CircRNA circ-ATAD1 Is Upregulated in Cervical Squamous Cell Carcinoma and Regulates Cell Proliferation and Apoptosis by Suppressing the Maturation of miR-218.

The oncogenic function of circ-ATAD1 has been characterized in gastric cancer, while its role in cervical squamous cell carcinoma (CSCC) is unclear. This study explored the role of circ-ATAD1 in CSCC. To evaluate the differential expression of circ-ATAD1, mature miR-218, and premature miR-218 in CSCC, a total of 62 CSCC patients were subjected to biopsies to collect CSCC and paired normal tissues. Gene expression levels were quantified by RT-qPCRs. Nuclear fractionation assay was performed to analyze the subcellular location of circ-ATAD1. CSCC cells were used to perform cell transfections to explore the crosstalk between circ-ATAD1 and miR-218. The roles of circ-ATAD1 and miR-218 in CSCC cell behaviors were explored by BrdU assay, Transwell assay, cell apoptosis assay, and cell stemness assay. CSCC tissues exhibited upregulated expression of circ-ATAD1, which was localized to both nucleus and cytoplasm. Mature miR-218 was downregulated in CSCC tissues and was inversely correlated with circ-ATAD1, while premature miR-218 was not differentially expressed in CSCC. Upregulation of circ-ATAD1 in CSCC cells decreased the expression levels of mature miR-218, but not that of premature miR-218. In addition, overexpression of circ-ATAD1 increased cell proliferation and decreased cell apoptosis, while overexpression of miR-218 decreased cell proliferation and increased cell apoptosis, and it also attenuated the effects of overexpression of circ-ATAD1 on cell proliferation. However, CSCC cell invasion, migration, and stemness were not affected by circ-ATAD1 and miR-218. Circ-ATAD1 is upregulated in CSCC and may regulate cell proliferation and apoptosis by suppressing the maturation of miR-218.

ATAD2 interacts with C/EBPß to promote esophageal squamous cell carcinoma metastasis via TGF-ß1/Smad3 signaling.

BACKGROUND: Distant metastasis is the leading cause of death for esophageal squamous cell carcinoma (ESCC) with limited treatment options and unsatisfactory effectiveness. Bromodomain (BRD) containing proteins are emerging targets for cancer therapy with promising effects. As a unique member of BRD family, the function and molecular mechanism of ATAD2 in cancer development is seldomly investigated. METHODS: The clinical impact of ATAD2 was assessed both at RNA and protein level in 75 and 112 ESCC patients separately. The biological function of ATAD2 was investigated in vitro and in vivo. Signaling pathway and downstream effectors of ATAD2 were identified by RNA sequencing, luciferase reporter, co-immunoprecipitation, chromatin immunoprecipitation, immunofluorescence and western blot assay. RESULTS: We found that elevated ATAD2 expression was significantly associated with lymph node metastasis, advanced clinical stage as well as poor survival of ESCC patients. Silencing ATAD2 significantly suppressed ESCC cell migration and invasion in vitro, and inhibited tumor growth and lung metastasis in vivo. Mechanically, we identified a new cofactor, C/EBPß. ATAD2 directly interacted with C/EBPß and promoted its nuclear translocation, which directly bound to the promoter region of TGF-ß1 and activated its expression. Further, we demonstrated that TGF-ß1 activated its downstream effectors in a Smad3 dependent manner. In addition, we further found that ATAD2 promoted ESCC metastasis through TGF-ß signaling induced Snail expression and the subsequent epithelial-mesenchymal transition. CONCLUSION: Our findings demonstrated the pro-metastatic function of ATAD2 and uncovered the new molecular mechanism by regulating C/EBPß/TGF-ß1/Smad3/Snail signaling pathway, thus providing a potential target for the treatment of ESCC metastasis.

TRIP13 upregulation is correlated with poor prognosis and tumor progression in esophageal squamous cell carcinoma.

Thyroid receptor-interacting protein 13 (TRIP13), a member of the AAA + ATPase super-family, has been proved to be upregulated and identified as a prognostic factor in multiple human cancers, However, the role of TRIP13 in esophageal squamous cell carcinoma (ESCC) and its clinic relevance remains unclear. In the present study, we performed database-mining and detected TRIP13 expression in 158 tissue samples (79 ESCC tissue and 79 matched adjunct non-cancerous tissues). We further investigated the correlation between TRIP13 expression and clinicopathological features and overall survival. Univariate and multivariate Cox regression analyses were applied to evaluate the potential prognostic value of TRIP13 in ESCC patients. In addition, the mechanisms involved in TRIP13 tumor-promoting effect was investigated. Data showed that TRIP13 expression was significantly increased in ESCC tissues, compared with the matched adjunct non-cancerous tissues. Expression of TRIP13 is significantly correlated with T status (P = 0.027), lymphatic metastasis (P = 0.017), and clinical stages of ESCC (P = 0.009). Kaplan-Meier analyses showed that patients with high TRIP13 expression had poor overall survival (P = 0.0022). Multivariate analysis indicated that TRIP13 expression might be an independent prognostic factor in ESCC patients (HR, 1.778, 95% confidence interval = 0.959-3.296, P = 0.028). Furthermore, downregulating TRIP13 in EC109 cell significantly attenuated the cell proliferation and progression, possibly by ß-catenin regulated EMT pathway. Conclusions: Our study demonstrated that TRIP13 might be a tumor promoting factor in ESCC and a promising prognostic indicator for ESCC patient.

Pontin Acts as a Potential Biomarker for Poor Clinical Outcome and Promotes Tumor Invasion in Hilar Cholangiocarcinoma.

Hilar cholangiocarcinoma (HC) is a devastating malignancy that carries a poor overall prognosis. As a member of the AAA+ superfamily, Pontin becomes highly expressed in several malignant tumors, which contributes to tumor progression and influences tumor prognosis. In our research, Pontin expression in tumor specimens resected from 86 HC patients was detected by immunohistochemistry. Interestingly, high expression of Pontin was significantly associated with lymph node metastasis (p = 0.011) and tumor node metastasis (TNM) stage (p = 0.005). The Kaplan-Meier overall survival rate and multivariate analyses were performed to evaluate the prognosis of patients with HC. Patients with high Pontin expression had significantly poorer overall survival outcomes. Multivariate analyses found that Pontin was an independent prognostic factor (p = 0.001). Moreover, bioinformatics analysis confirmed the increase in Pontin mRNA expression levels in cholangiocarcinoma tissues. In addition, in vitro experiments showed that Pontin expression was inhibited at the mRNA as well as protein levels after transfection with Pontin siRNA in human cholangiocarcinoma cell lines. Moreover, significant suppression of cell invasion was observed after the downregulation of Pontin. Taken together, the present study suggested that Pontin could act as a potential prognostic predictor, which might be a new valuable molecular candidate for the prevention and treatment of HC.

Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer.

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Up-regulation of Vps4A promotes neuronal apoptosis after intracerebral hemorrhage in adult rats.

Vps4, vacuolar protein sorting 4, belongs to ATPases Associated with diverse cellular Activities (AAA) protein family which is made up of Vps4A and Vps4B. Previous studies demonstrated that Vps4A plays vital roles in diverse aspects such as virus budding, the efficient transport of H-Ras to the PM (plasma membrane) and the involvement in the MVB (multivesiculate bodies) pathway. Interestingly, Vps4A is also expressed in the brain. However, the distribution and function of Vps4A in ICH diseases remain unclear. In this study, we show that Vps4A may be involved in neuronal apoptosis during pathophysiological processes of intracerebral hemorrhage (ICH). Based on the results of Western blot and immunohistochemistry, we found a remarkable up-regulation of Vps4A expression surrounding the hematoma after ICH. Double labeled immunofluorescence showed that Vps4A was co-expressed with NeuN but rarely with astrocytes and microglia. Morever, we detected that neuronal apoptosis marker active caspase-3 had co-localizations with Vps4A. Additionaly, Vps4A knockdown in vitro specifically leads to decreasing neuronal apoptosis coupled with increased Akt phosphorylation. All datas suggested that Vps4A was involved in promoting neuronal apoptosis via inhibiting Akt phosphorylation after ICH.

Suppressing male spermatogenesis-associated protein 5-like gene expression reduces vitellogenin gene expression and fecundity in Nilaparvata lugens Stål.

In our previous study with the brown planthopper (BPH), Nilaparvata lugens, triazophos (tzp) treatments led to substantial up-regulation of a male spermatogenesis-associated protein 5-like gene (NlSPATA5) compared to untreated controls. Mating with tzp-treated males significantly increased fecundity (as numbers of eggs laid), relative to females mated with untreated males. Because SPATA5 acts in mammalian sperm development and is expressed in testes, we posed the hypothesis that NlSPATA5 occurs in BPH seminal fluid and it operates in fecundity via mating. We tested the hypothesis by investigating the influence of suppressing NlSPATA5 expression in BPH males on fecundity. Reduced expression of NlSPATA5 led to decreased male accessory gland protein content and reproductive system development compared to controls. These changes in males led to prolonged pre-oviposition periods and decreased fecundity in females. For both genders, we recorded no difference in the body weight, oviposition periods, and longevity compared to controls. NlSPATA5 suppression in males also led to decreased fat body and ovarian protein content, yeast-like symbionts abundance and ovarian development as well as vitellogenin gene expression in their mating partners. We infer that increased NlSPATA5 expression may be one molecular mechanism of tzp-driven reproduction and population increases in BPH.