Linc00673-V3 positively regulates autophagy by promoting Smad3-mediated LC3B transcription in NSCLC.

Since its first discovery, long noncoding RNA Linc00673 has been linked to carcinogenesis and metastasis of various human cancers. Linc00673 had five transcriptional isoforms and their biological functions remained to be explored. Here we have reported that Linc00673-V3, one of the isoforms of Linc00673, promoted non-small cell lung cancer chemoresistance, and increased Linc00673-V3 expression level was associated with enhanced autophagy. Mechanistically, we discerned the existence of a stem-loop configuration engendered by the 1-100-nt and 2200-2275-nt fragments within Linc00673-V3. This structure inherently interacted with Smad3, thereby impeding its ubiquitination and subsequent degradation orchestrated by E3 ligase STUB1. The accumulation of Smad3 contributed to autophagy via up-regulation of LC3B transcription and ultimately conferred chemoresistance in NSCLC. Our results revealed a novel transcriptional regulation network between Linc00673-V3, Smad3, and LC3B, which provided an important insight into the interplay between autophagy regulation and non-canonical function of Smad3. Furthermore, the results from in vivo experiments suggested Linc00673-V3 targeted antisense oligonucleotide as a promising therapeutic strategy to overcome chemotherapy resistance in NSCLC.

PINK1-PTEN axis promotes metastasis and chemoresistance in ovarian cancer via non-canonical pathway.

BACKGROUND: Ovarian cancer is commonly associated with a poor prognosis due to metastasis and chemoresistance. PINK1 (PTEN-induced kinase 1) is a serine/threonine kinase that plays a crucial part in regulating various physiological and pathophysiological processes in cancer cells. METHODS: The ATdb database and "CuratedOvarianData" were used to evaluate the effect of kinases on ovarian cancer survival. The gene expression in ovarian cancer cells was detected by Western blot and quantitative real-time PCR. The effects of gene knockdown or overexpression in vitro were evaluated by wound healing assay, cell transwell assay, immunofluorescence staining, immunohistochemistry, and flow cytometry analysis. Mass spectrometry analysis, protein structure analysis, co-immunoprecipitation assay, nuclear-cytoplasmic separation, and in vitro kinase assay were applied to demonstrate the PINK1-PTEN (phosphatase and tensin homolog) interaction and the effect of this interaction. The metastasis experiments for ovarian cancer xenografts were performed in female BALB/c nude mice. RESULTS: PINK1 was strongly associated with a poor prognosis in ovarian cancer patients and promoted metastasis and chemoresistance in ovarian cancer cells. Although the canonical PINK1/PRKN (parkin RBR E3 ubiquitin protein ligase) pathway showed weak effects in ovarian cancer, PINK1 was identified to interact with PTEN and phosphorylate it at Serine179. Remarkably, the phosphorylation of PTEN resulted in the inactivation of the phosphatase activity, leading to an increase in AKT (AKT serine/threonine kinase) activity. Moreover, PINK1-mediated phosphorylation of PTEN impaired the nuclear import of PTEN, thereby enhancing the cancer cells' ability to resist chemotherapy and metastasize. CONCLUSIONS: PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import. PINK1 promotes ovarian cancer metastasis and chemotherapy resistance through the regulation of PTEN. These findings offer new potential therapeutic targets for ovarian cancer management.

Low dose PFDA induces DNA damage and DNA repair inhibition by promoting nuclear cGAS accumulation in ovarian epithelial cells.

Per- and polyfluoroalkyl substances (PFAS), the versatile anthropogenic chemicals, are popular with the markets and manufactured in large quantities yearly. Accumulation of PFAS has various adverse health effects on human. Albeit certain members of PFAS were found to have genotoxicity in previous studies, the mechanisms underlying their effects on DNA damage repair remain unclear. Here, we investigated the effects of Perfluorodecanoic acid (PFDA) on DNA damage and DNA damage repair in ovarian epithelial cells through a series of in vivo and in vitro experiments. At environmentally relevant concentration, we firstly found that PFDA can cause DNA damage in primary mouse ovarian epithelial cells and IOSE-80 cells. Moreover, nuclear cGAS increased in PFDA-treated cells, which leaded to the efficiency of DNA homologous recombination (HR) decreased and DNA double-strand breaks perpetuated. In vivo experiments also verified that PFDA can induce more DNA double-strand breaks lesions and nuclear cGAS in ovarian tissue. Taken together, our results unveiled that low dose PFDA can cause deleterious effects on DNA and DNA damage repair (DDR) in ovarian epithelial cells and induce genomic instability.

MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage.

Peritoneal metastasis is a key feature of advanced ovarian cancer, but the critical protein required for ovarian cancer metastasis and progression is yet to be defined. Thus, an unbiased high throughput and in-depth study is warranted to unmask the mechanism. Transcriptomic sequencing of paired primary ovarian tumors and metastases unveiled that MAP4K4, a serine/threonine kinase belongs to the Ste20 family of kinases, was highly expressed in metastatic sites. Increased MAP4K4 expression in metastasis was further validated in other independent patients, with higher MAP4K4 expression associated with poorer survival, higher level of CA125 and more advanced FIGO stage. Down regulation of MAP4K4 inhibited cancer cell adhesion, migration, and invasion. Notably, MAP4K4 was found to stabilize N-cadherin. Further results showed that MAP4K4 mediated phosphorylation of ADAM10 at Ser436 results in suppression of N-cadherin cleavage by ADAM10, leading to N-cadherin stabilization. Pharmacologic inhibition of MAP4K4 abrogated peritoneal metastases. Overall, our data reveal MAP4K4 as a significant promoter in ovarian cancer metastasis. Targeting MAP4K4 may be a potential therapeutic approach for ovarian cancer patients.

Low-dose BPA and its substitute BPS promote ovarian cancer cell stemness via a non-canonical PINK1/p53 mitophagic signaling.

The environmental toxicity of bisphenol A (BPA) and its analog like bisphenol S (BPS) have drawn wide attention, but their roles in cancer progression remain controversial. Here, we investigated the effect of BPA/BPS on the development of ovarian cancer. Human internal BPA/BPS exposure levels were analyzed from NHANES 2013-2016 data. We treated human ovarian cancer cells with 0-1000 nM BPA/BPS and found that 100 nM BPA/BPS treatment significantly increased Cancer Stem Cell (CSC) markers expression including OCT4, NANOG and SOX2. Cancer cell stemness evaluation induced by BPA/BPS was notably attenuated by the knockdown of PINK1 or Mdivi-1 treatment. The activation of PINK1 initiated mitophagy by inhibiting p-p53 nuclear translocation in a non-canonical manner. In vivo studies validated that BPA/BPS-exposed mice have higher tumor metastasis incidence compared with the control group, while mitophagy inhibition blocked such a promotion effect. In addition, CSC markers such as SOX2 had been found to be overexpressed in the tumor tissues of BPA/BPS exposure group. Taken together, the findings herein first provide the evidence that environmentally relevant BPA/BPS exposure could enhance ovarian cancer cell stemness through a non-canonical PINK1/p53 mitophagic pathway, raising concerns about the potential population hazards of BPA and other bisphenol analogs.

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This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01|‒|1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49|‒|2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48|‒|1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39|‒|1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32|‒|0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38|‒|0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75|‒|8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88|‒|6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

Association between Different Types of Tea Consumption and Risk of Gynecologic Cancer: A Meta-Analysis of Cohort Studies.

Plenty of studies have shown that tea has an effect of inhibiting gynecologic tumors. However, there still remained controversy of the association between tea and gynecologic tumors in epidemiological studies. In this study, PubMed, Embase, and Cochrane Database were used to search the literature from 1 January 1960 to 26 December 2022 to investigate the association between tea intake and gynecologic cancer risk. In total, 19 cohort studies with 2,020,980 subjects and 12,155 gynecological tumor cases were retrieved. The pooled relative risk (RR) of gynecologic tumor for tea intake was 1.00 (95% CI: 0.96-1.04). RRs were 0.94 (95% CI: 0.88-1.01) for ovarian cancer, 1.02 (95% CI: 0.97-1.07) for endometrial cancer, and 1.06 (95% CI: 0.91-1.23) for cervical cancer. Subgroup analyses were adopted based on the tea type and geographic location. Interestingly, significant preventive impact of non-herbal tea on ovarian cancer (pooled relative risk: 0.67; 95% CI: 0.55-0.81) was found, especially for black tea (pooled relative risk: 0.64; 95% CI: 0.51-0.80). Dose-response analysis indicated that although it is not statistically significant, a decreasing trend of ovarian cancer risk could be observed when the tea consumption was 1.40 to 3.12 cups/day. In conclusion, our findings suggested that ovarian cancer, but not other gynecologic cancers, could possibly be prevented by drinking non-herbal tea. In addition, the preventive impact of green tea on gynecologic cancer seemed to be relatively weak and needs further cohorts to validate it.

Toxicogenomics scoring system: TGSS, a novel integrated risk assessment model for chemical carcinogenicity prediction.

BACKGROUND: Given the increasing exposure of humans to environmental chemicals and the limitations of conventional toxicity test, there is an urgent need to develop next-generation risk assessment methods. OBJECTIVES: This study aims to establish a novel computational system named Toxicogenomics Scoring System (TGSS) to predict the carcinogenicity of chemicals coupling chemical-gene interactions with multiple cancer transcriptomic datasets. METHODS: Chemical-related gene signatures were derived from chemical-gene interaction data from the Comparative Toxicogenomics Database (CTD). For each cancer type in TCGA, genes were ranked by their effects on tumorigenesis, which is based on the differential expression between tumor and normal samples. Next, we developed carcinogenicity scores (C-scores) using pre-ranked GSEA to quantify the correlation between chemical-related gene signatures and ranked gene lists. Then we established TGSS by systematically evaluating the C-scores in multiple chemical-tumor pairs. Furthermore, we examined the performance of our approach by ROC curves or prognostic analyses in TCGA and multiple independent cancer cohorts. RESULTS: Forty-six environmental chemicals were finally included in the study. C-score was calculated for each chemical-tumor pair. The C-scores of IARC Group 3 chemicals were significantly lower than those of chemicals in Group 1 (P-value = 0.02) and Group 2 (P-values = 7.49 ×10-5). ROC curves analysis indicated that C-score could distinguish "high-risk chemicals" from the other compounds (AUC = 0.67) with a specificity and sensitivity of 0.86 and 0.57. The results of survival analysis were also in line with the assessed carcinogenicity in TGSS for the chemicals in Group 1. Finally, consistent results were further validated in independent cancer cohorts. CONCLUSION: TGSS highlighted the great potential of integrating chemical-gene interactions with gene-cancer relationships to predict the carcinogenic risk of chemicals, which would be valuable for systems toxicology.

Bidirectional Mendelian Randomisation Analysis Provides Evidence for the Causal Involvement of Dysregulation of CXCL9, CCL11 and CASP8 in the Pathogenesis of Ulcerative Colitis.

BACKGROUND AND AIMS: Systemic inflammation is well recognised to be associated with ulcerative colitis [UC], but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. METHODS: We first synthesised serum proteomic profiling data from two multicentred observational studies, in which a panel of systemic inflammatory proteins was analysed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomisation [TSMR] analysis from both forward and reverse directions using five genome-wide association study [GWAS] summary level data for serum proteomic profiles and the largest GWAS of 28 738 European-ancestry individuals for UC risk. RESULTS: Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci [cis-pQTLs] or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 [CXCL9] [OR 1.45, 95% CI 1.08, 1.95, p = 0.012] and C-C motif chemokine ligand 11 [CCL11] [OR 1.14, 95% CI 1.09, 1.18, p = 3.89 × 10-10]. Using both cis- and trans-acting pQTLs, an association of caspase-8 [CASP8] [OR 1.04, 95% CI 1.03, 1.05, p = 7.63 × 10-19] was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. CONCLUSION: Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.

Extracellular Vesicle-Packaged circATP2B4 Mediates M2 Macrophage Polarization via miR-532-3p/SREBF1 Axis to Promote Epithelial Ovarian Cancer Metastasis.

Ovarian cancer is one of the most common gynecologic malignancies with a highly immunosuppressive tumor microenvironment (TME) and poor prognosis. Circular RNA (circRNA) is a type of noncoding RNA with high stability, which has been shown to play an important role in biological processes and TME reprogramming in a variety of tumors. The biological function of a novel circRNA, circATP2B4, in epithelial ovarian cancer (EOC) was detected and evaluated. Transmission electron microscopy, differential ultracentrifugation and qRT-PCR were used to verify the existence of extracellular vesicles (EV)-packaged circATP2B4. Macrophage uptake of circATP2B4 was determined by EVs tracing. Dual luciferase reporter, FISH, Western blotting, and flow cytometry assays were used to investigate the interactions between circATP2B4 and miR-532-3p as well as sterol regulatory element-binding factor 1 (SREBF1) expression in macrophages. CircATP2B4 was upregulated in EOC tissues and positively correlated with ovarian cancer progression. Functionally, circATP2B4 promoted carcinogenic progression and metastasis of EOC both in vitro and in vivo. Mechanistically, EV-packaged circATP2B4 in EOC could be transmitted to infiltrated macrophages and acted as competing endogenous RNA of miR-532-3p to relieve the repressive effect of miR-532-3p on its target SREBF1. Furthermore, circATP2B4 induced macrophage M2 polarization by regulating the miR-532-3p/SREBF1/PI3Kα/AKT axis, thereby leading to immunosuppression and ovarian cancer metastasis. Collectively, these data indicate that circATP2B4-containing EVs generated by EOC cells promoted M2 macrophages polarization and malignant behaviors of EOC cells. Thus, targeting EVs-packaged circATP2B4 may provide a potential diagnosis and treatment strategy for ovarian cancer.

Identification of metastasis-related long non-coding RNAs in lung cancer through a novel tumor mesenchymal score.

Long non-coding RNAs (lncRNAs) have been proven to play critical roles in epithelial-mesenchymal transition (EMT) and metastasis of lung cancer. However, the biological functions and related mechanisms of lncRNAs are unclear. In addition, the EMT-based prognosis prediction in lung cancer still lacks investigation. Here, we established the methodology of identifying critical metastasis-related lncRNAs using comprehensive datasets of cancer transcriptome, genome and epigenome, and also provided tools for prognosis prediction in lung cancer. Initially, important mesenchymal marker genes were identified to compose the tumor mesenchymal score, which predicted patient prognosis in lung cancer, especially lung adenocarcinoma (LUAD). The score was also correlated with several crucial biological and physiological processes, such as tumor immune and hypoxia. Based on the score, lung cancer patients was classified into epithelial and mesenchymal subtypes, and lncRNAs which exhibited expressional dysregulation, promotor methylation alteration and copy number variation between the two subtypes in LUAD were identified and underwent further prognostic analyses. Finally, we identified 14 lncRNAs as EMT-related and significant biomarkers in prognosis prediction of LUAD. As validation, lncRNA RBPMS-AS1 was proven to be co-expressed with epithelial biomarkers, suppressive for A549 cell migration, invasion and EMT, and also significantly associated with better outcomes of LUAD patients, suggesting the potential of RBPMS-AS1 to serve as a lncRNA epithelial biomarker in metastasis of LUAD. Based on the identified lncRNAs, an EMT-linked lncRNA prognostic signature was further established. Taken together, our study provides robust predictive tools, potential lncRNA targets and feasible screening strategies for future study of lung cancer metastasis.

Friend or Foe? Implication of the autophagy-lysosome pathway in SARS-CoV-2 infection and COVID-19.

There is increasing amount of evidence indicating the close interplays between the replication cycle of SARS-CoV-2 and the autophagy-lysosome pathway in the host cells. While autophagy machinery is known to either assist or inhibit the viral replication process, the reciprocal effects of the SARS-CoV-2 on the autophagy-lysosome pathway have also been increasingly appreciated. More importantly, despite the disappointing results from the clinical trials of chloroquine and hydroxychloroquine in treatment of COVID-19, there is still ongoing effort in discovering new therapeutics targeting the autophagy-lysosome pathway. In this review, we provide an update-to-date summary of the interplays between the autophagy-lysosome pathway in the host cells and the pathogen SARS-CoV-2 at the molecular level, to highlight the prognostic value of autophagy markers in COVID-19 patients and to discuss the potential of developing novel therapeutic strategies for COVID-19 by targeting the autophagy-lysosome pathway. Thus, understanding the nature of such interactions between SARS-CoV-2 and the autophagy-lysosome pathway in the host cells is expected to provide novel strategies in battling against this global pandemic.

Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq.

Benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon compound, is a carcinogen that causes head and neck cancers. Despite intensive research, the molecular mechanism of BaP in the development of oral squamous cell carcinoma (OSCC) remains largely unknown. In the present study, the SCC-9 human OSCC cell line was cultured in vitro, separated into treatment groups, and treated with dimethyl sulfoxide or BaP at various concentrations. The malignant behavior ascribed to the BaP treatment was investigated by cell proliferation, clony formation assay, and Transwell assays. Furthermore, transcriptome sequencing was performed to detect the differentially expressed genes, followed by quantitative real-time PCR to measure the expression levels of nine of these genes. Moreover, the Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed the biological processes and signaling pathways in which the target genes were involved. Significant effects on SCC-9 cell proliferation, tumorigenicity, cell migration, and invasion were observed after exposure to 8 µM BaP. Additional results revealed that BaP inhibited apoptosis in a dose-dependent manner. The transcriptome sequencing results showed 137 upregulated genes and 135 downregulated genes induced by BaP, associated with tumor-related biological processes and signaling pathways, mainly including transcriptional dysregulation in cancer, the tumor necrosis factor signaling pathway, metabolism of xenobiotics by cytochrome P450, mitogen-activated protein kinase signaling pathway, and so forth. Our study demonstrates that BaP may regulate the expression of certain genes involved in tumor-associated signaling pathways, thereby promoting the proliferative, tumorigenic, and metastatic behaviors of OSCC cells while suppressing their apoptosis.

High expression of RIPK2 is associated with Taxol resistance in serous ovarian cancer.

BACKGROUND: Taxol resistance in serous ovarian cancer is responsible for its poor prognosis, yet the underlying mechanism is still poorly understood. Thus, we probed the mechanism of Taxol resistance in serous ovarian cancer with multiple bioinformatic methods to provide novel insights into potential therapies. METHODS: The differentially expressed genes (DEGs) in Taxol-sensitive and Taxol-resistant cell lines and their relationship with the overall survival (OS) and progression-free interval (PFI) of ovarian cancer patients were analyzed using gene expression datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The role of receptor interacting serine/threonine kinase 2 (RIPK2) was validated via identification of its coexpressed genes, functional analysis and generation of a protein-protein interaction (PPI) network. The single sample gene set enrichment analysis (ssGSEA) was used to explore immune infiltration, and genomic alterations of RIPK2 were also analyzed via cBio Cancer Genomics Portal (cBioProtal). RESULTS: RIPK2 was highly expressed in Taxol resistant ovarian cancer cell lines, and its high expression was also linked with shorter OS and PFI in serous ovarian cancer patients. The PPI network analysis and pathway analysis demonstrated that RIPK2 might participate in the positive regulation of NF-κB transcription factor activity. RIPK2 expression was related to tumor microenvironment alterations, which might participate in the formation of Taxol resistance. CONCLUSIONS: Our studies suggested that high expression of RIPK2 is related to Taxol resistance in serous ovarian cancer, and that RIPK2 induces Taxol resistance through NOD1/RIPK2/NF-κB inflammatory pathway activation and tumor microenvironment changes.

WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP.

The mammalian Atg18 ortholog WIPI2 is a key regulator of LC3 lipidation to promote autophagosome biogenesis during nonselective macroautophagy, while its functions in selective autophagy such as mitophagy remain largely unexplored. In this study, we explored the role of WIPI2 in PINK1-PRKN/parkin-mediated mitophagy. First, we found that WIPI2 is recruited to damaged mitochondria upon mitophagy induction. Second, loss of WIPI2 impedes mitochondrial damaging agents-induced mitophagy. Third, at molecular level, WIPI2 binds to and promotes AAA-ATPase VCP/p97 (valosin containing protein) to damaged mitochondria; and WIPI2 depletion blunts the recruitment of VCP to damaged mitochondria, leading to reduction in degradation of outer mitochondrial membrane (OMM) proteins and mitophagy. Finally, WIPI2 is implicated in cell fate decision as cells deficient in WIPI2 are largely resistant to cell death induced by mitochondrial damage. In summary, our study reveals a critical regulatory role of WIPI2 in mitochondrial recruitment of VCP to promote OMM protein degradation and eventual mitophagy.Abbreviations: ATG, autophagy related; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide chlorophenylhydrazone; CYCS, cytochrome c, somatic; HSPD1/HSP60, heat shock protein family D (Hsp60) member 1; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; NPLOC4, NPL4 homolog, ubiquitin recognition factor; OMM, outer mitochondrial membrane; OPTN, optineurin; PtdIns3P, phosphatidylinositol-3-phosphate; PINK1, PTEN induced kinase 1; PRKN/Parkin, parkin RBR E3 ubiquitin protein ligase; UBXN6/UBXD1, UBX domain protein 6; UFD1, ubiquitin recognition factor in ER associated degradation 1; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.

LncRNA CASC15, MiR-23b Cluster and SMAD3 form a Novel Positive Feedback Loop to promote Epithelial-Mesenchymal Transition and Metastasis in Ovarian Cancer.

Cancer Susceptibility Candidate 15 (CASC15), which is a newly identified long noncoding RNA crucial for epigenetic regulation in human tumors, was found to be associated with poor prognosis of the patients with ovarian cancer by utilizing The Cancer Genome Atlas and Gene Expression Omnibus database. Therefore, the purpose of this paper was to explore the functional role and latent molecular mechanism of CASC15 in the progression of ovarian cancer. In vitro and in vivo experiments validated CASC15 as an oncogenic lncRNA in ovarian cancer, which could enhance metastasis through TGF-ß-induced epithelial-mesenchymal transition progress. MiR-23b-3p and miR-24-3p, which are members of the miR-23b cluster, were identified to directly target CASC15 through luciferase assays. Further mechanistic investigations indicated that CASC15-mediated miR-23b-3p/miR-24-3p sequestration cooperatively upregulated SMAD3 expression, which, in turn, would permit increased CASC15 mRNA level as a transcription activation factor. This study first described a miR-23b-3p/miR-24-3p-mediated positive feedback loop between CASC15 and SMAD3, which may reflect the underlying molecular mechanism of CASC15's oncogenic function in ovarian cancer.

A novel lncRNA lnc-PPRL promotes pterygium development by activating PI3K/PDK1 signaling pathway.

A sight threatening, pterygium is a common proliferative and degenerative disease of the ocular surface. LncRNAs have been widely studied in the occurrence and development of various diseases, however, the study of lncRNAs in pterygium has just relatively lacking. In the present study, we performed the high-throughput RNA sequencing (HTS) technology to identify differentially expressed lncRNAs in pterygium. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out to forecast the regulatory and functional role of lncRNAs in pterygium. Notably, we identified a novel lncRNA, LOC102724238, which we named pterygium positively-related lncRNA (lnc-PPRL), was up-regulated in pterygium. Lnc-PPRL showed to be preferentially accumulated in cytoplasm, and it can promote cell proliferation, migration and invasion of human pterygium epithelium cells (hPECs). Further study of underlying mechanisms demonstrated that lnc-PPRL may exert its biological effect by activating canonical PI3K/PDK1 pathway, and subsequently promoting the activation of Akt/mTOR signaling pathway and its downstream effectors. Interestingly, lnc-PPRL was also proved to influence YAP nuclear localization. Taken together, our study firstly suggested that the "big molecule" lnc-PPRL have potential as a novel therapeutic target for the prevention and treatment of pterygium.

Toxic epidermal necrolysis associated with chemoimmunotherapy for lymphoma: case report and literature review.

Aim: The emergence of antitumor immunotherapy has been beneficial for patients with tumors, but more attention should be paid to the toxic side effects of chemoimmunotherapy. Here we describe a patient with NK/T-cell lymphoma who developed toxic epidermal necrolysis (TEN) during treatment with a regimen consisting of sintilimab combined with pegaspargase, gemcitabine and oxaliplatin (P-GemOx). Case presentation: A patient received six cycles of P-GemOx chemotherapy as first-line treatment; 1 year later, he received the same dose of P-GemOx combined with sintilimab as chemoimmunotherapy due to recurrence of NK/T-cell lymphoma. He developed a massive rash that quickly developed into TEN after the fourth chemoimmunotherapy. Conclusion: Although rare, cases of fatal TEN caused by single-agent PD-1 inhibitor or gemcitabine have been reported. Careful attention to drug-related cutaneous toxicities is needed when these two agents are combined. This report highlights the significance of TEN as a rapid and serious adverse event induced by chemoimmunotherapy.

Immune checkpoint inhibitors that block the interaction of PD-1 with its ligand, PD-L1, have been increasingly used in cancer therapy. However, some rare side effects induced by these drugs, such as toxic epidermal necrolysis (TEN), can be extremely dangerous. Here we describe a patient with natural killer/T-cell lymphoma who developed TEN during treatment with a combination of sintilimab and pegaspargase/gemcitabine/oxaliplatin (P-GemOx). The patient received six cycles of P-GemOx chemotherapy as first-line treatment and showed no skin reactions during or after treatment. However, 1 year later, the patient received the same dose of P-GemOx combined with sintilimab as second-line treatment for recurrent natural killer/T-cell lymphoma and developed a massive rash that quickly developed into TEN after four cycles of chemoimmunotherapy. Cutaneous toxicities are some of the most prevalent immune-related adverse events, both with anti-PD-1 and anti-PD-L1 agents, which correspond to a class effect.

Cholesterol-enriched membrane micro-domaindeficiency induces doxorubicin resistancevia promoting autophagy in breast cancer.

Drug resistance has become one of the largest challenges for cancer chemotherapies. Under certain conditions, cancer cells hijack autophagy to cope with therapeutic stress, which largely undermines the chemo-therapeutic efficacy. Currently, biomarkers indicative of autophagy-derived drug resistance remain largely inclusive. Here, we report a novel role of lipid rafts/cholesterol-enriched membrane micro-domains (CEMMs) in autophagosome biogenesis and doxorubicin resistance in breast tumors. We showed that CEMMs are required for the interaction of VAMP3 with syntaxin 6 (STX6, a cholesterol-binding SNARE protein). Upon disruption of CEMM, VAMP3 is released from STX6, resulting in the trafficking of ATG16L1-containing vesicles to recycling endosomes and subsequent autophagosome biogenesis. Furthermore, we found that CEMM marker CAV1 is decreased in breast cancer patients and that the CEMM deficiency-induced autophagy is related to doxorubicin resistance, which is overcome by autophagy inhibition. Taken together, we propose a novel model whereby CEMMs in recycling endosomes support the VAMP3 and STX6 interaction and function as barriers to limit the activity of VAMP3 in autophagic vesicle fusion, thus CEMM deficiency promotes autophagosome biogenesis and doxorubicin resistance in breast tumors.

Impact of antitumor regimens on the outcomes of cancer patients with COVID-19: a pooled analysis.

Since the outbreak of coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) discovered in December 2019, the disease has emerged as a global pandemic (Shi et al., 2020; World Health Organization, 2020). Several studies have shown a higher incidence of COVID-19, as well as related poor outcomes in patients with malignancies as compared with those without them (Liang et al., 2020; Tian et al., 2020). The impact of cancer on COVID-19 may be attri­buted to the use of antitumor treatments that may disturb the host response to SARS-CoV-2 infection (Wang et al., 2020), while the current studies on this topic have drawn controversial conclusions. Some implied that anticancer treatments might elevate the risk of death (García-Suárez et al., 2020; Liu et al., 2020). On the contrary, others pointed out that this association is not significant (Brar et al., 2020; Lee et al., 2020a). Although previous systematic reviews have investigated this important issue (Wang and Huang, 2020), the heterogeneity of findings is obvious and the general conclusion has remained unclear. Considering this ambiguity, it is difficult for clinicians to make therapeutic decisions when facing patients with both cancer and COVID-19; therefore, a high-quality and accurate evaluation of the impact of anticancer treatments on COVID-19 patients is necessary. Accordingly, we conducted a pooled analysis with the original data of each patient for the first time to provide a comprehensive perspective into the association between anticancer regimens and the outcomes of cancer patients with COVID-19.