RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas.

Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.

Role of circular RNA as competing endogenous RNA in ovarian cancer (Review).

Circular RNA (circRNA), a type of non­coding RNA, plays a regulatory role in biological processes. The special loop structure of circRNA makes it highly stable and specific in diseased tissues and cells, especially in tumors. Competing endogenous RNAs (ceRNAs) compete for the binding of microRNA (miRNA) at specific binding sites and thus regulate gene expression. ceRNAs play an important role in various diseases and are currently recognized as the most prominent mechanism of action of circRNAs. circRNAs can modulate the proliferation, migration, invasion and apoptosis of tumor cells through the ceRNA mechanism. With further research, circRNAs may serve as novel markers and therapeutic targets for ovarian cancer (OC). In the present review, the research progress of circRNAs as ceRNAs in OC was summarized, focusing on the effects of the circRNA/miRNA/mRNA axis on the biological functions of OC cells through mediating pivotal signaling pathways. The role of circRNAs in the diagnosis, prognostic assessment and treatment of OC was also discussed in the present review.

Construction and validation of prognostic nomogram and clinical characteristics for ovarian endometrioid carcinoma: an SEER-based cohort study.

BACKGROUND: Ovarian endometrioid carcinoma (OEC) is the second most commonly occurring ovarian epithelial malignancy, but the associated prognostic factors remain obscure. This study aimed to analyze independent prognostic factors for patients with OEC and to develop and validate a nomogram to predict the overall survival (OS) of these patients. METHODS: Clinical information of patients with OEC (2000-2019) was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were used to identify independent prognostic factors, and nomogram models were constructed using independent prognostic factors. Receiver operating characteristic (ROC) curve, calibration plots, and decision curve analysis (DCA) were used to verify the accuracy and validity of the nomogram. Kaplan-Meier curves were used to compare the differences in OS and cancer-specific survival (CSS) among subgroups. RESULTS: A total of 4628 patients with OEC were included, being divided into training (n = 3238) and validation (n = 1390) sets (7:3 ratio). On multivariate Cox analysis, AJCC stage, age, tumor size, differentiation, chemotherapy, and lymph node resection were significant predictors of survival outcomes (P < 0.05). Resection of 1-3 lymph nodes in early-stage OEC patients did not significantly prolong OS (P > 0.05), but resection of ≥ 4 lymph nodes in early-stage improved OS and CSS (P < 0.05). The OS of early-stage patients was not related to whether or not they received chemotherapy (P > 0.05). Lymph node resection and chemotherapy significantly improved the prognosis of patients with advanced OEC (P < 0.05). The c-index of nomogram prediction model was 0.782. ROC with good discrimination, calibration plots with high consistency, and DCA with large net benefit rate result in large clinical value. CONCLUSION: AJCC stage, differentiation, tumor size, age, chemotherapy, and lymph node dissection were prognostic factors of OEC. The constructed nomogram prediction model can effectively predict the prognosis of OEC patients and improve the accuracy of clinical decision-making.

Disruption of Bombyx mori nucleopolyhedrovirus ORF71 (Bm71) results in inefficient budded virus production and decreased virulence in host larvae.

The Bombyx mori nucleopolyhedrovirus (BmNPV) is a baculovirus that selectively infects domestic silkworm. BmNPV ORF71 (Bm71) is not a core set gene in baculovirus and shares 92 % amino acid sequence identity with Autographa californica multinucleocapsid NPV ORF88 (Ac88/cg30). Previously, it has been reported that virus lacking Ac88 had no striking phenotypes in cell lines or host larvae. However, the exact role of Bm71 during BmNPV life cycle remains unknown. In the present study, we constructed a Bm71-disrupted (Bm71-D) virus and assessed the effect of the Bm71 disruption on viral replication and viral phenotype throughout the viral life cycle. Results showed that the Bm71-D bacmid could successfully transfect Bm5 cell lines and produce infectious budded virus (BV). But the BV titer was 10- to 100-fold lower than that of the wild-type (WT) virus during infection, and the decreased BV titer was rescued by Bm71 gene repair virus (Bm71-R). A larval bioassay showed that Bm71-D virus took 7.5 h longer than the WT to kill Bombyx mori larvae. Transmission electron microscopy analysis indicated that the Bm71-D virus-infected cells had typical virogenic stroma, bundles of nucleocapsids and polyhedra. Taken together, these results suggest that Bm71 has important implications for determining BV yield and virulence in viral life cycle even though it is not an essential gene for replication of BmNPV.

The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation.

Organisms have evolved elaborate mechanisms to adjust intracellular nutrient levels in response to fluctuating availability of exogenous nutrients. During starvation, cells can enhance amino acid uptake and synthesis through the general amino acid control (GAAC) pathway, whereas nonessential cellular contents are recycled by autophagy. How these two pathways are coordinated in response to starvation is currently unknown. Here we show that the GAAC pathway couples exogenous amino acid availability with autophagy. Starvation caused deactivation of mTOR, which then activated autophagy. In parallel, serum/glutamine starvation activated the GAAC pathway, which up-regulated amino acid transporters, leading to increased amino acid uptake. This elevated the intracellular amino acid level, which in turn reactivated mTOR and suppressed autophagy. Knockdown of activating transcription factor 4, the major transcription factor in the GAAC pathway, or of SLC7A5, a leucine transporter, caused impaired mTOR reactivation and much higher levels of autophagy. Thus, the GAAC pathway modulates autophagy by regulating amino acid uptake and mTOR reactivation during serum/glutamine starvation.