An 11-Gene Signature Based on Treatment Responsiveness Predicts Radiation Therapy Survival Benefit Among Breast Cancer Patients

PurposeWe developed a strategy of building prognosis gene signature based on clinical treatment responsiveness to predict radiotherapy survival benefit in breast cancer patients.Methods and MaterialsAnalyzed data came from the public database. PFS was used as an indicator of clinical treatment responsiveness. WGCNA was used to identify the most relevant modules to radiotherapy response. Based on the module genes, Cox regression model was used to build survival prognosis signature to distinguish the benefit group of radiotherapy. An external validation was also performed.ResultsIn the developed dataset, MEbrown module with 534 genes was identified by WGCNA, which was most correlated to the radiotherapy response of patients. A number of 11 hub genes were selected to build the survival prognosis signature. Patients that were divided into radio-sensitivity group and radio-resistant group based on the signature risk score had varied survival benefit. In developed dataset, the 3-, 5-, and 10-year AUC of the signature were 0.814 (CI95%: 0.742–0.905), 0.781 (CI95%: 0.682–0.880), and 0.762 (CI95%: 0.626–0.897), respectively. In validation dataset, the 3- and 5-year AUC of the signature were 0.706 (CI95%: 0.523–0.889) and 0.743 (CI95%: 0.595–0.891). The signature had higher predictive power than clinical factors alone and had more clinical prognosis efficiency. Functional enrichment analysis revealed that the identified genes were mainly enriched in immune-related processes. Further immune estimated analysis showed the difference in distribution of immune micro-environment between radio-sensitivity group and radio-resistant group.ConclusionsThe 11-gene signature may reflect differences in tumor immune micro-environment that underlie the differential response to radiation therapy and could guide clinical-decision making related to radiation in breast cancer patients.

Mannose enhances the radio-sensitivity of esophageal squamous cell carcinoma with low MPI expression by suppressing glycolysis

Background To investigate the effect of mannose on radio-sensitivity of human esophageal squamous cell carcinoma (ESCC) cell line and its possible mechanism. Methods The expression of mannose phosphate isomerase (MPI) in human esophageal cancer cell lines were detected by Western blot. The inhibitory effect of mannose on human esophageal cancer cell lines were observed by MTT assay. Plate clone formation assay was performed to investigate the efficacy of mannose on radio-sensitivity of human esophageal cancer cells. The apoptosis rates of tumor cells treated with mannose and/or radiation therapy was calculated by flow cytometry. Furthermore, we analyzed intracellular metabolites using liquid chromatography mass spectrometry to identify selective sugar metabolites. Results MPI expression was various in human esophageal cancer cells. KYSE70 cells was associated with the highest MPI expression whereas KYSE450 cells had the lowest MPI expression level. When administrated with 11.1 mM/L mannose, the same inhibitory effect was observed in both KYSE70 and KYSE450 cell lines. Moreover, the inhibitory effect was significant on KYSE450 cell lines with an increased mannose concentration. The application of 11.1 mM/L mannose could significantly enhance the radio-sensitivity of KYSE450 cell line; and tumor cell apoptosis rate was also increased. However, there was limited efficacy of mannose on the radio-sensitivity and apoptosis rate of KYSE70 cell line. Additionally, intracellular metabolites analyzation revealed that glycolysis could be disturbed by mannose when combined with radiation therapy in esophageal cancer cells. Conclusion In esophageal cancer cell lines with low MPI expression, the administration of mannose was associated with enhanced radio-sensitivity.

DUSP6 regulates radio-sensitivity in glioblastoma by modulating the recruitment of p-DNAPKcs at DNA double-strand breaks

Glioblastoma (GBM) has poor median survival due to its resistance to chemo-radiotherapy regimen, resulting in tumor recurrence. Recurrent GBMs currently lack effective treatments. DUSP6 is known to be pro-tumorigenic and is up-regulated in GBM. We show that DUSP6 expression is significantly higher in recurrent GBM patient biopsies (n=11) compared to primary biopsies (n=11). Importantly, although reported as cytoplasmic protein, we found nuclear localization of DUSP6 in primary and recurrent patient samples and in parent and relapse population of GBM cell lines generated from in vitro radiation survival model. DUSP6 inhibition using BCI resulted in decreased proliferation and clonogenic survival of parent and relapse cells. Pharmacological or genetic inhibition of DUSP6 catalytic activity radio-sensitized primary and importantly, relapse GBM cells by inhibiting the recruitment of p-DNAPKcs, subsequently down-regulating the recruitment of γH2AX and 53BP1. This resulted in decreased cell survival and prolonged growth arrest upon irradiation in vitro and significantly increased the progression-free survival in orthotopic mouse models of GBM. Our study highlights a non-canonical function of DUSP6, emphasizing the potential application of DUSP6 inhibitors in the treatment of recurrent GBM.

Radio-sensitivity of irradiated seed, plantlets, callus, and in vitro leaves from Indigofera zollingeriana Miq by gamma rays

Test of radio-sensitivity is important to use as a recognizable effect of radiation. The optimal doses usually create maximum variability. Radio-sensitivity of each part of plants of Indigofera zollingeriana Miq to gamma rays had no report yet. This research aimed to know radio-sensitivity, optimal doses, and growth of M1 generation from each material of I. zollingeriana irradiated with gamma rays. Seed, plantlets, callus, and in vitro leaves were tested for radio sensitivity by gamma rays. Doses level used of Gamma rays were: 0 until 500 Gy. The value of LD50 of each material was evaluated using Curve-fit Analysis. Growth parameters from each material were observed for six weeks after planting and analyzed using IBM SPSS 22. Research showed that the sensitivity of each doses level was different for each source of the material plant. The seed had radio-sensitivity of gamma rays at dose 183.988 Gy, plantlet at dose 253.677 Gy, callus could not calculate, and in vitro leaves at dose 242.241 Gy.

MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS.

Role of miR-138 on Radio Sensitivity of Gastric Carcinoma Cells and Its Molecular Mechanism

To explore FOXP4 and miR-138 in gastric carcinoma (GC) and its related mechanisms. Sixty-eight GC patients from January 2018 to January 2019 were selected as group A, and 66 healthy people as group B. GC cells and gastric mucosal epithelial cells were purchased, sh-FOXP4, si-FOXP4, NC, miR-138-inhibitor, and miR-138-mimics were transfected into MKN-45 and NCI-N87 cells. The FOXP4 and miR-138 expression levels in samples were tested by qRT-PCR, and N-cadherin, vimentin, Fibronectin, Slug, E-Cadherin and Y-catenin downstream proteins in cells were detected by WB. The proliferation was tested by MTT assay, invasion was tested by Transwell assay, and apoptosis was detected by flow cytometry assay. F0XP4 was highly expressed in GC, miR-138 was poorly expressed in GC, and AUC of FOXP4 and miR-138 was > 0.8. FOXP4 and miR-138 were tied to the age, gender, tumor invasion, differentiation degree, tumor location and TNM stage of GC patients. Silent expression of FOXP4 and overexpression of miR-138 can promote apoptosis, inhibit cell growth and epithelial-mesenchymal transition (ETM). The two also can inhibit N-cadherin, vimentin, Fibronectin and Slug proteins, and promote E-Cadherin and y-catenin. Dual luciferase report confirmed that FOXP4 and miR-138 had targeted relationship. In terms of radiological parameters, the SF2 and D0 (Gy) values of transfected miR-138mimic+pcDNA3. 1-FOXP4 were dramatically higher than those of transfected miR-138mimic+pcDNA3. 1 cells, and SER was lower than those of transfected miR-138 mimic+ pcDNA3. 1 cells (P<0.05), suggesting FOXP4 partially adjusted the radiosensitization role of miR-138. In conclusion, miR-138 can regulate EMT of GC cells by adjusting F0XP4 and enhance radiosensitivity of those cells.

The Impact of Different Timing Schedules on Prostate HDR-Mono-Brachytherapy. A TCP Modeling Investigation

Background: Mechanistic TCP (tumor control probability) models exist that account for possible re-sensitization of an initially hypoxic tumor during treatment. This phenomenon potentially explains the better outcome of a 28-day vs 14-day treatment schedule of HDR (high dose rate) brachytherapy of low- to intermediate-risk prostate cancer as recently reported. Methods: A TCP model accounting for tumor re-sensitization developed earlier is used to analyze the reported clinical data. In order to analyze clinical data using individual TCP model, TCP distributions are constructed assuming inter-individual spread in radio-sensitivity. Results: Population radio-sensitivity parameter values are found that result in TCP population values which are close to the reported ones. Using the estimated population parameters, two hypothetical regimens are investigated that are shorter than the ones used clinically. The impact of the re-sensitization rate on the calculated treatment outcome is also investigated as is the anti-hypothesis that there is no re-sensitization during treatment. Conclusions: The carried out investigation shows that the observed clinical data cannot be described without assuming an initially hypoxic state of the tumor followed by re-oxygenation and, hence, re-sensitization. This phenomenon explains the better outcome of the prolonged treatment schedule compared to shorter regimens based on the fact that prostate cancer is a slowly repopulating tumor.

Increased Angiogenin Expression Correlates With Radiation Resistance and Predicts Poor Survival for Patients With Nasopharyngeal Carcinoma

Background: Despite the development of such multiple therapeutic approaches, approximately 20% patients experience recurrence. Identification of molecular markers for stratifying the different risks of tumour recurrence and progression is considered imperative.Methods: We used a RayBio Human Cytokine Antibody Array that simultaneously detected the levels of 297 proteins and profiled the conditioned medium of HONE1 cells and the radioresistant NPC cells HONE1-IR. We found Angiogenin(ANG) expression to be significantly increased in HONE1-IR and HONE1-IR cells exposed to 4-Gy X-ray radiation.Results: We investigated the expression of ANG in NPC tissues and explored its prognostic significance in patients with NPC. We found that ANG expression was increased in recurrent NPC tissues. Elevated expression of ANG induced radio-resistance in NPC cells, in addition to being significantly associated with shorter PFS, OS, and LRFS in patients with NPC. Multivariate analysis results revealed that ANG was an independent prognostic factor that predicted PFS, OS, and LRFS. Furthermore, a nomogram model was generated to predict OS in terms of ANG expression.Conclusion: Our results found the radioresistant function of ANG and proved the clinical prognostic significance of ANG, and the results could help predict radio-sensitivity and stratify high-risk patients or tumour recurrence.