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1.
Cancer Med ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31464090

RESUMO

RIG-I is associated with the occurrence and development of many tumors. However, the role of RIG-I in radiotherapy and chemotherapy in NPC has not been reported to date. In our study, RIG-I expression was significantly reduced in chemoradiotherapy-resistant NPC tissues and cells compared with that in therapy-sensitive tissues and cells. RIG-I expression increased in nonresistant NPC cells, including CNE1 and CNE2, in a dose-dependent manner with increasing chemotherapy drug concentration or radiotherapy dose. RIG-I overexpression promoted radiotherapy and chemotherapy sensitivity in NPC cells, leading to cellular apoptosis and increased expression of the proapoptotic factors BAX and caspase-3. Similarly, RIG-I knockdown in NPC cells promoted chemoradiotherapy resistance and reduced apoptosis. Analysis of microarray data indicated that the expression of IFN/JAK2 and endoplasmic reticulum (ER) stress response markers, such as JAK2, STAT1, IRF9, IFNB1, IRF3, p-IRF3, XBP1, ATF6, IFIT2, and ISG15, was inhibited in chemoradiotherapy-resistant cells compared with that in sensitive cells. Conversely, activation of IFN/JAK2 and ER stress response pathways in NPC cells reduced paclitaxel resistance and increased apoptosis. RIG-I promotes IFN/JAK2 and ER stress response-mediated apoptosis to inhibit chemoradiation resistance in nasopharyngeal carcinoma.

2.
World Neurosurg ; 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31442642

RESUMO

BACKGROUND: There are no standardized criteria to predict the prognosis of patients with low-grade gliomas. Therefore, novel prognostic biomarkers that can guide follow-up schedules and therapeutic approaches are urgently required in patients with low-grade gliomas. METHODS: One hundred and nineteen patients with World Health Organization (WHO) II gliomas were recruited between January 2010 and December 2016 from Xiangya Hospital for this study. We collected neutrophil and lymphocyte values from the full blood counts measured 24 h before surgery. Neutrophil-to-lymphocyte ratios (NLRs) were then calculated. The significance of the NLR was determined based on a nonparametric test. The Kaplan-Meier method was used to estimate survival rates. The influence of the NLR on progression-free survival (PFS) and overall survival (OS) was evaluated using univariate and multivariate Cox proportional hazards models. RESULTS: Preoperative NLRs were upregulated in patients with WHO II gliomas who relapsed or died. Preoperative NLRs were also significantly correlated with age, preoperative neutrophil values, and preoperative lymphocyte values. Compared with the low preoperative NLR group, patients with WHO II gliomas in the high preoperative NLR group had significantly higher relapse and lower survival rates. Additionally, the preoperative NLR and tumor type were independent prognostic parameters of PFS for WHO II gliomas, while only the preoperative NLR was an independent prognostic parameter of OS for WHO II gliomas. CONCLUSIONS: High preoperative NLRs were significantly associated with greater relapse and poor prognosis in patients with WHO II gliomas.

3.
J Cell Physiol ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332784

RESUMO

Colorectal cancer (CRC) is commonly known as one of the most prominent reasons for cancer-related death in China. Ras homolog enriched in brain (RHEB) and the mammalian target activity of rapamycin (mTOR) signaling pathway were found correlated with CRC, but their specific interaction in CRC was still to be investigated. Therefore, we explored whether RHEB gene silencing affected the cell proliferation, differentiation, and apoptosis by directly targeting the mTOR signaling pathway in cells previously harvested from CRC patients. A microarray analysis was subsequently conducted to investigate the relationship between RHEB and mTOR. Eighty-three adjacent normal tissues and CRC tissues were selected. Immunohistochemistry was carried out to detect the positive expression rates of RHEB and Ki-67 in the CRC tissues. Cells were then transfected with different siRNAs to investigate the potential effects RHEB would have on CRC progression. The expressions of RHEB, 4EBP1, ribosomal protein S6 kinase (p70S6K), proliferating cell nuclear antigen (PCNA), B cell lymphoma 2 (bcl-2), and bcl-2-associated X protein (bax) were determined and then the cell cycle, cell proliferation, and apoptotic rate were also measured. We identified RHEB and mTOR as upregulated genes in CRC. Cells treated with RHEB silencing showed a decreased extent of mTOR, p70S6K, 4EBP1 phosphorylation and expression of RHEB, Ki-67, mTOR, p70S6K, 4EBP1, bcl-2, and PCNA as well as decreased activity of cell proliferation and differentiation; although, the expression of bax was evidently higher. Collectively, our data propose the idea that RHEB gene silencing might repress cell proliferation and differentiation while accelerating apoptosis via inactivating the mTOR signaling pathway.

4.
Biosci Rep ; 39(5)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31040200

RESUMO

Radiotherapy is the primary treatment option for nasopharyngeal carcinoma (NPC). Local recurrence and metastasis caused by radioresistance become a bottleneck of curative effect for patients with NPC. Currently, serum predictive biomarkers of radioresistance are scare. We enrolled NPC patients, who underwent radiotherapy in the Department of Oncology, Xiangya Hospital, Central Southern University, and analyzed the serum proteins profiles in NPC patients using with quantitative label-free proteomics using ultra-definition MS. Patients were divided into those who were radioresistant and radiosensitive by the overall reduction (≤50% or >50%, respectively) in tumor extent. The MS/MS spectrum database search identified 911 proteins and 809 proteins are quantitatable. Eight proteins significantly up-regulated and 12 serum proteins were significantly down-regulated in the radioresistance group compared with radiosensitivity group (P<0.05). Finally, five proteins entered the optimal models, including secreted protein acidic and cysteine rich (SPARC) (P =0.032), serpin family D member 1S (ERPIND1) (P =0.040), complement C4B (C4B) (P =0.017), peptidylprolyl Isomerase B (PPIB) (P =0.042), and family with sequence similarity 173 member A (FAM173A) (P =0.017). In all patient, the area under the curves (AUC) for SPARC, SERPIND, C4B, PPIB, and FAM173A were 0.716 (95% CI: 0.574-0.881), 0.697 (95% CI: 0.837-0.858), 0.686 (95% CI: 0.522-0.850), 0.668 (95% CI: 0.502-0.834) and 0.657 (95% CI: 0.512-0.825), respectively. The AUC of five selected proteins was 0.968 (95% CI: 0.918-1.000) with the sensitivity of 0.941 and the specificity of 0.926. Our result indicated that a panel including five serum protein (SPARC SERPIND1 C4B PPIB FAM173A) based on serum proteomics provided a high discrimination ability for radiotherapy effects in NPC patients. Studies with larger sample size and longer follow-up outcome are required.

5.
Biosci Rep ; 39(6)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31092699

RESUMO

Introduction: The treatment strategy for low-grade gliomas (LGGs) is still controversial, and there are no standardized criteria to predict the prognosis of patients with LGGs. Magnetic resonance imaging (MRI) is a routine test for preoperative diagnosis for LGG and can reflect the destructive features for the tumor. In the present study, we aimed to explore the relationship between the MRI features and prognosis in patients with LGG.Methods: Clinical data of 80 patients with pathologically proved LGGs between January 2010 and December 2016 were analyzed retrospectively. MRI features were classified as contrast enhancement pattern (focal enhancement, diffuse enhancement and ring-like enhancement), necrosis and cysts based on the preoperative MR images. Kaplan-Meier method and multivariate analysis were performed on the data by SPSS software to explore the prognostic significance of MRI features.Results: Patients with cystic LGG had a significantly longer 5-year progression-free survival (PFS) than that with no cyst (90.9 ± 8.7 vs 65.7 ± 9.1%, P=0.045). Multivariate analysis further verified cyst as an independent prognosis factor for PFS (P=0.027, hazard ratio [HR] = 0.084). Additionally, patients with ring-like enhancement exhibited significantly longer 5-year PFS time in the Kaplan-Meier survival curves (100 vs 67.2 ± 7.7%, P=0.049). There was no significant difference in PFS and overall survival (OS) between patients with or without necrosis.Conclusion: Our study suggests that cyst formation and ring-like enhancement on preoperative MR images can be useful to predict a favorable prognosis in patients with LGGs.

6.
J Cell Physiol ; 234(11): 21380-21394, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31102273

RESUMO

Colorectal cancer (CRC) is a form of cancer developing from either the colon or rectum. Nowadays, research supports the functionality of exosome expressing microRNAs (miRNAs) as potential biomarker for various cancers including CRC. This study was performed with the intent of investigating the roles of both bone marrow-derived mesenchymal stem cells (BMSCs) and exosomal miR-16-5p in CRC by regulating integrin α2 (ITGA2). A microarray-based analysis was conducted to screen the CRC-associated differentially expressed genes (DEGs) as well as potential regulatory miRNAs. Next, the role of miR-16-5p in terms of its progression in association with CRC was determined. Subsequently, CRC cells were exposed to exosomes secreted by BMSCs transfected with miR-16-5p, isolated and cocultured with CRC cells in an attempt to identify the role of exosomes. Effects of BMSCs-derived exosomes overexpressing miR-16-5p on biological functions of CRC cells and tumorigenicity were all subsequently detected. Effects of miR-16-5p treated with CRC cells in regard to CRC in vivo were also measured. ITGA2 was overexpressed, while miR-16-5p was poorly expressed in CRC cells and miR-16-5p targeted ITGA2. The in vitro experiments revealed that the BMSCs-derived exosomes overexpressing miR-16-5p inhibited proliferation, migration, and invasion, while simultaneously stimulating the apoptosis of the CRC cells via downregulation of ITGA2. Furthermore, the results of in vivo experiments confirmed that the BMSCs-derived exosomes overexpressing miR-16-5p repressed the tumor growth of CRC. Collectively, BMSCs-derived exosomes overexpressing miR-16-5p restricted the progression of CRC by downregulating ITGA2.

7.
Sci Rep ; 9(1): 5967, 2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979930

RESUMO

This study aimed to explore the effects of radiochemotherapy on the neurocognitive function of patients with high-grade gliomas (HGG). The mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), event-related potential P300 (ERP-P300), and specific MRI parameters were compared, and the associations between specific MRI parameters and different doses of radiation were determined for before and up to 12 months after radiotherapy. There were no significant differences in MMSE, MoCA, or ERP-P300 before and after radiotherapy. Compared with pre-radiochemotherapy, fractional anisotropy (FA) in the contralateral hippocampus decreased at 6 and 9 months after radiotherapy. FA in the ipsilateral hippocampus before radiochemotherapy decreased compared with 6 months after radiotherapy. Compared to the end of radiotherapy, as well as 3- and 6-months post-radiotherapy, the regional cerebral blood volume (rCBV) in the genu of the corpus was significantly lower at 12 months post-radiotherapy. Some MRI parameters in different regions of the brain were negatively correlated with the mean and maximum dose. There was no significant effect of radiochemotherapy on the neurocognitive functioning of patients with HGGs found before radiochemotherapy until 12 months after radiotherapy. The radiation-induced FA decrease in the bilateral hippocampus preceded cognitive dysfunction, and DTI of the hippocampus may provide a useful biomarker for predicting radiation-induced neurocognitive impairment in patients with HGGs.

8.
Cancer Med ; 8(5): 2484-2495, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30938104

RESUMO

Colorectal cancer (CRC) is still the third most common cancer in the world with a limited prognosis due to the chemoresistance of CRC cells to 5-fluorouracil (5-FU)-based chemotherapy. In our previous study, we revealed that miR-204 overexpression could sensitize CRC cell to 5-FU treatment through targeting HMGA2/PI3K signaling pathway; however, miR-204 expression in CRC tissues is abnormally downregulated. Long non-coding RNAs (lncRNAs) dysregulation has been reported in human diseases, including cancer. Also, lncRNA can regulate cancer cell proliferation, invasion, migration, as well as chemoresistance. LncRNA prostate cancer-associated transcript 6 (PCAT6) acts as an oncogene in many cancers; herein, PCAT6 expression was abnormally upregulated in CRC tissues and cell lines, suggesting its potential role in CRC. Further, we assessed the specific function and mechanism of PCAT6 in CRC. Furthermore, we revealed that PCAT6 knockdown attenuated CRC chemoresistance to 5-FU through miR-204/HMGA2/PI3K; miR-204 inhibition could partially reverse the effect of PCAT6 knockdown. Taken together, we demonstrate that the abnormal PCAT6 overexpression inhibits miR-204 expression in CRC, thereby promoting HMGA2/PI3K signaling activity, ultimately enhancing the chemoresistance of CRC cells to 5-FU; PCAT6 represents a promising target for dealing with CRC chemoresistance.

9.
DNA Repair (Amst) ; 78: 37-44, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954901

RESUMO

DNA double strand breaks (DSBs) are a severe threat to genome integrity and a potential cause of tumorigenesis, which is a multi-stage process and involves many factors including the mutation of oncogenes and tumor suppressors, some of which are transcribed microRNAs (miRNAs). Among more than 2000 known miRNAs, miR-21 is a unique onco-miRNA that is highly expressed in almost all types of human tumors and is associated with tumorigenesis through its multiple targets. However, it remains unclear whether there is any functional link between DSBs and miR-21 expression and, if so, does the link contribute to DSB-induced genomic instability/tumorigenesis. To address this question, we used DNA-PKcs-/- (deficient in non-homologous end-joining (NHEJ)) and Rad54-/- (deficient in homologous recombination repair (HRR)) mouse embryonic fibroblasts (MEFs) since NHEJ and HRR are the major pathways for DSB repair in mammalian cells. Our results indicate that levels of miR-21 are elevated in these DSB repair (DSBR) deficient cells, and ionizing radiation (IR) further increases these levels in both wild-type (WT) and DSBR-deficient cells. Interestingly, IR stimulated growth in soft agar and this effect was greatly reduced by blocking miR-21 expression in both WT and DSBR-deficient cells. Taken together, our results suggest that either IR or DSBR-deficient can lead to an upregulation of miR-21 levels and that miR-21 is associated with IR-induced cell growth in soft agar. These results may help our understanding of DSB-induced tumorigenesis and provide information that could facilitate the development of new strategies to prevent DSB-induced carcinogenesis.

10.
Cancer Res ; 79(6): 1191-1203, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30674532

RESUMO

Bromodomain and extraterminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that death receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer cells. Induction of DR5, following BET inhibition, was mediated by endoplasmic reticulum stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in colorectal cancer cells containing a mutation in speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a colorectal cancer xenograft model, BETi combined with chemotherapy suppressed the tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against colorectal cancer due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved colorectal cancer combination therapies.Significance: These findings reveal how BET inhibition sensitizes chemotherapy and kills a subset of colon cancer cells with specific genetic alterations and may provide a new molecular marker for improving colon cancer therapies.

11.
Cancer Med ; 8(1): 67-79, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30578604

RESUMO

Studies on nasopharyngeal carcinoma (NPC) in five electronic databases were systematically searched online from the inception to June 5, 2018. Quality of the included studies was assessed using the updated Quality Assessment of Diagnostic Accuracy Studies 2. Data of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the 95% confidence intervals were pooled using a bivariate random-effect model. Forty-four studies with 61 groups of data and totally 3369 patients were included in the qualitative and quantitative synthesis analysis. The overall estimated sensitivity and specificity of positron emission tomography/computed tomography/magnetic resonance imaging (PET-CT/MRI) for local recurrent/residual NPC were 0.90 and 0.85, respectively. The pooled area under the curve of (AUC) of PET-CT/MRI in the summary receiver operator characteristic curve was 0.94. Subgroup analysis showed MRI vs PET-CT had lower sensitivity (0.83 vs 0.92) and specificity (0.78 vs 0.89). The AUCs of MRI and PET-CT were 0.87 and 0.96, respectively. No-cross of 95% CI was found in MRI vs PET/CT (0.87-0.90 vs 0.94-0.98). Meta-regression showed PET/CT vs MRI was a potential source of heterogeneity. PET/CT and MRI both showed quite high overall ability in diagnosing local recurrent/residual NPC, but the subgroup analysis indicated PET-CT was superior over MRI in diagnosis of local recurrence and residue of NPC after radiotherapy. The examination methods affected the heterogeneity within studies.

12.
Front Oncol ; 8: 548, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524968

RESUMO

Since resistance to radiotherapy remains refractory for the clinical management of nasopharyngeal cancer (NPC), further understanding the mechanisms of radioresistance is necessary in order to develop more effective NPC treatment and improve prognosis. In this study, an integrated quantitative proteomic approach involving tandem mass tag labeling and liquid chromatograph-mass spectrometer was used to identify proteins potentially responsible for the radioresistance of NPC. The differential radiosensitivity in NPC model cells was examined through clonogenic survival assay, CCK-8 viability assay, and BrdU incorporation analysis. Apoptosis of NPC cells after exposure to irradiation was detected using caspase-3 colorimetric assay. Intracellular reactive oxygen species (ROS) was detected by a dichlorofluorescin diacetate fluorescent probe. In total, 5,946 protein groups were identified, among which 5,185 proteins were quantified. KEGG pathway analysis and protein-protein interaction enrichment analysis revealed robust activation of multiple biological processes/pathways in radioresistant CNE2-IR cells. Knockdown of MAPK15, one up-regulated protein kinase in CNE2-IR cells, significantly impaired clonogenic survival, decreased cell viability and increased cell apoptosis following exposure to irradiation, while over-expression of MAPK15 promoted cell survival, induced radioresistance and reduced apoptosis in NPC cell lines CNE1, CNE2, and HONE1. MAPK15 might regulate radioresistance through attenuating ROS accumulation and promoting DNA damage repair after exposure to irradiation in NPC cells. Quantitative proteomic analysis revealed enormous metabolic processes/signaling networks were potentially involved in the radioresistance of NPC cells. MAPK15 might be a novel potential regulator of radioresistance in NPC cells, and targeting MAPK15 might be useful in sensitizing NPC cells to radiotherapy.

13.
Biosci Rep ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30509965

RESUMO

We conducted comprehensive analyses to assess the diagnostic ability of miRNA-451 in cancers. Systematical online search was conducted in PubMed, Web of Science, China's national knowledge infrastructure, and VIP databases from inception to July 31, 2017. The bivariate random effect model was used for calculating sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under cure (AUC). The whole pooled sensitivity and specificity were 0.85 (0.77-0.90) and 0.85 (0.78-0.90) with their 95% confidence interval (95%CI), respectively. The pooled AUC was 0.91 (95%CI: 0.89-0.94). Positive likelihood ratio was 5.57 (95%CI: 3.74-8.31), negative likelihood ratio was 0.18 (95%CI: 0.11-0.28), and diagnostic odds ratio was 31.33 (95%CI: 15.19-64.61). Among Asian population. The sensitivity and specificity were 0.85 (95%CI: 0.77-0.91) and 0.86 (95%CI: 0.78-0.91), respectively. The positive likelihood ratio and negative likelihood ratio were 5.87 (95%CI: 3.78-9.12) and 0.17 (95%CI: 0.11-0.28). The diagnostic odds ratio and AUC were 34.31 (15.51-75.91) and 0.92 (0.89-0.94). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and AUC for digestive system cancer were 0.83, 0.88, 6.87, 0.20, 35.13 and 0.92. The other cancers were 0.87, 0.81, 4.55, 0.16, 28.51, and 0.90. For sample source, the results still remain consistent. Our results indicated miRNA-451 have a moderate diagnostic ability for cancers, and could be a potential early screening biomarker, and considered as an adjuvant diagnostic index when being combined with others clinical examinations.

14.
Future Oncol ; 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30457348

RESUMO

Esophageal cancer (EC) patients receiving radiotherapy are at a high risk of malnutrition, which can increase the side effects of radiotherapy, reduce the accuracy and sensitivity of radiotherapy and decrease treatment effect. Therefore, timely and correct nutritional treatment is crucial. To date, however, neither consensus nor guidelines on enteral nutrition (EN) specifically for EC patients receiving radiotherapy exist. Accordingly, an expert consensus conference was held to establish consensus on the use of EN in EC patients receiving radiotherapy. It reflected the opinions of a multidisciplinary group of experts and a review of the current literature, and established common guidelines for nutritional screening and assessment, nutrition counseling, indication for EN, access and formulas of EN, effect evaluation, nutrition plan adjustment, and home enteral nutrition.

15.
Mol Med Rep ; 18(6): 5603-5613, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30365052

RESUMO

Numerous microRNAs (miRs) have been implicated in breast cancer; however, the molecular mechanism is not fully understood. The present study examined the function and regulatory mechanism of miR­181 in breast cancer. Reverse transcription­quantitative polymerase chain reaction and western blot analysis were used to examine the RNA and protein expression. MTT assay, wound healing assay and transwell assay were conducted to study cell proliferation, migration and invasion. Luciferase reporter gene assay was used to confirm targeting relationship. The results suggested that the miR­181 expression levels were significantly higher in breast cancer cell lines and clinical tissue samples. The increased expression of miR­181 was markedly associated with higher clinical stage and lymph node metastasis. The patients with high miR­181 expression demonstrated worse prognosis compared with those with a low expression of miR­181. Small interfering RNA­induced miR­181 downregulation significantly inhibited breast cancer cell proliferation, migration and invasion in vitro, and tumor growth in vivo. Protein sprouty homolog 4 (SPRY4), downregulated in breast cancer tissues and cell lines, was observed to be a novel target gene of miR­181. Downregulation of SPRY4 was significantly associated with breast cancer progression in addition to poor prognosis. Knockdown of SPRY4 rescued the inhibitory effects of miR­181 downregulation on the malignant phenotypes of breast cancer cells. Thus, the present study demonstrated that miR­181 serves a promoting role in breast cancer at least in part through the inhibition of SPRY4 expression. The present results expand the understanding of the miR­181/SPRY4 axis' function during for the malignant progression of breast cancer.

16.
Biochem Biophys Res Commun ; 505(1): 274-281, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30245131

RESUMO

Using Tandem Mass Tags (TMT) labeling and LC-MS/MS analysis of peptides from two cell lines (CNE2 and its radioresistant subclone CNE2-IR), we identified 754 proteins differentially expressed in CNE2-IR compared to CNE2. MAP2K6 was identified as a candidate radioresistance-related protein kinase. In vitro functional analysis revealed that over-expression of MAP2K6 significantly enhanced cell survival and colony formation following irradiation in NPC cells. Further, knockdown of MAP2K6 in radioresistant NPC cells led to decreased colony formation and increased apoptotic cells following irradiation. However, the effect of MAP2K6 in regulating the radioresistance in NPC cells did not seem to depend on p38/MAPK activity. Importantly, MAP2K6 might be required for leukemia inhibitory factor receptor (LIFR)-regulated radioresistance, as the expression levels of MAP2K6 affected LIFR/p70S6K signaling activation in NPC cells. Further, MAP2K6 kinase activity is required to activate LIFR/p70S6K signaling and to confer pro-survival effect on NPC cells. In conclusion, MAP2K6 might be an important regulator of LIFR-induced radioresistance in NPC.

17.
J Cancer ; 9(17): 3109-3116, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210634

RESUMO

Introduction: EphA2 is a crucial oncogene in gastric cancer (GC) development and metastasis, and miR-302b can target EphA2 in gastric cancer. This study plans to investigate their relationship and clinical significance in clinical samples. Materials and Methods: We explored the correlation of the expression of EphA2 and miR-302b, and their clinical significance in the training (n=226) cohort of GC patients, and then validated the results in the validation (n=128) cohort. Results: miR-302b was remarkably downregulated in GC tissues, while high EphA2 expression were detected, and they were inversely correlated both in mRNA and protein, (r=-0.4209, P<0.0001; r=-0.336, P <0.001, respectively). Furthermore, the pattern of high EphA2 and low miR-302b expression were found to be associated with poor overall survival in stage IV GC patients in both training and validation cohort. Conclusions: The expression of miR-302b and EphA2 was inversely correlated, and had prognostic significance on GC in clinic.

18.
Cancer Med ; 7(11): 5611-5620, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30267476

RESUMO

GNA13 has been found overexpressed in various types of cancer, which is related to tumor metastasis and progression. However, the biological functions of GNA13 in colorectal cancer (CRC) progression remain unclear. This study aimed to explore the role of GNA13 in CRC and investigate the mechanism of how GNA13 promotes tumor growth. Interestingly, our findings showed that GNA13 is commonly upregulated in CRC, where these events are associated with a worse histologic grade and poor survival. Increased expression levels of GNA13 promoted cell growth, migration, invasion, and epithelial-mesenchymal transition, whereas GNA13 silencing abrogated these malignant phenotypes. In addition, overexpressing GNA13 in cancer cells increased the levels of the chemokines CXCL1, CXCL2, and CXCL4, which contributed to CRC proliferation and colony formation. Moreover, our mechanistic investigations suggest that the NF-κB/p65 signaling pathway was activated by the increase in GNA13 levels. Inhibiting the NF-κB/p65 pathway with an inhibitor decreased GNA13-induced migration, invasion and CXCL chemokine level increases, indicating the critical role of NF-κB/p65 signaling in mediating the effects of GNA13 in CRC. Together, these results demonstrate a key role of GNA13 overexpression in CRC that contributes to malignant behavior in cancer cells, at least in part through stimulating angiogenesis and increasing the levels of the NF-κB-dependent chemokines CXCL1, CXCL2, and CXCL4.

19.
Cancer Lett ; 436: 119-128, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30118845

RESUMO

T-cell immunoglobulin domain and mucin domain-4 (Tim-4) is overexpressed in several tumors and is correlated with enhanced tumor development and metastasis. In this study, we investigated the physiological alterations and molecular events related to Tim-4 overexpression in a mouse model of colorectal cancer (CRC). In the current study, we observed that Tim-4 is upregulated in CRC tissues compared with neighboring normal tissues. In addition, statistical analysis revealed that elevated Tim-4 expression was strongly linked to distant metastasis, TNM stage and reduced overall survival duration in CRC patients. An orthotopic model was employed to explore the function of Tim-4 in CRC development through the implantation of Tim-4-overexpressing CT26 murine colon adenocarcinoma cells. It was observed that Tim-4 overexpression considerably enhanced CRC tumorigenesis in vivo and promoted angiogenesis through the upregulation of vascular endothelial growth factor (VEGF). In CT26 cells, Tim-4 overexpression increased the aldehyde dehydrogenase-1 (ALDH1) level, indicating an increase in cancer stem cell (CSC)-like properties. Furthermore, we determined that Tim-4 activates PI3K/AKT/mTOR signaling in CRC cells. Tim-4-overexpressing cancer cells recruited tumor-associated macrophages (TAMs), thereby accelerating cancer development. Therefore, our results strongly indicate that Tim-4 overexpression promotes proliferation and tumor stroma remodeling in CRC. PI3K/AKT/mTOR activation might be crucial in Tim-4-linked tumor development. This finding might offer a new strategy for therapeutic intervention.

20.
Radiat Oncol ; 13(1): 160, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157899

RESUMO

BACKGROUND: Lack of animal model of radiation induced muscle fibrosis, this study aimed to establish such a model by using 90 Gy single dose irradiation to mimic clinical relevance and also to explore the potential post-irradiation regenerative mechanism. METHODS: SD rats were randomly divided into dose investigation groups and time gradient groups. Group1-6 were irradiated with a single dose of 65Gy, 70Gy, 75Gy, 80Gy, 85Gy and 90Gy respectively, and the degree of rectus femoris fibrosis in the irradiated area was detected at 4 weeks after irradiation. Group 7-9 were irradiated with a single dose of 90Gy, and the results were detected 1, 2, 4, and 8 weeks after irradiation. Then the general condition of rats was recorded. Masson staining was used to detect muscle fibrosis. The ultrastructure of muscles was observed by electron microscope, and the expression changes of satellite cell proliferation and differentiation related genes were detected by quantitative real-time-PCR. RESULTS: A single dose of 90Gy irradiation could cause muscle fibrosis in rats. As time goes on, the severity of muscle fibrosis and the expression of TGF- ß1 increased. Significant swelling of mitochondria, myofilament disarrangement and dissolution, obvious endothelial cell swelling, increased vascular permeability, decrease of blood cell, deposition of fibrosis tissue around the vessel could be found compared with the control group. At around the 4th week, the expressions of Pax7, Myf5, MyoD, MyoG, Mrf4 increased. CONCLUSION: Irradiation of 90Gy can successfully establish the rat model of radiation-induced muscle fibrosis. This model demonstrated that regenerative process was initiated by the irradiation only at an early stage, which can serve a suitable model for investigating regenerative therapy for post-radiation muscle fibrosis.

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