hsa_circ_0000417 downregulation suppresses androgen receptor expression and apoptotic signals in human foreskin fibroblasts via sponging miR-6756-5p.

BACKGROUND: Dysregulated apoptosis of penile mesenchymal cells during male urethragenesis has been previously demonstrated to underly hypospadiac urethral closure failure, and androgen receptor (AR) has been shown to play a central role in regulating penile mesenchyme cell proliferation and survival. However, the regulatory mechanisms upstream and downstream of AR remain poorly understood. Our clinical data and bioinformatics analysis previously indicated that hsa_circ_0000417, a circRNA significantly downregulated in hypospadias preputial specimens, may act as a ceRNA for AR via sequestering hsa_miR-6756-5p, and that the biological functions of hsa_circ_0000417 may significantly involve the PI3K/AKT pathway. In this study, we employed human foreskin fibroblasts (HFF-1) to experimentally validate this putative hsa_circ_0000417/miR-6756-5p/AR axis and its impact on penile mesenchymal cell proliferation and apoptosis. METHOD AND RESULTS: We showed that hsa_circ_0000417 knockdown significantly promoted proliferation and suppressed apoptosis of HFF-1 cells. Mechanistically, hsa_circ_0000417 functioned as a molecular sponge for miR-6756-5p in HFF-1 cells and relieved the latter's translational repression on AR mRNA, leading to decreased AKT activation and increased expression of pro-apoptotic proteins BAX and cleaved-caspase 9. Conversely, elevated levels of miR-6756-5p resulted in diminished AR expression concomitant with enhanced AKT activation and HFF-1 cell proliferation. CONCLUSIONS: Collectively, our data describe for the first time a circRNA-mediated post-transcriptional regulatory mechanism of AR and its functional consequences in penile mesenchymal cells in the context of hypospadias. These findings may contribute to advancing our current understanding of the roles of AR and mesenchymal cell fate decisions during penile morphogenesis.

Downregulation of annexin A3 promotes ionizing radiation-induced EGFR activation and nuclear translocation and confers radioresistance in nasopharyngeal carcinoma.

Radioresistance currently poses a significant challenge to successful disease control of nasopharyngeal carcinoma (NPC). We previously uncovered that annexin A3 (ANXA3), a calcium-dependent phospholipid binding protein, is underexpressed in radioresistant NPC cells and mouse xenografts. This study aims to further unravel the mechanistic basis underlying ANXA3-mediated radioresistance in NPC. We show that either innate ANXA3 downregulation or short hairpin RNA(shRNA)-based knockdown of ANXA3 confers resistance to ionizing radiation (IR) in NPC both in vitro and in mouse xenograft models in vivo, whereas radiosensitization was observed when ANXA3 was ectopically expressed. Mechanistically, ANXA3 knockdown dramatically enhances IR-induced epidermal growth factor receptor (EGFR) phosphorylation and nuclear translocation, leading to increased post-IR phosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) concomitant with markedly accelerated DNA DSB repair. In addition, pretreatment with cetuximab efficiently abrogated the radioresistant phenotype of ANXA3-low cells as well as the ANXA3 knockdown-induced post-IR EGFR nuclear accumulation, suggesting that EGFR is an essential mediator for ANXA3 depletion-mediated radioprotection in NPC. Collectively, this work reveals for the first time a critical role of ANXA3 in radiation survival and DNA repair mechanism of NPC and provides mechanistic evidence to support ANXA3 as a potential therapeutic target to improve radiocurability for NPC.

Depicting the Implication of miR-378a in Cancers.

MicroRNA-378a (miR-378a), including miR-378a-3p and miR-378a-5p, are encoded in PPARGC1B gene. miR-378a is essential for tumorigenesis and is an independent prognostic biomarker for various malignant tumors. Aberrant expression of miR-378a affects several physiological and pathological processes, including proliferation, apoptosis, tumorigenesis, cancer invasion, metastasis, and therapeutic resistance. Interestingly, miR-378a has a dual functional role in either promoting or inhibiting tumorigenesis, independent of the cancer type. In this review, we comprehensively summarized the role and regulatory mechanisms of miR-378a in cancer development, hoping to provide a direction for its potential use in cancer therapy.

Annexin A3, a Calcium-Dependent Phospholipid-Binding Protein: Implication in Cancer.

Annexin A3 (ANXA3), also known as lipocortin III and placental anticoagulant protein III, has been reported to be dysregulated in tumor tissues and cancer cell lines, and harbors pronounced diagnostic and prognostic value for certain malignancies, such as breast, prostate, colorectal, lung and liver cancer. Aberrant expression of ANXA3 promotes tumor cell proliferation, invasion, metastasis, angiogenesis, and therapy resistance to multiple chemotherapeutic drugs including platinum-based agents, fluoropyrimidines, cyclophosphamide, doxorubicin, and docetaxel. Genetic alterations on the ANXA3 gene have also been reported to be associated with the propensity to form certain inherited, familial tumors. These diverse functions of ANXA3 in tumors collectively indicate that ANXA3 may serve as an attractive target for novel anticancer therapies and a powerful diagnostic and prognostic biomarker for early tumor detection and population risk screening. In this review, we dissect the role of ANXA3 in cancer in detail.

Excavating novel diagnostic and prognostic long non-coding RNAs (lncRNAs) for head and neck squamous cell carcinoma: an integrated bioinformatics analysis of competing endogenous RNAs (ceRNAs) and gene co-expression networks.

Long non-coding RNAs (lncRNAs) have been demonstrated to fine-tune gene regulations that govern a broad spectrum of oncogenic processes. Nonetheless, our understanding of the roles of lncRNAs and their interactions with miRNAs and mRNAs in HNSCC is still highly rudimentary. Here, we present a comprehensive bioinformatics analysis in which competing endogenous RNA (ceRNA) network construction and weighted gene co-expression network analysis (WGCNA) were combined to explore novel diagnostic and prognostic lncRNAs for HNSCC. Differentially expressed mRNAs (DEGs), miRNAs (DEMs) and lncRNAs (DELs) were identified based on the RNA sequencing data and clinical data retrieved from TCGA database. LncRNA-regulated ceRNA networks were constructed based on the interactive RNA pairs predicted by miRDB, miRcode and TargetScan. WGCNA was conducted to identify lncRNAs that were significantly correlated with patient overall survival (OS) and HNSCC tumor. RT-qPCR was employed to validate the expression of lncRNAs in HNSCC cell lines and patient sera. A ceRNA network consisting of 90 DEGs, 7 DEMs and 67 DELs associated with clinical traits was established. WGCNA and Kaplan-Meier survival analysis revealed that 5 DELs (MIR4435-2 HG, CASC9, LINC01980, STARD4-AS1 and MIR99AHG) were significantly correlated with OS of HNSCC patients, whereas DEL PART1 was most significantly correlated with the HNSCC tumor. The in silico predicted expression patterns of PART1, LINC01980 and MIR4435-2 HG were further validated in HNSCC cell lines and patient sera. Collectively, the present study provided novel insights into the lncRNA-regulated ceRNA networks in HNSCC and identified novel lncRNAs that harbor diagnostic and prognostic potentials for HNSCC.Abbreviations BP, biological process. CC, cellular component. ceRNA, competing endogenous RNA. DEG, differential expressions of mRNA. DEL, differentially expressed lncRNA. DEM, differentially expressed miRNA. ESCC, esophageal squamous cell carcinoma. FPKM, Fragments Per Kilobase Million. GO, Gene Ontology. GS, gene significance. HNSCC, head and neck squamous cell carcinoma. KEGG, Kyoto Encyclopedia of Genes and Genomes. LncRNA, long non-coding RNA. MCC, Maximal Clique Centrality. ME, module eigengenes. MF, molecular functions. MM, module membership. MRE, miRNA-binding site. MYO5A, Myosin-Va. PART1, prostate androgen-regulated transcript 1. RBM3, RNA­binding motif protein 3. TCGA, The Cancer Genome Atlas. TOM, topological overlap measure. TSCC, tongue squamous cell carcinoma. WGCNA, weighted gene co-expression network analysis.