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CircRNAs (circular RNA) are reported to regulate onset and progress multiple cancers. Nonetheless, the function along with the underlying mechanisms of circRNAs in HER‐2‐positive breast cancer (BC) remains unclear. CircRNA microarrays were performed to elucidate expression profiles of HER‐2‐positive BC cells. circRNA levels were quantified using qRT‐PCR assay. Various in vitro along with in vivo assays were employed to further explore the effects of circGFRA1 in the progress of HER‐2‐positive BC and interactions of circGFRA1, miR‐1228 and AIFM2 in Her‐2‐positive BC. CircGFRA1 was remarkably upregulated in HER‐2‐positive BC. Knockdown of circGFRA1 could attenuate HER‐2‐positive BC progression by inhibiting the proliferation, infiltration and migratory ability of HER‐2‐positive BC cells. Through ceRNA mechanism, circGFRA1 could bind to miR‐1228 and alleviate inhibitory activity of miR‐1228 on targeted gene AIFM2. In summary, circGFRA1‐miR‐1228‐AIFM2 axis regulates HER‐2‐positive BC. CircGFRA1 is a novel promising treatment option for HER‐2‐positive BC.

Background: Pyroptosis, a kind of programmed cell death characterized by the rupture of cell membranes and the release of inflammatory substances, plays an important role in the occurrence and development of cancer. However, few studies focus on the pyroptosis-associated long non-coding RNAs (lncRNAs) in breast cancer (BC). The prognostic value of pyroptosis-associated lncRNAs and their relationship with tumor microenvironment (TME) in BC remain unclear. The purpose of this study was to explore the prognostic role of pyroptosis-associated lncRNAs and their relationship with TME in BC.Methods: The transcriptome data and clinical data of female BC patients were downloaded from The Cancer Genome Atlas (TCGA) database. A total of 937 patients were randomly assigned to either training set or validation set. A pyroptosis-associated lncRNA signature was constructed in the training set and verified in the validation set. Functional analysis and immune microenvironment analysis related to pyroptosis-associated lncRNAs were performed. A nomogram based on the risk score and clinical characteristics was established.Results: A 9-pyroptosis-associated lncRNA signature was constructed to separate BC patients into two risk groups. High-risk patients had poorer prognosis than low-risk patients. The risk score was proven to be an independent prognostic factor by multivariate Cox regression analysis. Function analysis and immune microenvironment analysis showed that low-risk BC tended to be an immunologically “hot” tumor. A nomogram was constructed with risk score and clinical characteristics. Receiver operating characteristic curve (ROC) analysis demonstrated credible predictive power of the nomogram. The area under time-dependent ROC curve (AUC) reached 0.880 at 1 year, 0.804 at 3 years, and 0.769 at 5 years in the training set, and 0.799 at 1 year, 0.794 at 3 years, and 0.728 at 5 years in the validation set.Conclusion: We identified a novel pyroptosis-associated lncRNA signature that was an independent prognostic indicator for BC patients. Pyroptosis-associated lncRNAs had potential relationship with the immune microenvironment and might be therapeutic targets for BC patients.

Background: Long non-coding RNAs play crucial roles in various biological activities and diseases. The role of long intergenic non-coding RNA01638 (linc01638) in breast cancer, especially in HER2-positive breast cancer, remains largely unknown. Objective: To investigate the effect of linc01638 on tumorigenesis in HER2-positive breast cancer. Methods: We first used qRT-PCR to detect linc01638 expression in HER2-positive breast cancer cells and tissues. Then we analyzed the effects of linc01638 expression in HER2-positive breast cancer cells through cell apoptosis assay, cell proliferation assay, colony formation assay, and cell invasion assay. We conducted mouse xenograft model to further confirm the role of linc01638 in HER2-positive breast cancer. Moreover, we used Western blot and IHC analysis to access the effect of linc01638 on DNMTs, BRCA1 and PTEN expressions in transplanted tumors. Results: Linc01638 was found to be remarkably overexpressed in HER2-positive breast cancer cells and tissues. Suppression of linc01638 enhanced cell apoptosis, as well as inhibited the growth and invasiveness of HER2-positive breast cancer cells in vitro and tumor progression and metastasis in vivo. Furthermore, inhibition of linc01638 by shRNA attenuated expression of DNMT1, DNMT3a, and DNMT3b, and promoted expression of BRCA1 and PTEN in HER2-positive breast cancer cells and mouse xenograft models. Linc01638 might be a promising biomarker and therapeutic target for treatment of HER2-positive breast cancer.

Background Additional mechanisms of temozolomide (TMZ) resistance in gliomas remain uncertain. The aim of this study was to identify another DNA repair mechanism involving forkhead box O1 (FoxO1) and replicator C2 (RFC2) in gliomas. Methods We established glioma cells against TMZ, U87R, by exposure to TMZ. Proliferation rate Cell counting kit-8 (CCK8) was used, and epithelial-mesenchymal transition (EMT)-related markers were detected by western blot. The association between FoxO1 and RFC2 was analyzed by heat maps and scatter plot, and Real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to detect the effect of FoxO1 on the expression of RFC2. The regulation effect of FoxO1 on RFC2 expression was analyzed by luciferase reporter gene assay. Knockdown of FoxO1/RFC2 was achieved via short hairpin RNA (shRNA), the effect of knockdown on the proliferation was determined by CCK8 assay and colony formation assay, and apoptosis was examined by flow cytometry and immunoblotting. Results The TMZ-resistant glioma cell line, U87R, was established. The FoxO1 and RFC2 proteins increased significantly in U87R. The expression of FoxO1 and RFC2 were positively related in glioma tissues. We found that FoxO1 contributes to TMZ resistance and cell survival via regulating the expression of RFC2. Moreover, FoxO1 functions as a transcriptional activator to RFC2 by binding to the promoter of RFC2. Furthermore, knockdown of FoxO1/RFC2 suppressed cell proliferation, TMZ resistance, and induced apoptosis in U87R. Conclusions The FoxO1/RFC2 signaling pathway promotes glioma cell proliferation and TMZ resistance, suggesting that the FoxO1/RFC2 pathway may be a potential target for TMZ-resistant glioma therapy.

Jialing Wu,&ast; Kaiyun You,&ast; Xingsheng Qiu,&ast; Ting Shen, Juanjuan Song, Changlong Chen, Yanhui Jiang, Yimin Liu Department of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yimin Liu; Yanhui JiangDepartment of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Yuexiu District, Guangzhou City, Guangdong Province, People’s Republic of ChinaTel +86 18922182513Email liuyimin@mail.sysu.edu.cn; jiangyh26@mail.sysu.edu.cnPurpose: Local failure after endoscopic laryngeal surgery (ELS) for early glottic cancer mounts a challenge to researchers to investigate risk factors of recurrence. The present study was therefore designed to explore the prognostic factors in patients who underwent ELS for early glottic cancer.Patients and Methods: We reviewed 328 patients with T1-2N0 glottic cancer who were treated with either ELS or open surgery between 2007 and 2018 at our institution. Survival, univariate and multivariate analyses were performed in different groups (ELS vs open surgery; < 65 vs ≥ 65 years).Results: Age was discovered to be the independent prognostic factor of DFS for patients treated with ELS (HR = 3.673, p = 0.003), but not for patients who underwent open surgery. Survival analysis performed on young patients (< 65 years) showed that survival outcomes between different surgery modalities were significantly different (ELS vs open surgery: five-year DFS: 72.5 vs 84.7%, p = 0.034). Univariate and multivariate analyses further confirmed the finding, whereas these results did not appear in old patients (≥ 65 years).Conclusion: Young patients (< 65 years) treated with ELS had less favorable oncologic outcomes than those treated with open surgery. Young patients (< 65 years) are advised to consider open surgery over ELS.Keywords: early glottic cancer, age, recurrence, prognostic factor, surgery

BackgroundElevated pretreatment lactate dehydrogenase (LDH) has been associated with poor prognosis in various malignancies; however, its prognostic role in hypopharyngeal cancer remains elusive. In this study, we aimed to assess the association between pretreatment LDH and clinical outcome of hypopharyngeal cancer.MethodsWe retrospectively collected 198 hypopharyngeal cancer patients treated with surgery in our institution between 2004 and 2018. The prognostic role of pretreatment LDH was explored by using univariate and multivariate analyses. Besides, subgroup analysis was performed based on T stage.ResultsThree-year and Five-year of disease-free survival (DFS, 67.0 vs. 57.4%, 65.8 vs. 39.8%, p = 0.007) and overall survival (OS, 74.8 vs. 68.9%, 66.8 vs. 50.8%, p = 0.006) exhibited significant differences between low LDH level and high LDH level groups. Univariate analysis showed that pretreatment elevated serum LDH served as an unfavorable determinant with regard to DFS and OS. Further multivariate analysis also confirmed that LDH was an independent predictor for DFS and OS. Additionally, N status and age were also found to be significantly associated with both DFS and OS.ConclusionPretreatment elevated serum LDH is an inferior prognostic factor for patients with hypopharyngeal cancer. These results should be validated by more multicenter and prospective studies.

Radical resection is regarded as the primary treatment for early rectal cancer, and tumor volume is an independent predictor of many other types of cancer. The purpose of the present study is to assess the effect of tumor volume on the survival of patients with early rectal cancer treated with radical surgery.A total of 270 patients with histologically confirmed stage T1/2 N0 rectal cancer who underwent radical resection between September 2006 and September 2014 were enrolled in this study. The tumor volume was measured based on the preoperative pelvic MRI. The clinical significance of tumor volume with respect to patients' outcomes was evaluated, and the multivariate Cox proportional regression model was used to analyse the risk factors for survival of these patients.The median follow-up period was 57.6 months. The tumor volume was significantly correlated with preoperative Hb, CEA level and number of retrieved lymph nodes (all p 0.05). The large tumor group had a lower disease-free survival (DFS) rate than the small tumor group (5-year DFS rate: 80.4% vs 89.6%, p = 0.042), whereas there was no difference in the overall survival rate. The 5-year local recurrence rates for patients in the large and small tumor groups were 10.5% and 3.0%, respectively (p = 0.030). Additionally, the tumor volume was an independent clinical predictor for both DFS and local recurrence-free survival (LRFS).In conclusion, the tumor volume is significantly associated with DFS and LRFS of patients with stage T1/2 N0 rectal cancer who underwent radical resection alone. Tumor volume may be considered an important indicator for neoadjuvant or adjuvant therapeutic interventions.

Objective To determine the prognostic effect of adjuvant radiation and clinicopathological variables in surgically treated patients with small cell carcinoma of the cervix (SCCC). Methods Clinical data of SCCC patients with International Federation of Gynaecology and Obstetrics (FIGO) stage I-II underwent radical surgery from May 2000 to August 2014 at Sun Yat-sen Memorial Hospital were retrospectively reviewed. Forty-three patients with SCCC were included to this study. Chi-square test or Fisher’s exact test, Student’s t test or Mann–Whitney U test, Kaplan–Meier method and multivariate analysis of Cox proportional hazards regression were used for statistical analysis. P Results Among 43 patients (median age, 49 years old) recruited, 25(58.1%) had stage I, 18(41.9%) had stage II disease. The 5-year overall survival (OS) rate was 39.54%, and the 5-year disease free survival (DFS) was 27.91%. Distant metastasis was the main cause of treatment failure (71.9%). Patients with adjuvant chemoradiation displayed lower rate of local recurrence than those with adjuvant chemotherapy (10.7% vs 60.0%, P P = 0.001, 0.004 respectively). Age was also an independent predictor of OS (P = 0.004). Adjuvant radiation appeared to significantly improve DFS (HR = 0.383, 95% CI, 0.185–0.791), but not OS. Conclusions Adjuvant radiotherapy could improve the local control and prolong DFS in surgically treated SCCC. However, a large prospective clinical trial is needed to confirm this.

Long non-coding RNA (LncRNA) actin filament-associated protein1-antisense RNA 1 (AFAP1-AS1) is overexpressed in various types of cancers and plays an important role in tumor progression and prognosis. This study investigates the role of AFAP1-AS1 in tumor progression in triple-negative breast cancer (TNBC). We found that AFAP1-AS1 was overexpressed in TNBC tissues and cells. Overexpression of LncRNA AFAP1-AS1 was associated with poor prognosis in TNBC patients. Moreover, we demonstrated that upregulation of AFAP1-AS1 promoted cell proliferation and invasion, and inhibited cell apoptosis in vitro, while overexpression of AFAP1-AS1 promoted tumor growth in vivo. Our results also revealed that upregulation of AFAP1-AS1 activated Wnt/β-catenin pathway to promote tumorigenesis and cell invasion by increasing the expression of C-myc and epithelial-mesenchymal transition-related molecules in TNBC. Collectively, AFAP1-AS1 can be an independent prognostic marker and an effective therapeutic target of triple- negative breast cancer.

// Songhua Xiao 1, * , Zhen Yang 2, * , Xingsheng Qiu 3, * , Ruiyan Lv 1 , Jun Liu 1 , Ming Wu 4 , Yiwei Liao 4 , Qing Liu 4 1 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guanzhou, Guangdong, China 2 Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China 3 Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China 4 Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China * These authors have contributed equally to this work Correspondence to: Qing Liu, email: chingliucn@yahoo.com Keywords: glioblastoma, TMZ, MGMT, miR-29c, chemoresistance Received: November 28, 2015 Accepted: May 28, 2016 Published: July 1, 2016 ABSTRACT Temozolomide (TMZ) is the most commonly used alkylating agent in glioma chemotherapy. However growing resistance to TMZ remains a major challenge to clinicians. The DNA repair protein O 6 -methylguanine-DNA methytransferase (MGMT) plays critical roles in TMZ resistance. Promoter methylation can inhibit MGMT expression and increase chemosensitivity. Here, we described a novel mechanism regulating MGMT expression. We showed that miR-29c suppressed MGMT expression indirectly via targeting specificity protein 1 (Sp1). MiR-29c overexpression increased TMZ efficacy in cultured glioma cells and in mouse xenograft models. The miR-29c levels were positively correlated with patient outcomes. Our data suggest miR-29c may be potential therapeutic targets for glioma treatment.

Andrographolide (AND), a diterpenoid lactone isolated from Andrographis paniculata, has been shown to have radiosensitivity in several types of cancer. Whether AND can radiosensitize ovarian cancer remains unknown. The present study investigated the radiosensitizing effects of AND in human ovarian SKOV3 xenografts and examined the molecular mechanisms of AND-mediated radiosensitization. Nude mice bearing human ovarian SKOV3 were treated with AND to investigate the effects of drug administration on tumor growth, radiosensitivity, apoptosis, and autophagy. Subsequent Western blot analysis and monodansylcadaverine (MDC) staining (autophagy analysis) were used to determine the role of AND. Finally, the pathway of apoptosis was characterized by caspase-3 activity assay as well as TUNEL analysis. AND potently sensitized SKOV3 xenografts to radiation. Moreover, apoptosis and autophagy in radiation combined with drug-treated xenografts increased significantly compared with the simple drug or single radiation treatment. This result was associated with an increase in the Bax/Bcl-2 protein ratio and p-p53 expression after exposure to combination treatment. Meanwhile, the level of Beclin 1 and Atg5 and the conversion from LC3-I to LC3-II, three important proteins involved in autophagy, were increased. AND acts as a strong radiosensitizer in human ovarian SKOV3 xenografts in vivo by increasing the Bax/Bcl-2 protein ratio and promoting the activation of caspase-3, leading to enhanced apoptosis as well as autophagy.

Aldehyde dehydrogenase 1 (ALDH1), also known as aldehyde dehydrogenase 1 family, is composed of six enzymes that are expressed at high levels in stem cells and are involved in the regulation of stem cell function. Increased ALDH1 activity has been found in the stem cell populations of leukemia and some solid tumors including breast cancer (BC). However, which ALDH1's isoenzymes are contributing to ALDH1 activity has not been determined. In addition, the prognostic value of individual ALDH1 isoenzyme is not clear. In the current study, we investigated the prognostic value of ALDH1 isoenzymes in BC patients through "the Kaplan-Meier plotter" (KM plotter) database, in which updated gene expression data and survival information are from a total of 3455 BC patients. ALDH1A1 messenger RNA (mRNA) high expression was found to be correlated to worsen overall survival (OS) for all BC patients. ALDH1A2 and ALDH1L1 mRNA high expressions were found to be correlated to better OS for all BC patients. Both of ALDH1A3 and ALDH1B1 mRNA high expressions were not found to be correlated to OS for all BC patients. These results strongly support that ALDH1A1 was only a biomarker for predicting poor survival of BC patients among ALDH1 isoenzymes. ALDH1A1 might be a major contributor of ALDH1 activity in BC, since only ALDH1A1 mRNA high expression was found to be significantly correlated to worsen OS for all BC patients.

The study was to investigate the effect of moxibustion on the serum IL-2, IL-12 levels and NK cell and ascitic tumor cell activities in H-22 mice with tumor and its mechanisms. The method used in the study was that the IL-2 and IL-12 levels were determined by the double antibody method with ELISA, and the NK cell activities by the MTT measure. The results showed that moxibustion elevated the serum IL-2 and IL-12 levels and the NK cell activities of the mice with tumor, and the elevations were of significance as compared with the controls (P0.05). It is concluded that moxibustion can inhibit the growth of tumor, which is related to the increase of the serum IL-2 and IL-12 levels and the strengthening of NK cell activities.