Hypoxia inhibits the iMo/cDC2/CD8+ TRMs immune axis in the tumor microenvironment of human esophageal cancer.

BACKGROUND: Esophageal cancer (ESCA) is a form of malignant tumor associated with chronic inflammation and immune dysregulation. However, the specific immune status and key mechanisms of immune regulation in this disease require further exploration. METHODS: To investigate the features of the human ESCA tumor immune microenvironment and its possible regulation, we performed mass cytometry by time of flight, single-cell RNA sequencing, multicolor fluorescence staining of tissue, and flow cytometry analyses on tumor and paracancerous tissue from treatment-naïve patients. RESULTS: We depicted the immune landscape of the ESCA and revealed that CD8+ (tissue-resident memory CD8+ T cells (CD8+ TRMs) were closely related to disease progression. We also revealed the heterogeneity of CD8+ TRMs in the ESCA tumor microenvironment (TME), which was associated with their differentiation and function. Moreover, the subset of CD8+ TRMs in tumor (called tTRMs) that expressed high levels of granzyme B and immune checkpoints was markedly decreased in the TME of advanced ESCA. We showed that tTRMs are tumor effector cells preactivated in the TME. We then demonstrated that conventional dendritic cells (cDC2s) derived from intermediate monocytes (iMos) are essential for maintaining the proliferation of CD8+ TRMs in the TME. Our preliminary study showed that hypoxia can promote the apoptosis of iMos and impede the maturation of cDC2s, which in turn reduces the proliferative capacity of CD8+ TRMs, thereby contributing to the progression of cancer. CONCLUSIONS: Our study revealed the essential antitumor roles of CD8+ TRMs and preliminarily explored the regulation of the iMo/cDC2/CD8+ TRM immune axis in the human ESCA TME.

Camrelizumab, chemotherapy and apatinib in the neoadjuvant treatment of resectable oesophageal squamous cell carcinoma: a single-arm phase 2 trial.

Background: In resectable oesophageal squamous cell carcinoma (ESCC), the efficacy of camrelizumab combined with chemotherapy and apatinib followed by minimally invasive oesophagectomy is not clear. We aimed to fill this knowledge gap. Methods: This investigator-initiated, single-arm, prospective, phase 2 trial was performed at the Second Affiliated Hospital of Zhejiang University, China. Patients (aged 18-75 years) who were histologically or cytologically diagnosed with ESCC were deemed suitable to participate in this trial. Patients received 2-3 cycles of neoadjuvant therapy with camrelizumab, nedaplatin, albumin paclitaxel, and apatinib; each cycle was repeated every 14 days. Surgery occurred 4-6 weeks after the last neoadjuvant treatment cycle. The primary outcome was the pathological complete response (PCR) rate of the tumour and lymph nodes. The changes in the peripheral blood immunoprofile among patients without PCR (ie, non-PCR [NPCR]) and with PCR were assessed by mass cytometry. This study was registered with ClinicalTrials.gov, NCT04666090. Findings: 42 patients were enrolled between November 23, 2020 and December 31, 2022. The disease control rate was 100.0% (95% CI, 91.6-100%), and the objective response rate was 83.3% (95% CI, 68.6-93.0%). Six (14.3%) patients experienced grade 3 adverse events. The most common were white blood cell count decrease (31.0%), alopecia (81.0%), asthenia (38.1%), and reactive cutaneous capillary endothelial proliferation (35.7%). 41 patients received minimally invasive oesophagectomy; all 41patients achieved R0 resection, and 18 (43.9%, 95% CI, 28.5-60.3%) patients achieved PCR. The median follow-up was 23 months and the 2-year survival rate was 85.9%. T-cell subsets in both the PCR and NPCR groups exhibited consistency in response to neoadjuvant therapy. In contrast, some of natural killer (NK) cells (NK-C03, NK-C11), B cells (B-C06) and monocytes (M-C05), exhibited significant differences between the PCR and NPCR groups before neoadjuvant therapy. M-C06 had a significant difference in the PCR group and NPCR group after neoadjuvant therapy. NK-C12 and B-C15 showed significant differences both before and after neoadjuvant therapy. Interpretation: The application of camrelizumab, chemotherapy and apatinib in the neoadjuvant setting for locally advanced ESCC has shown promising antitumour activity and an acceptable safety profile in this single-arm study. In the neoadjuvant setting, NK cell, B cell, and monocyte subsets exhibited greater predictive power for immunotherapy responsiveness than T-cell subsets. Longer follow-up to assess survival outcomes and a phase 3 randomised trial are needed to further evaluate the proposed treatment. Funding: The China Anti-Cancer Association and the "Leading Goose" Research and Development Project of Zhejiang Province.

Identification of Synergies in Fe, Co-Coordinated Polyphthalocyanines Scaffolds for Electrochemical CO2 Reduction Reaction.

The synergistic interaction between the isolated metal sites promoted the electrocatalytic activity of the catalysts. However, the structural heterogeneity of the isolated sites makes it challenging to evaluate this effect accurately. In this work, metal-coordinated polyphthalocyanine molecules (Fe-PPc, Co-PPc, FeCo-PPc) with long-range ordered and precise coordination structures are used as a platform to study the synergies of different isolated metal sites in the electrochemical CO2 reduction reaction. The combination means of experimental and theoretical calculation clearly reveal that the coexistence of Fe and Co sites in PPc significantly enhances the conjugation effect of the macrocycle. This enhancement subsequently causes the metal sites to lose more electrons, thereby improving their adsorption of CO2 and facilitating the formation of intermediate *COOH on them. As a result, FeCo-PPc achieves a CO partial current density of about 57.4 mA/cm2 with a high turnover frequency of over 49000 site-1 h-1 at -0.9 V (vs RHE).

Distinct Regulation of ASCL1 by the Cell Cycle and Chemotherapy in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive and lethal malignancy. Achaete-scute homolog 1 (ASCL1) is essential for the initiation of SCLC in mice and the development of pulmonary neuroendocrine cells (PNEC), which are the major cells of origin for SCLC. However, the regulatory mechanism of ASCL1 in SCLC remains elusive. Here, we found that ASCL1 expression gradually increases as the tumors grow in a mouse SCLC model, and is regulated by the cell cycle. Mechanistically, CDK2-CyclinA2 complex phosphorylates ASCL1, which results in increased proteasome-mediated ASCL1 protein degradation by E3 ubiquitin ligase HUWE1 during mitosis. TCF3 promotes the multisite phosphorylation of ASCL1 through the CDK2-CyclinA2 complex and the interaction between ASCL1 and TCF3 protects ASCL1 from degradation. The dissociation of TCF3 from ASCL1 during mitosis accelerates the degradation of ASCL1. In addition, chemotherapy drugs greatly reduce the transcription of ASCL1 in SCLC cells. Depletion of ASCL1 sensitizes SCLC cells to chemotherapy drugs. Together, our study demonstrates that ASCL1 is a cell-cycle-regulated protein and provides a theoretical basis for applying cell-cycle-related antitumor drugs in SCLC treatment. Implications:Our study revealed a novel regulatory mechanism of ASCL1 by cell cycle and chemotherapy drugs in SCLC. Treating patients with SCLC with a combination of ASCL1-targeting therapy and chemotherapy drugs could potentially be beneficial.

Paravertebral vs Epidural Anesthesia for Video-assisted Thoracoscopic Surgery: A Randomized Trial.

BACKGROUND: The choice of postoperative pain management for patients who experience moderate to severe acute pain after thoracoscopic surgery is debatable. This study aimed to determine whether paravertebral block (PVB) provides more benefits than thoracic epidural analgesia (TEA) for thoracoscopic surgery. METHODS: From February 2020 to April 2022, patients without chronic pain who were scheduled to undergo thoracoscopic surgery were randomly assigned to the PVB group or the TEA group. The visual analogue scale score was used to measure the degree of pain when the patients were at rest or coughing. RESULTS: In total, 176 eligible patients were enrolled in this study. No significant difference in the visual analogue scale score was found between the 2 groups at rest (P = .395) or with coughing (P = .157). Additionally, there was no significant difference in the average pain score between these 2 states (P = .221). The median time for catheter placement in the PVB group was 5 minutes, which was shorter than that (14 minutes) in the TEA group (P < .001). Moreover, the catheter placement failure rate in the PVB group was lower than that in the TEA group (P = .038). The incidence of hypotension (P = .016) and urinary retention (P = .006) in the PVB group was lower than that in the TEA group. CONCLUSIONS: PVB can provide pain relief that is similar to that of TEA but with no additional puncture pain, a shorter catheter placement time, and fewer side effects in patients undergoing video-assisted thoracoscopic surgery.

[Corrigendum] Role of the EZH2/miR­200 axis in STAT3­mediated OSCC invasion.

Following the publication of the above article, an interested reader drew to the authors' attention that, in Figs. 7A and 8A. apparently the same mouse had been featured to represent two different experimental groups, albeit displaying distinct fluorescence values. Moreover, following an independent investigation in the Editorial Office, an additional instance of probable data duplication was also noted, comparing between the 'SCC15 / si­NC' cell migration image in Fig. 2D and the 'SCC15­EV' migration assay image in Fig. 1C. After having consulted their original data, the authors realized that these errors arose during the process of assembling the images for Figs. 2 and 8. First, the image for the DZNep (42d) experiment in Fig. 7A had inadvertently been used for the mimic NC (7d) experiment in Fig. 8A; moreover, the 'SCC15 / si­NC' cell migration image in Fig. 2D had been selected incorrectly. The revised versions of Figs. 2 and 8, showing the correct data for the the 'SCC15 / si­NC' cell migration image in Fig. 2D and the mimic NC (7d) experiment in Fig. 8A, are shown on the next two pages. The authors regret that these errors went unnoticed prior to publication, and thank the Editor of International Journal of Oncology for allowing them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they also apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 52: 1149­1164, 2018; DOI: 10.3892/ijo.2018.4293].

Aquaporin-1 inhibition exacerbates ischemia-reperfusion-induced lung injury in mouse.

BACKGROUND: Ischemia-reperfusion injury (IRI), which involves severe inflammation and edema, is an inevitable feature of the lung transplantation process and leads to primary graft dysfunction (PGD). The activation of aquaporin 1 (AQP1) modulates fluid transport in the alveolar space. The current study investigated the role of AQP1 in ischemia-reperfusion (IR)-induced lung injury. METHODS: A mouse model of lung IR was established by clamping the left lung hilar for 1 h and released for reperfusion for 24 h. The AQP1 inhibitor acetazolamide (AZA) was administered 3 days before lung ischemia with a dose of 100 mg/kg per day via gavage. Lung injury was evaluated using the ratio of wet-to-dry weight, peripheral bronchial epithelial thickness, degree of angioedema, acute lung injury score, neutrophil infiltration, and cytokine concentrations in bronchoalveolar lavage fluid. RESULTS: Compared with sham treatment, ischemia with no reperfusion (IR 0h) and ischemia with reperfusion for 24 h (IR 24 h) significantly upregulated AQP1 expression, increased the wet/dry weight ratio, angioedema, neutrophil infiltration and cytokine production (interleukin -6 and tumor necrosis factor -α) and thickened the peripheral bronchial epithelium. AZA exacerbated inflammation and pulmonary edema. CONCLUSION: AQP1 may exert a protective effect against IR-induced lung injury, which could be attributed to alleviating pulmonary edema and inflammation. AQP1 upregulation might be a potential application to alleviate lung IRI and decrease the incidence of PGD.

Necrostatin-1 Alleviates Lung Ischemia-Reperfusion Injury via Inhibiting Necroptosis and Apoptosis of Lung Epithelial Cells.

Lung ischemia-reperfusion injury (LIRI) is associated with many diseases, including primary graft dysfunction after lung transplantation, and has no specific and effective therapies. Necroptosis contributes to the pathogenesis of ischemia-reperfusion injury. Necrostatin-1 (Nec-1), the necroptosis inhibitor targeting RIPK1, has been reported to alleviate ischemia-reperfusion injury in various organs. However, the underlying mechanism of Nec-1 in LIRI remains unclear. In this paper, an in vivo LIRI model was built up by left lung hilar clamping in mice, and an in vitro cold ischemia-reperfusion (CI/R) model using BEAS-2B cells was applied to mimic the lung transplantation setting. We found Nec-1 significantly alleviated ischemia-reperfusion-induced lung injury, cytokine releasing, and necroptosis of epithelial cells in mouse lungs. In vitro, Nec-1 also mitigated CI/R-induced cell death and inflammatory responses in BEAS-2B cells, and these protective effects were achieved by simultaneously inhibiting the formation of necrosome and RIPK1-dependent apoptosis. However, Nec-1 decreased the necrosome number but increased the apoptosis level in lung tissues after ischemia reperfusion. We further clarified that Nec-1 could also attenuate lung injury by promoting neutrophil apoptosis from flow cytometry. In conclusion, Nec-1 alleviated lung ischemia-reperfusion injury by inhibiting necroptosis and apoptosis of epithelial cells and promoting the apoptosis of neutrophils. Thus, Nec-1 could be a promising medication against primary graft dysfunction after lung transplantation.

LOX and Its Methylation Impact Prognosis of Diseases and Correlate with TAM Infiltration in ESCA.

Background: ESCA is one of the digestive tract tumors with a high fatality. It is implicated in an intricate gene regulation process, but the pathogenesis remains ambiguous. Methods: The study used the packages of Limma from R software to analyze DEGs of ESCA in the GEO database and TCGA database. We employed the DAVID website for enrichment analysis, and the string database constructed the PPI network. Hub genes were identified from ESCA DEGs with Cytoscape MCODE. We evaluated the clinical relevance of LOX expression and its DNA methylation in the cBioPortal database and explored the roles of LOX in ESCA immunity, especially immune cell infiltration levels and immune checkpoint expression, by immunedeconv package of R software. Conclusions: The overexpression of LOX in ESCA is regulated by DNA hypomethylation; LOX overexpression or LOX hypomethylation can predict a worse prognosis in patients with ESCA. Besides, LOX may be involved in TIME regulation, promoting the infiltration levels and function of TAM. Hence, high LOX expression affected by DNA hypomethylation has an essential role in patients with ESCA, which may become an effective prognostic marker and therapeutic target.

m7G-related gene NUDT4 as a novel biomarker promoting cancer cell proliferation in lung adenocarcinoma.

Background: Lung cancer is the leading cause of mortality in cancer patients. N7-methylguanosine (m7G) modification as a translational regulation pattern has been reported to participate in multiple types of cancer progression, but little is known in lung cancer. This study attempts to explore the role of m7G-related proteins in genetic and epigenetic variations in lung adenocarcinoma, and its relationship with clinical prognosis, immune infiltration, and immunotherapy. Methods: Sequencing data were obtained from the Genomic Data Commons (GDC) Data Portal and Gene Expression Omnibus (GEO) databases. Consensus clustering was utilized to distinguish m7G clusters, and responses to immunotherapy were also evaluated. Moreover, univariate and multivariate Cox and Least absolute shrinkage and selection operator LASSO Cox regression analyses were used to screen independent prognostic factors and generated risk scores for constructing a survival prediction model. Multiple cell types such as epithelial cells and immune cells were identified to verify the bulk RNA results. Short hairpin RNA (shRNA) Tet-on plasmids, Clustered Regularly Interspaced Short Palindromic Repeats CRISPR/Cas9 for knockout plasmids, and nucleoside diphosphate linked to moiety X-type motif 4 (NUDT4) overexpression plasmids were constructed to inhibit or promote tumor cell NUDT4 expression, then RT-qPCR, Cell Counting Kit-8 CCK8 proliferation assay, and Transwell assay were used to observe tumor cell biological functions. Results: Fifteen m7G-related genes were highly expressed in tumor samples, and 12 genes were associated with poor prognosis. m7G cluster-B had lower immune infiltration level, worse survival, and samples that predicted poor responses to immunotherapy. The multivariate Cox model showed that NUDT4 and WDR4 (WD repeat domain 4) were independent risk factors. Single-cell m7G gene set variation analysis (GSVA) scores also had a negative correlation tendency with immune infiltration level and T-cell Programmed Death-1 PD-1 expression, but the statistics were not significant. Knocking down and knocking out the NUDT4 expression significantly inhibited cell proliferation capability in A549 and H1299 cells. In contrast, overexpressing NUDT4 promoted tumor cell proliferation. However, there was no difference in migration capability in the knockdown, knockout, or overexpression groups. Conclusions: Our study revealed that m7G modification-related proteins are closely related to the tumor microenvironment, immune cell infiltration, responses to immunotherapy, and patients' prognosis in lung adenocarcinoma and could be useful biomarkers for the identification of patients who could benefit from immunotherapy. The m7G modification protein NUDT4 may be a novel biomarker in promoting the progression of lung cancer.

YAP drives fate conversion and chemoresistance of small cell lung cancer.

Small cell lung cancer (SCLC) has a high degree of plasticity and is characterized by a remarkable response to chemotherapy followed by the development of resistance. Here, we use a mouse SCLC model to show that intratumoral heterogeneity of SCLC is progressively established during SCLC tumorigenesis. YAP/TAZ and Notch are required for the generation of non-neuroendocrine (Non-NE) SCLC tumor cells, but not for the initiation of SCLC. YAP signals through Notch-dependent and Notch-independent pathways to promote the fate conversion of SCLC from NE to Non-NE tumor cells by inducing Rest expression. In addition, YAP activation enhances the chemoresistance in NE SCLC tumor cells, while the inactivation of YAP in Non-NE SCLC tumor cells switches cell death induced by chemotherapy drugs from apoptosis to pyroptosis. Our study demonstrates that YAP plays critical roles in the establishment of intratumoral heterogeneity and highlights the potential of targeting YAP for chemoresistant SCLC.

Long Non-Coding RNA OIP5-AS1 Inhibits the Proliferation and Migration of Esophageal Squamous Carcinoma Cells by Targeting FOXD1/miR-30a-5p Axis and the Effect of Micro- and Nano-Particles on Targeting Transfection System.

Esophageal cancer is one of the most common human malignancies and ranks sixth for global mortality; the major histological type is esophageal squamous cell carcinoma (ESCC). Here we assessed the effect of long non-coding (lnc) RNA OIP5-AS1 on the miR-30a-5p/Forkhead box protein D1 (FOXD1) axis in ESCC and investigated the underlying mechanism involving the ERK1/2 signaling pathway. lnc RNA OIP5-AS1 was highly expressed in human ESCC tissues and cells, targeted miR-30a-5p, and inhibited miR-30a-5p expression. Additionally, in human ESCC tissues, miR-30a-5p was poorly expressed, whereas FOXD1 mRNA and protein were highly expressed, with a negative correlation between miR-30a-5p and FOXD1 expression. miR-30a-5p targeted and inhibited FOXD1 expression. FOXD1 promoted the proliferation and invasion of ESCC and was related to the ERK1/2 signaling pathway; ERK1/2 inhibitors (LY-3214996) reversed the biological function of FOXD1. miR-30a-5p combined with FOXD1 regulated ERK1/2 expression and inhibited tumor growth in vivo. In this study, micro- and nano-particles were used as carriers to construct Nanocapsules carrying miR-30a-5p mimics and miR-30a-5p inhibitor through self-assembly method, so as to realize an efficient Nanocapsules delivery system of miR-30a-5p to esophageal cancer cells. It provides insights into targeted drug therapy and the development of micro- and nano-particles carriers.

Therapeutic method for early-stage second primary non-small lung cancer: analysis of a population-based database.

BACKGROUND: Early-stage non-small lung cancer patients may survive long enough to develop second primary lung cancers. However, few studies have accurately described the therapeutic method, evaluation or prognostic factors for long-term survival in this complex clinical scenario. METHODS: Patients who had first and second primary non-small lung cancer in the Surveillance, Epidemiology, and End Results database between 2004 and 2015 were evaluated. Patients were included when their tumors were pathologically diagnosed as non-small lung cancer and in the early-stage (less than 3 cm and with no lymph node metastasis). Therapeutic methods were categorized as lobectomy, sublobectomy or no surgery. The influence of different therapeutic methods on the overall survival rate was compared. RESULTS: For the first primary tumor, patients who underwent lobectomy achieved superior survival benefits compared with patients who underwent sublobectomy. For the second primary tumor, long-term survival was similar in patients who underwent lobectomy and those who underwent sublobectomy treatment. The multivariate analysis indicated that age, disease-free time interval, sex, and first and second types of surgery were independent prognostic factors for long-term survival. Our results showed that the 5-year overall survival rate was 91.9% when the disease-free interval exceeded 24 months. CONCLUSION: Lobectomy for the first primary tumor followed by sublobectomy for the second primary tumor may be a beneficial therapeutic method for patients. If the disease-free interval exceeds 24 months, the second primary tumor will have no influence on the natural course for patients diagnosed with a first primary non-small lung cancer.

Targeting of EZH2 inhibits epithelial­mesenchymal transition in head and neck squamous cell carcinoma via regulating the STAT3/VEGFR2 axis.

Tumor metastasis regulated by epithelial­mesenchymal transition (EMT) plays a significant role in the development of human cancers, whereas the molecular mechanisms of this process in head and neck squamous cell carcinoma (HNSCC) remain elusive. In this study, we found that inhibition of enhancer of zeste homolog 2 (EZH2) resulted in suppressed EMT in HNSCC in vitro and in vivo. We reported that signal transducer and activator of transcription factor 3 (STAT3)/vascular endothelial growth factor receptor 2 (VEGFR2) axis served as the downstream signaling of EZH2 and mediated EMT in HNSCC. EZH2 inhibition downregulated the expression of key molecules of the STAT3/VEGFR2 axis and EMT­related markers, while the expression of E­cadherin was upregulated in HNSCC cells. Targeting the EZH2/STAT3/VEGFR2 axis significantly reduced motility of HNSCC cells. Furthermore, EZH2 knockdown reduced the growth of xenograft HNSCC tumors via inhibiting the EZH2/STAT3/VEGFR2 axis. In conclusion, we proposed that EZH2 regulates EMT and tumor invasion and metastasis in HNSCC by governing the STAT3/VEGFR2 axis. These findings provide a rationale for developing novel strategies to treat invasive and metastatic HNSCC via targeting the EZH2/STAT3/VEGFR2 pathway.

A novel STAT3 inhibitor, HJC0152, exerts potent antitumor activity in glioblastoma.

Aberrant expression and activation of signal transducer and activator of transcription 3 (STAT3) is implicated in several malignancies, including glioblastoma, and is correlated with poor outcomes in patients with glioblastoma, rendering STAT3 a potential therapeutic target. However, few STAT3 inhibitors have been approved for clinical use. We recently developed an orally active small-molecule compound with anti-STAT3 activity, HJC0152. This study aimed to test the effect of this novel drug on glioblastoma cell lines, and provide possibility to improve clinic prognosis of patients with glioblastoma in the future. In the present study, we aimed to determine the effects of HJC0152 on the growth, proliferation, and chemosensitivity of glioblastoma cell lines and xenograft tumors. We found that HJC0152 inactivated STAT3 via inhibiting phosphorylation of the Tyr705 residue. In vitro, HJC0152 suppressed the proliferation and motility of glioblastoma cells, induced apoptosis, and enhanced the chemosensitivity of glioblastoma cells. Furthermore, HJC0152 inhibited the growth of glioblastoma xenograft tumors in vivo. This study provides a rationale for developing HJC0152 as a STAT3-targeting therapy for treating human glioblastoma in the future.

PVP intercalated metallic WSe2 as NIR photothermal agents for efficient tumor ablation.

Transition metal dichalogenides (TMDCs) with unique layered structures hold promising potential as transducers for photothermal therapy. However, the low photothermal conversion efficiency and poor stability in some cases limit their practical applications. Herein, we demonstrate the fabrication of ultrathin homogeneous hybridized TMDC nanosheets and their use for highly efficient photothermal tumor ablation. In particular, the nanosheets were composed of metallic WSe2 intercalated with polyvinylpyrrolidone (PVP), which was facilely prepared through a solvothermal process from the mixture of selenourea crystals, WCl6 powder along with PVP polymeric nanogel. Our characterizations revealed that the obtained nanosheets exhibited excellent photothermal conversion efficiency, therapeutic demonstration with improved biocompatibility and physiological stability attributing to the combined merits of metallic phase of WSe2 and hydrophilic PVP insertion. Both the histological analysis of vital organs and in vitro/in vivo tests confirmed the nanosheets as actively effective and biologically safe in this phototherapeutic technique. Findings from this non-invasive experiment clearly emphasize the explorable therapeutic efficacy of the layered-based hybrid agents in future cancer treatment planning procedures.

TGF-ß-induced STAT3 overexpression promotes human head and neck squamous cell carcinoma invasion and metastasis through malat1/miR-30a interactions.

Aberrant signal transducer and activator of transcription 3 (STAT3) signaling is a critical factor that drives the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC). However, the underlying mechanisms of STAT3 overexpression and regulation of HNSCC metastasis remain unknown. In the current study, we demonstrated that upregulated TGF-ß may promote epithelial-mesenchymal transition (EMT) through STAT3 activation. In addition, we explored the contributions of STAT3 to HNSCC with a specific focus on its transcriptional regulation and its interaction with the long noncoding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (malat1). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays revealed that STAT3 could bind to the malat1 promoter region and transcriptionally activate malat1 expression; then, malat1 interacted reciprocally with miR-30a, inducing EMT and accelerating HNSCC metastasis. In summary, our discoveries illuminate how aberrant STAT3 activation confers an oncogenic function in HNSCC and therefore may provide a theoretical foundation for STAT3 as a therapeutic target in HNSCC.

STAT3/HOTAIR Signaling Axis Regulates HNSCC Growth in an EZH2-dependent Manner.

Purpose: PI3K and STAT3 are frequently activated in cancer progression. However, little is known about the underlying mechanisms by which PI3K and STAT3 regulate head and neck squamous cell cancer (HNSCC) growth. The lncRNA HOX transcript antisense RNA (HOTAIR) was found to modulate the progression of HNSCC. In this study, we attempted to establish the correlation of PI3K/STAT3/HOTAIR signaling with the progression of HNSCC and its sensitivity toward platinum-based and targeted anti-EGFR combination therapy.Experimental Design: We first analyzed the STAT3/HOTAIR and PI3K/AKT level in human HNSCC samples. We then activated or suppressed STAT3/HOTAIR and determined the effects on HNSCC cell proliferation in vitro and the growth of UM1 xenograft tumor, an orthotopic model of HNSCC. The sensitivity of HNSCC cells toward cisplatin and cetuximab was determined by in vitro assays.Results: HNSCC samples showed significantly robust expression/activation of STAT3, HOTAIR, PI3K, and AKT, compared with normal squamous epithelium. STAT3 inhibition with WP1066 decreased HOTAIR level and sensitized HNSCC to cisplatin or cetuximab. STAT3 promoted HOTAIR transcription and its interaction with pEZH2-S21, resulting in enhanced growth of HNSCC cells. In addition, overexpression of HOTAIR promoted the growth of UM1 xenograft tumors in vivoConclusions: Our results suggest that STAT3 signaling promotes HNSCC progression via regulating HOTAIR and pEZH2-S21 in HNSCC with PI3K overexpression/activation. These findings provide a rationale to target the STAT3/HOTAIR/pEZH2-S21 regulatory axis for treating patients with HNSCC. Clin Cancer Res; 24(11); 2665-77. ©2018 AACR.

Role of the EZH2/miR-200 axis in STAT3-mediated OSCC invasion.

Abnormal activation of signal transducer and activator of transcription 3 (STAT3) serves a pivotal role in oral squamous cell carcinoma (OSCC) tumor cell invasion into normal tissues or distant organs. However the downstream regulatory network of STAT3 signaling remains unclear. The present study aimed to investigate the potential mechanism underlying how STAT3 triggers enhancer of zeste homolog 2 (EZH2) expression and inhibits microRNA (miR)-200a/b/429 expression in SCC25 and SCC15 cells in vitro and in vivo. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect expression, and numerous functional tests were conducted to explore cancer metastasis. The results indicated that when STAT3 signaling activity was attenuated by Stattic or enhanced with a STAT3 plasmid, the EZH2/miR-200 axis was markedly altered, thus resulting in modulation of the invasion and migration of OSCC cell lines. In addition, loss of function of EZH2 compromised the oncogenic role of STAT3 in both cell lines. F-actin morphology and the expression of epithelial-mesenchymal transition markers were also altered following disruption of the STAT3/EZH2/miR-200 axis. An orthotopic tumor model derived from SCC15 cells was used to confirm that targeting STAT3 or EZH2 suppressed OSCC invasion in vivo. In conclusion, the EZH2/miR-200 axis was revealed to mediate antitumor effects by targeting STAT3 signaling; these findings may provide a novel therapeutic strategy for the treatment of OSCC.

Ferromagnetism in CVT grown tungsten diselenide single crystals with nickel doping.

Two dimensional (2D) single crystal layered transition materials have had extensive consideration owing to their interesting magnetic properties, originating from their lattices and strong spin-orbit coupling, which make them of vital importance for spintronic applications. Herein, we present synthesis of a highly crystalline tungsten diselenide layered single crystal grown by chemical vapor transport technique and doped with nickel (Ni) to tailor its magnetic properties. The pristine WSe2 single crystal and Ni-doped crystal were characterized and analyzed for magnetic properties using both experimental and computational aspects. It was found that the magnetic behavior of the 2D layered WSe2 crystal changed from diamagnetic to ferromagnetic after Ni-doping at all tested temperatures. Moreover, first principle density functional theory (DFT) calculations further confirmed the origin of room temperature ferromagnetism of Ni-doped WSe2, where the d-orbitals of the doped Ni atom promoted the spin moment and thus largely contributed to the magnetism change in the 2D layered material.