Abemaciclib plus endocrine therapy versus chemotherapy after progression on prior palbociclib in HR+/HER2- metastatic breast cancer: A single center real-world study in China.

BACKGROUND: Cyclin-dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard-of-care for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib-based ET in Chinese patients with HR+/HER2- MBC. METHODS: From 414 consecutive patients with HR+/HER2- MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease-free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression-free survival (PFS) compared using the Kaplan-Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group. RESULTS: The median PFS was 6.0 months (95% confidence interval [CI]: 3.94-8.06) in abemaciclib group and 4.0 months (95% CI, 2.52-5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first-line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd-line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069). CONCLUSION: Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2- MBC after progression on prior palbociclib-based therapy in addition to chemotherapy.

YTHDC1-dependent m6A modification modulated FOXM1 promotes glycolysis and tumor progression through CENPA in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) exhibits heightened aggressiveness compared with other breast cancer (BC) subtypes, with earlier relapse, a higher risk of distant metastasis, and a worse prognosis. Transcription factors play a pivotal role in various cancers. Here, we found that factor forkhead box M1 (FOXM1) expression was significantly higher in TNBC than in other BC subtypes and normal tissues. Combining the findings of Gene Ontology (GO) enrichment analysis and a series of experiments, we found that knockdown of the FOXM1 gene attenuated the ability of TNBC cells to proliferate and metastasize both in vivo and in vitro. In addition, Spearman's test showed that FOXM1 significantly correlated with glycolysis-related genes, especially centromere protein A (CENPA) in datasets (GSE76250, GSE76124, GSE206912, and GSE103091). The effect of silencing FOXM1 on the inhibition of CENPA expression, TNBC proliferation, migration, and glycolysis could be recovered by overexpression of CENPA. According to MeRIP, the level of m6A modification on FOMX1 decreased in cells treated with cycloleucine (a m6A inhibitor) compared with that in the control group. The increase in FOXM1 expression caused by YTHDC1 overexpression could be reversed by the m6A inhibitor, which indicated that YTHDC1 enhanced FOXM1 expression depending on m6A modification. Therefore, we concluded that the YTHDC1-m6A modification/FOXM1/CENPA axis plays an important role in TNBC progression and glycolysis.

Variant allele frequency in circulating tumor DNA correlated with tumor disease burden and predicted outcomes in patients with advanced breast cancer.

PURPOSE: In patients with first-line advanced breast cancer (ABC), the correlation between ctDNA variant allele frequency (VAF) and tumor disease burden, and its prognostic value remains poorly investigated. METHODS: This study included patients with ABC diagnosed at Peking University Cancer Hospital who performed ctDNA test before receiving first-line treatment. Baseline plasma samples were collected for assessing ctDNA alterations and VAF with next-generation sequencing. The sum of tumor target lesion diameters (SLD) was measured with imaging methods according to RECIST 1.1 criteria. RESULTS: The final cohort included 184 patients. The median age of the cohort was 49.4 (IQR: 42.3-56.8) years. The median VAF was 15.6% (IQR: 5.4%-33.7%). VAF showed positive correlation with SLD in patients with relatively large tumor lesions (r = 0.314, p = 0.003), but not in patients with small tumor lesions (p = 0.226). VAF was associated with multiple metastasis sites (p = 0.001). Multivariate Cox regression analysis showed that high VAF was associated with shorter overall survival (OS) (HR: 3.519, 95% confidence interval (CI): 2.149-5.761), and first-line progression-free survival (PFS) (HR: 2.352, 95%CI: 1.462-3.782). Combined VAF and SLD improved prediction performance, both median OS and PFS of patients in VAF(H)/SLD(H) group were significantly longer than VAF(L)/SLD(L) group (mOS: 49.3 vs. 174.1 months; mPFS: 9.6 vs. 25.3 months). CONCLUSION: ctDNA VAF associated with tumor disease burden, and was a prognostic factor for patients with ABC. A combination of ctDNA test and radiographic imaging might enhance tumor burden evaluation, and improve prognosis stratification in patients with ABC.

Cu- and Al-Decorated Monolayer TiSe2 for Enhanced Gas Detection Sensitivity: A DFT Study.

The rapid industrial development has contributed to worsening global pollution, necessitating the urgent development of highly sensitive, cost-effective, and portable gas sensors. In this work, the adsorption of CO, CO2, H2S, NH3, NO, NO2, O2, and SO2 gas molecules on pristine and Cu- and Al-decorated monolayer TiSe2 has been investigated based on first-principles calculations. First, the results of the phonon spectrum and ab initio molecular dynamics simulations demonstrated that TiSe2 is dynamically stable. In addition, compared to pristine TiSe2 (-0.029 to -0.154 eV), the adsorption energy of gas molecules (excluding CO2) significantly decreased after decorated with Cu or Al (-0.212 to -0.977 eV in Cu-decorated TiSe2, -0.438 to -2.896 eV in Al-decorated TiSe2). Among them, NH3 and NO2 have the lowest adsorption energies in Cu and Al-decorated TiSe2, respectively. Further research has shown that the decrease in adsorption energy of gas molecules is mainly due to orbital hybridization and charge transfer between decorated Cu and Al atoms and gas molecules. These findings suggest that TiSe2 decorated with Cu and Al can effectively improve its sensitivity to NH3 and NO2, respectively, making it promising in gas sensing applications.

Efficacy and safety of PEG-rhG-CSF versus rhG-CSF in preventing chemotherapy-induced-neutropenia in early-stage breast cancer patients.

BACKGROUND: To compare the clinical value of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and pegylated rhG-CSF(PEG-rhG-CSF) in early-stage breast cancer (EBC) patients receiving adjuvant chemotherapy, compare the efficacy of PEG-rhG-CSF with different dose and explore the timing of rhG-CSF rescue treatment. METHODS: Patients in two PEG-rhG-CSF subgroups were given 3 mg or 6 mg PEG-rhG-CSF within 24 ~ 48 h after chemotherapy for preventing myelosuppression, while patients in the rhG-CSF group were given rhG-CSF. Observation indicators include the incidence of febrile neutropenia (FN) and grade 3/4 chemotherapy-induced-neutropenia (CIN), the overall levels and nadir values of white blood cells (WBC) and absolute neutrophil count (ANC), comparison of WBC and ANC curves over time, the incidence of CIN-related complications, the incidence of adverse events in each group and the timing of rescue treatment for rhG-CSF. RESULTS: There was no significant difference in the incidence of FN in the first cycle among the groups (P = 0.203). But the incidence of ≥ 3 grade CIN in two PEG-rhG-CSF subgroups was significantly lower than that in the rhG-CSF group (P < 0.001). The overall WBC and ANC levels in the PEG-rhG-CSF group were significantly higher than those in the rhG-CSF group (P < 0.001). In terms of CIN-related complications, less chemotherapy delay rate (1.1 vs. 7.5%, P = 0.092), less dose reduction rate (6.9 vs. 7.5%, P = 1.000), less antibiotic use rate (3.4 vs. 17.5%, P = 0.011) and less proportion of rhG-CSF rescue therapy (24.1 vs. 85.0%, P < 0.001) in the PEG-rhG-CSF group, and there were no significant differences between PEG-rhG-CSF subgroups. In the incidence of adverse events among the groups, there were no statistical differences. All patients undergoing rhG-CSF rescue treatment were mainly 4 grade (63.6%) and 3 grade (25.5%) CIN, and 10.9% of patients with 1 ~ 2 grade CIN who had high infection risk or had been infected. CONCLUSION: PEG-rhG-CSF has better efficacy and equal tolerance compared with rhG-CSF in preventing CIN in EBC patients receiving EC regimen. Moreover, a half-dose 3 mg PEG-rhG-CSF also had good efficacy. Last, patients with ≥ 3 grade CIN and others who have been assessed to be at high risk of infection or have co-infection should consider rhG-CSF or even antibiotic rescue treatment.

Development and validation of a combined hypoxia and ferroptosis prognostic signature for breast cancer.

Background: Hypoxia is involved in tumor biological processes and disease progression. Ferroptosis, as a newly discovered programmed cell death process, is closely related to breast cancer (BC) occurrence and development. However, reliable prognostic signatures based on a combination of hypoxia and ferroptosis in BC have not been developed. Method: We set The Cancer Genome Atlas (TCGA) breast cancer cohort as training set and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) BC cohort as the validation set. Least Absolute Shrinkage and Selection Operator (LASSO) and COX regression approaches were used to construct ferroptosis-related genes (FRGs) and hypoxia-related genes (HRGs) prognostic signature (HFRS). The CIBERSORT algorithm and ESTIMATE score were used to explore the relationship between HFRS and tumor immune microenvironment. Immunohistochemical staining was used to detect protein expression in tissue samples. A nomogram was developed to advance the clinical application of HFRS signature. Results: Ten ferroptosis-related genes and hypoxia-related genes were screened to construct the HFRS prognostic signature in TCGA BC cohort, and the predictive capacity was verified in METABRIC BC cohort. BC patients with high-HFRS had shorter survival time, higher tumor stage, and a higher rate of positive lymph node. Moreover, high HFRS was associated with high hypoxia, ferroptosis, and immunosuppression status. A nomogram that was constructed with age, stage, and HFRS signature showed a strong prognostic capability to predict overall survival (OS) for BC patients. Conclusion: We developed a novel prognostic model with hypoxia and ferroptosis-related genes to predict OS, and characterize the immune microenvironment of BC patients, which might provide new cures for clinical decision-making and individual treatment of BC patients.

Identification of m6A modification patterns and development of m6A-hypoxia prognostic signature to characterize tumor microenvironment in triple-negative breast cancer.

Background: N6-methylation (m6A) modification of RNA has been found to have essential effects on aspects of the tumor microenvironment (TME) including hypoxia status and mobilization of immune cells. However, there are no studies to explore the combined effect of m6A modification and hypoxia on molecular heterogeneity and TME of triple-negative breast cancer (TNBC). Methods: We collected The Cancer Genome Atlas (TCGA-TNBC, N=139), the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC-TNBC, N=297), the GSE103091, GSE21653, and GSE135565 series from the Gene Expression Omnibus (GEO-TNBC, N=247), and FUSCCTNBC (N=245) for our study. The non-negative matrix factorization algorithm was used to cluster TNBC samples. Immune cell infiltration was analyzed by the CIBERSORT algorithm. The enrichment scores were calculated by single-sample gene set enrichment analysis(ssGSEA) to characterize TME in TNBC samples. Immunohistochemistry (IHC) and qRT-PCR were performed to detect the gene expression. Results: Based on the expression of m6A-related genes, we identified three distinct m6A clusters (denoted A, B, and C) in TNBC samples. Comparing the TME characteristics among the three clusters, we observed that cluster C was strongly related to hypoxia status and immune suppression, whereas clusters A and B displayed more immune cell infiltration. Therefore, we combine m6A and hypoxia related genes to classify two m6A-hypoxia clusters of TNBC and screened six prognostic genes by LASSO-Cox regression to construct a m6A-hypoxia signature(MHPS), which divided TNBC samples into high- and low-risk groups. We identified different TME features, immune cell infiltration between the two groups, and a better immunotherapy response was observed in the low-risk group. A nomogram was constructed with tumor size, lymph node, and risk score to improve clinical application of MHPS. Conclusion: We identified distinct TME characteristics of TNBC based on three different m6A modification patterns. Then, we constructed a specific m6A-hypoxia signature for TNBC to evaluate risk and predict immunotherapy response of patients, to enable more accurate treatment in the future.

Impact of homologous recombination deficiency biomarkers on outcomes in patients with early breast cancer: a systematic review protocol.

INTRODUCTION: Patients with breast cancer with homologous recombination deficiency (HRD) such as germline BRCA1/2 mutations would respond to DNA-damaging drugs. Several clinical studies have revealed that HRD biomarkers were associated with the outcomes of patients with early breast cancer (EBC). However, no systematic review has determined the prognostic role of HRD biomarkers in patients with EBC. Therefore, this study will systematically combine and analyse the results of previous studies, to facilitate the clinical use of HRD detection in EBC. METHODS AND ANALYSIS: We will search five databases including PubMed, Cochrane Library, EMBASE, OVID and Web of Science through December 2021, with no language restriction. Two reviewers will independently screen all records based on pre-established inclusion and exclusion criteria. The main outcomes include pathological complete response, disease-free survival and Ooerall survival. In addition, all studies included must contain the detection of HRD score, HRD status or HRD-related gene mutational status and protein expression. Data extraction will be carried out by two reviewers independently according to a self-designed template. The Newcastle-Ottawa Quality Assessment Scale and Jadad Scale will be used for quality assessment for cohort studies and randomised clinical trials, respectively. Review Manager V.5.3.5 will be used to perform meta-analysis. Both the Q test and I2 statistic will be used to assess heterogeneity. Subgroup and sensitivity analyses will be conducted if significant heterogeneity appears and cannot be reduced by using a random-effect model. ETHICS AND DISSEMINATION: Ethical approval is not required for a systematic review. The results will be disseminated through international and national conferences or peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42021286522.

Efficacy and Safety of Initial 5 Years of Adjuvant Endocrine Therapy in Postmenopausal Hormone Receptor-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis.

Purpose: To identify the optimal initial 5 years of adjuvant endocrine therapy for hormone receptor-positive postmenopausal early breast cancer (EBC) patients. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE to obtain relevant studies published between January 2000 and January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival and overall survival and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the value of surface under the cumulative ranking curve (SUCRA) was used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) [hazard ratio (HR) 0.91, 95% confidence interval (95%CI) 0.87-0.96], anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusion: The sequential use of aromatase inhibitors, which has the best curative effects and relatively mild side effects, may be the optimal treatment mode for hormone receptor-positive postmenopausal EBC patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs. Systematic Review Registration: [website], identifier [registration number].

Identification of mutation patterns and circulating tumour DNA-derived prognostic markers in advanced breast cancer patients.

BACKGROUND: The correlations between circulating tumour DNA (ctDNA)-derived genomic markers and treatment response and survival outcome in Chinese patients with advanced breast cancer (ABC) have not been extensively characterized. METHODS: Blood samples from 141 ABC patients who underwent first-line standard treatment in Peking University Cancer Hospital were collected. A next-generation sequencing based liquid biopsy assay (PredicineCARE) was used to detect somatic mutations and copy number variations (CNVs) in ctDNA. A subset of matched blood samples and tumour tissue biopsies were compared to evaluate the concordance. RESULTS: Overall, TP53 (44.0%) and PIK3CA (28.4%) were the top two altered genes. Frequent CNVs included amplifications of ERBB2 (24.8%) and FGFR1 (8.5%) and deletions of CDKN2A (3.5%). PIK3CA/TP53 and FGFR1/2/3 variants were associated with drug resistance in hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-positive (HER2 +) patients. The comparison of genomic variants across matched tumour tissue and ctDNA samples revealed a moderate to high concordance that was gene dependent. Triple-negative breast cancer (TNBC) patients harbouring TP53 or PIK3CA alterations had a shorter overall survival than those without corresponding mutations (P = 0.03 and 0.008). A high ctDNA fraction was correlated with a shorter progression-free survival (PFS) (P = 0.005) in TNBC patients. High blood-based tumor mutation burden (bTMB) was associated with a shorter PFS for HER2 + and TNBC patients (P = 0.009 and 0.05). Moreover, disease monitoring revealed several acquired genomic variants such as ESR1 mutations, CDKN2A deletions, and FGFR1 amplifications. CONCLUSIONS: This study revealed the molecular profiles of Chinese patients with ABC and the clinical validity of ctDNA-derived markers, including the ctDNA fraction and bTMB, for predicting treatment response, prognosis, and disease progression. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03792529. Registered January 3rd 2019, https://clinicaltrials.gov/ct2/show/NCT03792529 .

Single AAV-mediated CRISPR-Nme2Cas9 efficiently reduces mutant hTTR expression in a transgenic mouse model of transthyretin amyloidosis.

Transthyretin (TTR) amyloidosis is a hereditary life-threatening disease characterized by deposition of amyloid fibrils. The main causes of TTR amyloidosis are mutations in the TTR gene that lead to the production of misfolded TTR protein. Reducing the production of toxic protein in the liver is a validated strategy to treat TTR amyloidosis. In this study, we established a humanized mouse model that expresses mutant human TTR (hTTR; V30M) protein in the liver to model TTR amyloidosis. Then, we compared the efficiency of reducing the expression of mutant hTTR by dual adeno-associated virus 8 (AAV8)-mediated split SpCas9 with that by single AAV8-mediated Nme2Cas9 in this model. With two gRNAs targeting different exons, dual AAV-mediated split SpCas9 system achieved efficiencies of 37% and 34% reduction of hTTR mRNA and reporter GFP expression, respectively, in the liver. Surprisingly, single AAV-mediated Nme2Cas9 treatment resulted in 65% and 71% reduction of hTTR mRNA and reporter GFP, respectively. No significant editing was identified in predicted off-target sites in the mouse and human genomes after Nme2Cas9 targeting. Thus, we provide proof of principle for using single AAV-mediated CRISPR-Nme2Cas9 to effectively reduce mutant hTTR expression in vivo, which may translate into gene therapy for TTR amyloidosis.

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer.

Rationale: Previous studies have reported on the role of extracellular acidity in the metastasis of numerous cancers. However, the involvement of long noncoding RNA (lncRNA) in the extracellular acidity-induced cancer metastasis of pancreatic cancer (PC) remains unclear. Methods: Different expression levels of lncRNAs in PC cells under normal and acidic conditions were compared by RNA sequencing (RNA-seq). The effects of antisense lncRNA of metastasis suppressor 1 (MTSS1-AS) on acidic PC cells were assessed by gain- and loss-of-function experiments. Fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, Western blot, luciferase reporter, and Chromatin immunoprecipitation assays were employed to determine the regulatory mechanisms of MTSS1-AS in the acidity-induced metastasis of PC cells. The expression of MTSS1-AS and associated pathways were compared in PC samples and peritumoral normal tissues. Results: RNA-seq demonstrated that MTSS1-AS was significantly downregulated in pancreatic cells cultured with the acidic medium. The overexpression of MTSS1-AS remarkably inhibited the acidity-promoted metastasis of PC cells by upregulating the expression of its sense gene metastasis suppressor 1 (MTSS1). Mechanistically, MTSS1-AS scaffolded the interaction between E3 ubiquitin-protein ligase STIP1 homology and U-box containing protein 1 (STUB1) and transcription regulator myeloid zinc finger 1 (MZF1), leading to ubiquitination-mediated degradation of MZF1. Further, MZF1 inhibited the expression of MTSS1 by binding to the MTSS1 promoter. Thus, the acidity-reduced MTSS1-AS facilitated the stability of MZF1 and its inhibitory effect on MTSS1 transcription, thereby promoting the metastasis of PC cells under acidic conditions. Moreover, MTSS1-AS was transcriptionally repressed by the binding of MYC proto-oncogene (Myc) with initiator (Inr) elements of the MTSS1-AS promoter. Meanwhile, MTSS1-AS mutually repressed the expression of Myc by impairing the MZF1-mediated transcription activation of Myc, thereby forming a negative feedback loop between MTSS1-AS and Myc in acidic PC cells. In accordance with the experimental results, MTSS1-AS and MTSS1 were downregulated in PC and correlated with poor overall survival. Conclusions: The results implicated that a reciprocal feedback loop between Myc and MTSS1-AS contributed to the extracellular acidity-promoted metastasis of PC, and indicated that MTSS1-AS was a valuable biomarker and therapeutic target for PC.

Hypoxia-induced feedback of HIF-1α and lncRNA-CF129 contributes to pancreatic cancer progression through stabilization of p53 protein.

Rationale: Emerging evidences have highlighted the critical roles of lncRNAs in human cancer development. The work sought to assess the biological role and potential underlying mechanisms of lncRNA-CF129 (CF129) which is significantly reduced in pancreatic cancer (PC). Methods: CF129 expression and its association with multiple clinicopathologic characteristics in PC specimens were analyzed. The role of CF129 both in vitro and in vivo was assessed, with RNA pull-down and immunoprecipitation assays being performed to detect the interaction between CF129 and p53 and E3 ligase MKRN1. Chromatin immunoprecipitation and luciferase assays were utilized to identify the interaction between p53 and FOXC2 promoter, HIF-1α/HDAC1 complex and CF129 promoter, FOXC2 and HIF-1α promoter, respectively. Results: CF129 levels were markedly lower in PC compared with paired non-tumor adjacent tissues. Low CF129 expression predicted short overall survival in PC patients. CF129 inhibited invasion and metastasis of PC cells in a FOXC2-dependent manner. In addition, CF129 regulates FOXC2 transcription through association with mutant p53. CF129 directly binds to p53 and E3 ligase MKRN1, and such an interaction leading to p53 protein ubiquitination and degradation. Furthermore, CF129 is a hypoxia-responsive lncRNA, which is transcriptionally downregulated by binding between HIF-1α/HDAC1 complex and CF129 promoter. Finally, it is revealed that HIF-1α is reciprocally regulated by FOXC2 in transcriptional level. Clinically, CF129 downregulation coordinates overexpression of FOXC2. Conclusions: Our study suggests that CF129 inhibits pancreatic cell proliferation and invasion by suppression of FOXC2 transcription, which depends on MKRN1-mediated ubiquitin-dependent p53 degradation. The HIF-1α/CF129/ p53/FOXC2 axis may function as a potential biomarker and therapeutic target.

LncRNA-MTA2TR functions as a promoter in pancreatic cancer via driving deacetylation-dependent accumulation of HIF-1α.

Rationale: Hypoxia has been proved to contribute to aggressive phenotype of cancers, while functional and regulatory mechanism of long noncoding RNA (lncRNA) in the contribution of hypoxia on pancreatic cancer (PC) tumorigenesis is incompletely understood. The aim of this study was to uncover the regulatory and functional roles for hypoxia-induced lncRNA-MTA2TR (MTA2 transcriptional regulator RNA, AF083120.1) in the regulation of PC tumorigenesis. Methods: A lncRNA microarray confirmed MTA2TR expression in tissues of PC patients. The effects of MTA2TR on proliferation and metastasis of PC cells and xenograft models were determined, and the key mechanisms by which MTA2TR promotes PC were further dissected. Furthermore, the expression and regulation of MTA2TR under hypoxic conditions in PC cells were assessed. We also assessed the correlation between MTA2TR expression and PC patient clinical outcomes. Results: We found that metastasis associated protein 2 (MTA2) transcriptional regulator lncRNA (MTA2TR) was overexpressed in PC patient tissues relative to paired noncancerous tissues. Furthermore, we found that depletion of MTA2TR significantly inhibited PC cell proliferation and invasion both in vitro and in vivo. We further demonstrated that MTA2TR transcriptionally upregulates MTA2 expression by recruiting activating transcription factor 3 (ATF3) to the promoter area of MTA2. Consequentially, MTA2 can stabilize the HIF-1α protein via deacetylation, which further activates HIF-1α transcriptional activity. Interestingly, our results revealed that MTA2TR is transcriptionally regulated by HIF-1α under hypoxic conditions. Our clinical samples further indicated that the overexpression of MTA2TR was correlated with MTA2 upregulation, as well as with reduced overall survival (OS) in PC patients. Conclusions: These results suggest that feedback between MTA2TR and HIF-1α may play a key role in regulating PC tumorigenesis, thus potentially highlighting novel avenues PC treatment.

miR­145 suppresses ovarian cancer progression via modulation of cell growth and invasion by targeting CCND2 and E2F3.

MicroRNAs (miRNA/miRs) have been demonstrated to be critical post­transcriptional modulators of gene expression during tumorigenesis. Numerous miRNAs have been revealed to be downregulated in human epithelial ovarian cancer (EOC). In the present study, it was observed that the expression of miR­145 was decreased in EOC tissues and cell lines. Overexpression of miR­145 inhibited the proliferation, migration and invasion of EOC cells. The D­type cyclin 2, cyclin D2 (CCND2), and E2F transcription factor 3 (E2F3) were confirmed to be targets of miR­145. In addition, restoration of these 2 genes significantly reversed the tumor suppressive effects of miR­145. Collectively, the results indicated that miR­145 serves a critical role in suppressing the biological behavior of EOC cells by targeting CCND2 and E2F3. Therefore, miR­145 was suggested to be a potential miRNA­based therapeutic target in ovarian cancer.

A highly sensitive gas sensor employing biomorphic SnO2 with multi-level tubes/pores structure: bio-templated from waste of flax.

Metal oxide gas sensors with porous structures are widely used in numerous applications ranging from health monitoring and medical detection to safety; in this study, we report a highly sensitive SnO2 gas sensor with a multi-level tube/pore structure prepared via biomimetic technology using flax waste as a bio-template and a simple wet chemical process combined with subsequent annealing. Indeed, MLTPS not only maintained and improved the excellence of porous structure gas sensing materials with abundant active sites and large surface-to-volume ratios, but also overcame the deficiency of the lack of gas diffusion channels in porous gas sensing materials. Thus, this novel multi-level tube/pore SnO2 gas sensor exhibited significantly enhanced sensing performance, e.g. an ultra-low response concentration (250 ppb), a high response (87.9), a fast response (9.2 s), a low operating temperature (130 °C) and good stability, for formaldehyde. On the basis of these results, via the reuse of agricultural waste, this study provides a new concept for the low-cost synthesis of environmentally friendly and effective multi-level tube/pore gas sensor materials.

Upregulation of Circular RNA VPS13C-has-circ-001567 Promotes Ovarian Cancer Cell Proliferation and Invasion.

BACKGROUND: Circular RNAs (circRNAs) comprise a class of noncoding RNA molecules that play an important role in several normal cellular functions, as well as tumorigenesis in humans. However, the expression patterns and biological functions of circRNAs in ovarian cancer (OC) remain unclear. METHODS: Therefore, we investigated the expression profiles and biological functions of certain circRNAs in OC tumor tissues. The expression of three circRNAs (VPS13C-has-circ-001567, RAD50-has-circ-00718, and SPECC1-has-circ-000013) was detected by real-time polymerase chain reaction in OC cell lines, and also in tumor and pericarcinous tissues obtained from 20 patients with OC. The function of VPS13C-has-circ-001567 in SKOV3 and OV-1063 cells was investigated by knockdown of VPS13C-has-circ-001567 and then analyzing any resultant effects on the cell cycle, cell proliferation, apoptosis, and cell invasion ability. E-cadherin and N-cadherin expressions were analyzed by immunofluorescence and western blotting. Finally, the tumorigenicity of OC cells was assessed in nude mice. RESULTS: The results showed that VPS13C-has-circ-001567 was expressed at significantly higher levels in OC tumor tissues compared with pericarcinous tissues, and this overexpression was associated with tumor node metastasis stage and lymph node metastasis. We found that knockdown of VPS13C-has-circ-001567 significantly promoted apoptosis and inhibited the proliferation of SKOV3 and OV-1063 cells in vitro. Knockdown of VPS13C-has-circ-001567 led to cell cycle arrest at G1 phase and decreased the percentage of S1 phase cells. Additionally, knockdown of VPS13C-has-circ-001567 decreased the invasion ability of SKOV3 and OV-1063 cells, and also changed the levels of E-cadherin and N-cadherin expressions. Knockdown of VPS13C-has-circ-001567 significantly reduced the tumorigenicity of OC cells. CONCLUSIONS: Taken together, our results suggest that VPS13C-has-circ-001567 plays a role in the development of OC and might be a prognostic marker and therapeutic target for OC.

Nutrient Stress-Dysregulated Antisense lncRNA GLS-AS Impairs GLS-Mediated Metabolism and Represses Pancreatic Cancer Progression.

Cancer cells are known to undergo metabolic reprogramming, such as glycolysis and glutamine addiction, to sustain rapid proliferation and metastasis. It remains undefined whether long noncoding RNAs (lncRNA) coordinate the metabolic switch in pancreatic cancer. Here we identify a nuclear-enriched antisense lncRNA of glutaminase (GLS-AS) as a critical regulator involved in pancreatic cancer metabolism. GLS-AS was downregulated in pancreatic cancer tissues compared with noncancerous peritumor tissues. Depletion of GLS-AS promoted proliferation and invasion of pancreatic cancer cells both in vitro and in xenograft tumors of nude mice. GLS-AS inhibited GLS expression at the posttranscriptional level via formation of double stranded RNA with GLS pre-mRNA through ADAR/Dicer-dependent RNA interference. GLS-AS expression was transcriptionally downregulated by nutrient stress-induced Myc. Conversely, GLS-AS decreased Myc expression by impairing the GLS-mediated stability of Myc protein. These results imply a reciprocal feedback loop wherein Myc and GLS-AS regulate GLS overexpression during nutrient stress. Ectopic overexpression of GLS-AS inhibited proliferation and invasion of pancreatic cancer cells by repressing the Myc/GLS pathway. Moreover, expression of GLS-AS and GLS was inversely correlated in clinical samples of pancreatic cancer, while low expression of GLS-AS was associated with poor clinical outcomes. Collectively, our study implicates a novel lncRNA-mediated Myc/GLS pathway, which may serve as a metabolic target for pancreatic cancer therapy, and advances our understanding of the coupling role of lncRNA in nutrition stress and tumorigenesis.Significance: These findings show that lncRNA GLS-AS mediates a feedback loop of Myc and GLS, providing a potential therapeutic target for metabolic reprogramming in pancreatic cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1398/F1.large.jpg.See related commentary by Mafra and Dias, p. 1302.

YY1-regulated LINC00152 promotes triple negative breast cancer progression by affecting on stability of PTEN protein.

Thousands of lncRNAs have been identified but few have been functionally characterized in triple negative breast cancer (TNBC). LINC00152 was known as cytoskeleton regulator RNA (CYTOR) and expressed in various cancers including breast cancer. But the underlying molecular mechanism of LINC00152 in pathogenesis of TNBC have not been elucidated. In our study, we identified that LINC00152 expression was dramatically elevated in TNBC tissue and cells. Inhibition or overexpression of LINC00152 obviously increased or suppressed PTEN protein expression but did not affect the mRNA expression level. Our further experiments showed up-regulated LINC00152 in TNBC obviously enhanced NEDD4-1 mediated ubiquitination and degradation of PTEN protein. Finally, we demonstrated that YY1 bound with LINC00152 promotor and mostly inhibited the transcription of LINC00152. Furthermore, analysis of clinical samples resource retrieved from databases suggested high LINC00152 expression was correlated with ER or PR negative expression, late TNM stage and lymphatic invasion, as well as shorter overall survival time in patients. Consequently, this study firstly reveals that up-regulated LINC00152 mediates PTEN protein stability attenuation in TNBC.

Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription.

The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.