermore, CARM1 regulates arginine methylation of Smad7, activates the TGF-ß/Smad pathway and induces epithelial-to-mesenchymal transition (EMT), thereby promoting SCLC chemoresistance. Collectively, our study firstly demonstrates that ESRP1 inhibits the TGF-ß/Smad signaling pathway by regulating alternative splicing of CARM1, thereby reversing chemoresistance of SCLC. The splicing factor ESRP1 may serve as a new drug resistance marker molecule and a potential therapeutic target in SCLC patients.

Circulating Tumor Cells Counting Act as a Potential Prognostic Factor in Cervical Cancer.

BACKGROUND: Circulating tumor cells (CTCs) hold huge potential for both clinical applications and basic research into the management of cancer, but the relationship between CTC count and cervical cancer prognosis remains unclear. Therefore, research on this topic is urgently required. OBJECTIVE: This study investigated whether CTCs were detectable in patients with cervical cancer and whether CTC count was an indicator of prognosis. METHODS: We enrolled 107 patients with pathologically confirmed cervical cancer. CTCs were detected after radiotherapy or concurrent cisplatin-containing chemotherapy in all patients. We evaluated all medical records and imaging data as well as follow-up information to calculate progression-free survival (PFS). PFS was defined as the time until first diagnosis of tumor progression or death. We also analyzed the relationship between CTC count and patient age, disease stage, histological differentiation, tumor size, and pathological type. RESULTS: CTCs were identified in 86 of 107 patients (80%), and the CTC count ranged from 0 to 27 cells in 3.2 mL blood. The median progression-free survival (PFS) was 43.1 months. Patients in which CTCs were detected had a significantly shorter PFS than CTC-negative patients (P = 0.018). Multivariate analysis indicated that CTC count was an independent negative prognostic factor for survival. However, no correlation was observed between CTC count and patient age, disease stage, histological differentiation, tumor size, and pathological type. CONCLUSION: CTC count is an independent negative prognostic factor for cervical cancer.

PITPNC1 fuels radioresistance of rectal cancer by inhibiting reactive oxygen species production.

BACKGROUND: Neoadjuvant radiotherapy is a commonly used method for the current standard-of-care for most patients with rectal cancer, when the effects of radioresistance are limited. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1), a lipid-metabolism-related gene, has previously been proved to manifest pro-cancer effects in multiple types of cancer. However, whether PITPNC1 plays a role for developing radioresistance in rectal cancer patients is still unknown. Therefore, this study aims to investigate the role of PITPNC1 in rectal cancer radioresistance. METHODS: Patient-derived tissue were used to detect the difference in the expression level of PITPNC1 between radioresistant and radiosensitive patients. Bioinformatic analyses of high-throughput gene expression data were applied to uncover the correlations between PITPNC1 level and oxidative stress. Two rectal cancer cell lines, SW620, and HCT116, were selected in vitro to investigate the effect of PITPNC1 on radioresistance, reactive oxygen species (ROS) generation, apoptosis, and proliferation in rectal cancer. RESULTS: PITPNC1 is highly expressed in radioresistant patient-derived rectal cancer tissues compared to radiosensitive tissue; therefore, PITPNC1 inhibits the generation of ROS and improves the extent of radioresistance of rectal cancer cell lines and then inhibits apoptosis. Knocking down PITPNC1 facilitates the production of ROS while application of the ROS scavenger, N-acetyl-L-cysteine (NAC), could reverse this effect. CONCLUSIONS: PITPNC1 fuels radioresistance of rectal cancer via the inhibition of ROS generation.

Fatty liver is a risk factor for liver metastasis in Chinese patients with non-small cell lung cancer.

BACKGROUND: The hepatic microenvironment, which may include chronic inflammation and fibrosis, is considered to contribute to the development of liver metastases. Hepatic steatosis (HS) might cause liver inflammation and fibrosis. However, to date, no studies have investigated the impact of HS on liver metastasis in patients with non-small cell lung cancer (NSCLC). METHODS: A retrospective cohort study was performed on patients who received NSCLC treatment at two hospitals affiliated with the Southern Medical University from January 2005 to December 2015. The patients were grouped according to the presence of HS. The clinicopathological features of patients between the two groups were compared. The effect of HS on liver metastasis and overall metastasis was evaluated, adjusting for other confounders using Cox regression analyses. RESULTS: In total, 1,873 patients with NSCLC with no distant metastases were included in this study, and 408 (21.8%) patients were diagnosed with HS (at the time of diagnosis or before diagnosis). Liver metastases occurred in 166 (8.9%) patients. Liver metastasis-free survival was significantly worse in the study (HS) group (hazard ratio (HR) 1.42; (95% CI [1.03-1.96]); P = 0.031). Multivariate regression analysis demonstrated that HS was an independent risk factor for liver metastasis (HR 1.43; 95% CI [1.02-2.01]; P = 0.039). However, HS was not associated with overall metastasis of NSCLC (HR 0.99; 95% CI [0.84-1.17]; P = 0.895). CONCLUSION: Hepatic steatosis was an independent predictor of liver metastasis from in patients with NSCLC.

Elevated Levels of TNF-α and Decreased Levels of CD68-Positive Macrophages in Primary Tumor Tissues Are Unfavorable for the Survival of Patients With Nasopharyngeal Carcinoma.

Due to the critical role of inflammation in nasopharyngeal carcinoma, we aim to investigate the correlation between nasopharyngeal carcinoma prognosis and the levels of tumor necrosis factor α and macrophages for the development of new prognostic models. The levels of tumor necrosis factor-α and CD68-positive macrophages were measured in 111 primary nasopharyngeal carcinoma specimens by immunohistochemistry. Kaplan-Meier analysis showed that, compared with nonelevated tumor necrosis factor-α levels, elevated tumor necrosis factor α levels were correlated with poorer 10-year distant metastasis-free survival (24.5% vs 5.2%, P = .004) and bone metastasis-free survival (17.0% vs 0.0%, P = .001). Multivariate analysis revealed that tumor necrosis factor α level was an independent prognostic factor for distant metastasis-free survival (hazard ratio = 16.765, P = .001), while the level of CD68-positive macrophages was a favorable independent prognostic factor for cancer-specific survival (hazard ratio = 0.481, P = .023) and disease-free survival (hazard ratio = 0.403, P = .010). Additionally, several prognostic models that considered tumor-node-metastasis stage alone or in combination with tumor necrosis factor α and/or CD68-positive macrophage levels were compared by receiver operating characteristic curve analysis. Interestingly, the T_score model, which considered the tumor necrosis factor α level alone, could better predict the distant metastasis-free survival and bone metastasis-free survival, whereas the MT model, which considered the combination of T stage and CD68-positive macrophage level, could better predict the cancer-specific survival and disease-free survival of patients with nasopharyngeal carcinoma. Elevated tumor necrosis factor-α levels and decreased CD68-positive macrophage levels in primary nasopharyngeal carcinoma tissues are unfavorable prognostic indicators in nasopharyngeal carcinoma. The T_score model or the MT model could be better prognostic models than those currently available for nasopharyngeal carcinoma and could be used to select high-risk patients and aid in the design of individualized immunotherapy.

Differentiation of Recurrence from Radiation Necrosis in Gliomas Based on the Radiomics of Combinational Features and Multimodality MRI Images.

PURPOSE: To classify radiation necrosis versus recurrence in glioma patients using a radiomics model based on combinational features and multimodality MRI images. METHODS: Fifty-one glioma patients who underwent radiation treatments after surgery were enrolled in this study. Sixteen patients revealed radiation necrosis while 35 patients showed tumor recurrence during the follow-up period. After treatment, all patients underwent T1-weighted, T1-weighted postcontrast, T2-weighted, and fluid-attenuated inversion recovery scans. A total of 41,284 handcrafted and 24,576 deep features were extracted for each patient. The 0.623 + bootstrap method and the area under the curve (denoted as 0.632 + bootstrap AUC) metric were used to select the features. The stepwise forward method was applied to construct 10 logistic regression models based on different combinations of image features. RESULTS: For handcrafted features on multimodality MRI, model 7 with seven features yielded the highest AUC of 0.9624, sensitivity of 0.8497, and specificity of 0.9083 in the validation set. These values were higher than the accuracy of using handcrafted features on single-modality MRI (paired t-test, p < 0.05, except sensitivity). For combined handcrafted and AlexNet features on multimodality MRI, model 6 with six features achieved the highest AUC of 0.9982, sensitivity of 0.9941, and specificity of 0.9755 in the validation set. These values were higher than the accuracy of using handcrafted features on multimodality MRI (paired t-test, p < 0.05). CONCLUSIONS: Handcrafted and deep features extracted from multimodality MRI images reflecting the heterogeneity of gliomas can provide useful information for glioma necrosis/recurrence classification.

Long noncoding RNA LINC02582 acts downstream of miR-200c to promote radioresistance through CHK1 in breast cancer cells.

Radiotherapy is essential to treat breast cancer and microRNA (miRNA) miR-200c is considered as a radiosensitizer of breast cancer. However, the molecular mechanisms by which miR-200c regulates radiosensitivity remain largely unknown. In the present study, we showed that induction of miR-200c led to widespread alteration in long noncoding RNA (lncRNA) expression in breast cancer cells. We identified lncRNA LINC02582 as a target of miR-200c. Inhibition of LINC02582 expression increased radiosensitvity, while overexpression of LINC02582 promoted radioresistance. Mechanistically, LINC02582 interacts with deubiquitinating enzyme ubiquitin specific peptidase 7 (USP7) to deubiquitinate and stabilize checkpoint kinase 1 (CHK1), a critical effector kinase in DNA damage response, thus promoting radioresistance. Furthermore, we detected an inverse correlation between the expression of miR-200c vs. LINC02582 and CHK1 in breast cancer samples. These findings identified LINC02582 as a downstream target of miR-200c linking miR-200c to CHK1, in which miR-200c increases radiosensitivity by downregulation of CHK1.

Selective Radiotherapy after Distant Metastasis of Nasopharyngeal Carcinoma Treated with Dose-Dense Cisplatin plus Fluorouracil.

PURPOSE: To investigate the efficacy and safety of selective radiotherapy after distant metastasis of nasopharyngeal carcinoma (NPC) treated with dose-dense cisplatin plus fluorouracil. MATERIALS AND METHODS: Eligible patients were randomly assigned to a study group treated with dose-dense cisplatin plus fluorouracil following selective radiotherapy and a control group receiving traditional cisplatin plus fluorouracil following selective radiotherapy according to a 1:1 distribution using a digital random table method. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate, relapse or progression rate in the radiation field and treatment toxicity. RESULTS: Of 52 patients in the study group, 20 cases underwent radiotherapy., while in the control group of 51 patients, 16 underwent radiotherapy. The median PFS, median OS, survival rates in 1, 2 and 3 years in study and control group were 20.9 vs 12.7months, 28.3 vs 18.8months, 85.2%vs 65.9%, 62.2% vs 18.3%, and 36.6%vs 5.2% (p values of 0.00, 0.00, 0.04, 0.00 and 0.00, respectively). Subgroup analysis showed that the median OS and survival rates of 1, 2, 3 years for patients undergoing radiotherapy in the study group better than that in control group( 43.2vs24.1 months, 94.1% vs 86.7%, 82.4% vs 43.3%, 64.7% vs 17.3%, (p=0.00, 0.57, 0.04 and 0.01, respectively). The complete response rate, objective response rate after chemotherapy and three months after radiotherapy, relapse or progression rate in radiation field in study group and in control group were 19.2% vs 3.9%, 86.5% vs 56.9%, 85% vs 50%, 95% vs 81.3% and 41.3% vs 66.7% (p =0.03, 0.00, 0.03,0.30, 0.01 respectively). The grade 3-4 acute adverse reactions in the study group were significantly higher than in the control group (53.8% vs 9.8%, p=0.00). CONCLUSIONS: The survival of patients benefits from selective radiotherapy after distant metastasis of NPC treated with dose-dense cisplatin plus fluorouracil.

[Expression of multidrug resistance gene in nasopharyngeal carcinoma cells after irradiation exposure].

OBJECTIVE: To examine the changes in the function and expression of multidrug resistance gene (mdr1) and P-gly-coprotein (P-gp) in nasopharyngeal carcinoma (NPC) CNE1 cell following irradiation for determining the sequential order of radiotherapy and chemotherapy in the treatment of NPC. METHODS: The expressions of mdr1 gene and its protein P-gp as well as the function of P-gp efflux were examined in CNE1 cells before and after irradiation exposure by reverse transcriptional polymerase chain reaction (RT-PCR), Western blotting and flow cytometry, respectively. RESULTS: Irradiation of CNE1 cells induced a long-term overexpression of mdr1 gene and P-gp and reduction in intracellular daunorubicin accumulation. CONCLUSION: Irradiation decreases the chemotherapy sensitivity of CNE1 cell, and induction chemotherapy should be therefore performed before radiotherapy in the treatment of advanced NPC.

Data mining and bioinformatics of the expression data of esophageal squamous cell carcinoma.

The aim is to explore the molecular regulation mechanism of the pathogenesis of the esophageal squamous cell carcinoma. The expression data of esophageal squamous cell carcinoma were obtained from the GEO database. The differential expression genes were identified by the BRB-array tools and the pathway was analyzed by DAVID online tools. The class comparison analysis showed that there were 376 differential expression genes. These genes involved in many tumor-related pathways. What is more, these pathways had common genes. As a conclusion, it was helpful to comprehensively understand the pathogenesis of esophageal squamous carcinoma using data mining and bioinformatics analysis of esophageal squamous cell carcinoma. It would offer new ideas for target therapy of the esophageal squamous cell carcinoma.

A systems biology approach to study the biology characteristics of esophageal squamous cell carcinoma by integrating microRNA and messenger RNA expression profiling.

Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors. The aim of this study was to investigate the biology characteristics of ESCC by analyzing microRNA and mRNA expression profile. We used BRB-array tools to analyze the deregulated microRNA and mRNA between esophageal squamous cell carcinomas and paired normal adjacent tissues. We used miRTrail and protein-protein interaction methods to explore the related pathways and networks of deregulated microRNA and mRNA. By combining the results of pathways and networks, we found that the deregulated microRNA and their deregulated target mRNA are enriched in the following pathways: DNA replication, cell cycle, ECM-receptor interaction, focal adhesion, mismatch repair, and pathways in cancer. The results showed that many deregulated microRNAs and mRNAs may play a vital role in the pathogenesis of ESCC, and the systems biology approach is very helpful to explore molecular mechanism of ESCC.

[Effects of short hairpin RNA targeting epidermal growth factor receptor on the radiosensitivity of human nasopharyngeal carcinoma xenografts in nude mice].

OBJECTIVE: To investigate the effect of the vector carrying short hairpin RNA targeting epidermal growth factor receptor (shRNA-EGFR) on the radiosensitivity of human nasopharyngeal carcinoma xenografts in nude mice. METHODS: shRNA-EGFR was transfected into human nasopharyngeal carcinoma cell line CNE1 via Lipofectamine 2000. The transfected cells were collected for quantitative RT-PCR detection of the expression level of EGFR mRNA. Western blotting was used to examine the expression of EGFR protein. CNE1 cells were inoculated into nude mice and the tumor volume was measured every 2 days. shRNA-EGFR was intratumorally injected in the mice, and 16 days after radiotherapy, the mice were sacrificed and tumors examined for radiosensitivity. RESULTS: shRNA-EGFR was effectively delivered via Lipofectamine 2000 into CNE cells to result in a significant downregulation of EGFR mRNA and protein expressions (P<0.05). A significant difference was noted in the tumor volume and weight in the tumor-bearing nude mice between shRNA-EGFR plus radiotherapy group and the control, exclusive radiotherapy and shRNA-EGFR groups (P<0.05). CONCLUSION: shRNA-EGFR combined with radiotherapy can effectively inhibit the growth of nasopharyngeal carcinoma in nude mice. shRNA-EGFR can enhance sensitivity of nasopharyngeal carcinoma to radiotherapy.