Understanding the molecular mechanisms regulating tumor dissemination and therapeutic resistance is of central importance for effective cancer therapies. Here, we report that nerve growth factor ...(NGF) and its receptor TrkA facilitate epithelial-mesenchymal transition (EMT) and EGFR inhibitor resistance via STAT3 activation in head and neck squamous cell carcinoma (HNSCC). Both NGF and TrkA expression were elevated in HNSCC, indicating poor clinical outcomes. NGF was highly expressed in cancer cells and nerves in perineural niche, whereas TrkA expression was higher in cancer cells with perineural invasion. The NGF/TrkA axis could promote HNSCC cell dissemination and trigger EMT via STAT3 activation. Moreover, we discovered that the NGF/TrkA axis conferred resistance to the EGFR inhibitor erlotinib via EMT processes in HNSCC cells. Blocking TrkA signaling markedly reversed EMT and sensitized HNSCC cells to erlotinib in both in vitro and in vivo models. Overall, our results demonstrate novel evidence that the paracrine NGF/TrkA axis favors EMT and confers EGFR-targeted therapeutic resistance in HNSCC.
•Paracrine NGF/TrkA axis triggers EMT in HNSCC perineural niche.•NGF/TrkA axis confers resistance to the EGFR kinase inhibitor erlotinib via EMT and STAT3 signaling in HNSCC cells.•TrkA could be a novel therapeutic target for overcoming EGFR-targeted therapeutic resistance in HNSCC patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autophagy modulation is a potential therapeutic strategy for tongue squamous cell carcinoma (TSCC). Melatonin possesses significant anticarcinogenic activity. However, whether melatonin induces ...autophagy and its roles in cell death in TSCC are unclear. Herein, we show that melatonin induced significant apoptosis in the TSCC cell line Cal27. Apart from the induction of apoptosis, we demonstrated that melatonin‐induced autophagic flux in Cal27 cells as evidenced by the formation of GFP‐LC3 puncta, and the upregulation of LC3‐II and downregulation of SQSTM1/P62. Moreover, pharmacological or genetic blockage of autophagy enhanced melatonin‐induced apoptosis, indicating a cytoprotective role of autophagy in melatonin‐treated Cal27 cells. Mechanistically, melatonin induced TFE3(Ser321) dephosphorylation, subsequently activated TFE3 nuclear translocation, and increased TFE3 reporter activity, which contributed to the expression of autophagy‐related genes and lysosomal biogenesis. Luzindole, a melatonin membrane receptor blocker, or MT2‐siRNA partially blocked the ability of melatonin to promote mTORC1/TFE3 signaling. Furthermore, we verified in a xenograft mouse model that melatonin with hydroxychloroquine or TFE3‐siRNA exerted a synergistic antitumor effect by inhibiting autophagy. Importantly, TFE3 expression positively correlated with TSCC development and poor prognosis in patients. Collectively, we demonstrated that the melatonin‐induced increase in TFE3‐dependent autophagy is mediated through the melatonin membrane receptor in TSCC. These data also suggest that blocking melatonin membrane receptor‐TFE3‐dependent autophagy to enhance the activity of melatonin warrants further attention as a treatment strategy for TSCC.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
In our previous studies, enhancer of zeste homolog 2 (EZH2) has been proven to be a key oncogenic driver in oral squamous cell carcinoma (OSCC). However, the regulatory mechanisms on EZH2 remain ...poorly understood in OSCC. Here, through multi-transcriptomics, bioinformatics analysis, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), the co-expression network of long noncoding RNA RC3H2 (RC3H2), microRNA-101-3p (miR-101-3p), and EZH2 were screened and validated as a competing endogenous RNA (ceRNA) mechanism in OSCC. Silencing of RC3H2 inhibited OSCC cell proliferation, colony formation, migration, and invasion in vitro and reduced the expression of EZH2 and H3K27Me3, whereas RC3H2 overexpression significantly promoted OSCC cell growth, colony formation, migration, invasion, and xenograft tumor growth in vivo and increased the expression of EZH2 and H3K27Me3. A fluorescence in situ hybridization (FISH) assay verified that RC3H2 was predominately localized to the cytoplasm. RNA pull-down and luciferase activity assays showed that miR-101-3p was physically bound to RC3H2 as well as EZH2, and its inhibitor reversed the inhibitory effect of RC3H2 knockdown on progression of OSCC. Taken together, our findings demonstrate that RC3H2 as completive endogenous RNA sponging miR-101-3p targets EZH2 and facilitates OSCC cells’ malignant behavior.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The diagnosis and treatment of Sjogren's syndrome (SS) are commonly conducted by rheumatologists and stomatologists. The purpose of this study was to compare the scientometric characteristics of SS ...publications by rheumatologists and stomatologists.
All the papers on cheilitis were comprehensively retrieved from the Scopus database, and divided into rheumatologists and stomatologists groups.
There were 3245 and 1209 papers on SS were published by rheumatologists and stomatologists, respectively. For the most-cited top-200 papers, the total citation count was 29,764 and the h index was 108 for SS publications by rheumatologists; whereas the count is 19,891 and h index is 81 for publications by stomatologists. Interestingly, we observed that accumulated citations of the publications by stomatologists cooperated with rheumatologists were larger than those by stomatologists alone during 2012–2022. The more common keywords such as saliva, salivation, minor salivary glands, parotid gland, submandibular gland, sialography, lip, dental caries, and hyposalivation were reported by stomatologists. The more frequent keywords such as rheumatoid factor, fatigue, lymphoma, interstitial lung disease, arthralgia, Raynaud phenomenon, lymphadenopathy, and vasculitis were reported by rheumatologists.
This study firstly reports the scientometric characteristics of SS publications by rheumatologists and stomatologists. The scale and citations of rheumatologists' publications greatly outweigh those of stomatologists, suggesting stomatologists can cooperate more with rheumatologists regarding SS research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous ...internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism, and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-β expression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.
Oral squamous cell carcinoma (OSCC) is the most common type of oral malignancy, and metastasis accounts for the poor prognosis of OSCC. Autophagy is considered to facilitate OSCC development by ...mitigating various cellular stresses; nevertheless, the mechanisms of autophagy in OSCC cell proliferation and metastasis remain unknown. In our study, high-sensitivity label-free quantitative proteomics analysis revealed nuclear protein 1 (NUPR1) as the most significantly upregulated protein in formalin-fixed paraffin-embedded tumour samples derived from OSCC patients with or without lymphatic metastasis. Moreover, NUPR1 is aberrantly expressed in the OSCC tissues and predicts low overall survival rates for OSCC patients. Notably, based on tandem mass tag-based quantitative proteomic analysis between stable NUPR1 knockdown OSCC cells and scrambled control OSCC cells, we confirmed that NUPR1 maintained autophagic flux and lysosomal functions by directly increasing transcription factor E3 (TFE3) activity, which promoted OSCC cell proliferation and metastasis in vitro and in vivo. Collectively, our data revealed that the NUPR1-TFE3 axis is a critical regulator of the autophagic machinery in OSCC progression, and this study may provide a potential therapeutic target for the treatment of OSCC.
Following a thorough assessment of the safety and potential efficacy of the procedure, and securing ethics approval from the Ethics Committees of the Shanghai Mental Health Center and Shanghai Ninth ...People’s Hospital, we initiated an investigator-initiated trial of the ‘Cervical Shunting to Unclog cerebral Lymphatic Systems (CSULS) surgical procedure’ (registration number: Another important distinction is in the diagnoses: our patient met the biological diagnostic criteria for AD, as outlined by the National Institute on Aging-Alzheimer’s Association criteria,6 whereas Xie et al’s patients did not. ...we compared biological measures, such as positron emission tomography (PET) scans and magnetic resonance imaging (MRI), before and after CSULS to confirm its efficacy. Ethics approval This study involves human participants and was approved by the Shanghai Mental Health Center Ethics Committee (SMHC-2024-01) and Shanghai Ninth People’s Hospital Ethics Committee (SH9H-2023-T423-2).
Abstract
Background
Late diagnosis of a salivary fistula increases the risk of wound infection and scarring. The purpose of the present study was to identify a quantitative predictor of postoperative ...salivary fistula for cases treated with surgery.
Methods
Demographic, intraoperative and postoperative parameters for 57 cases that received surgery for benign parotid tumours were recorded from June 2017 to June 2018, of which 18 cases developed salivary fistulas. These data were analysed using univariate and binary logistic regression analyses as well as receiver operating curve analysis.
Results
Drain fluid amylase concentration was positively correlated with salivary fistula development (
p
< 0.001), with an odds ratio of 1.14 for a 1 KU/L increase in concentration and an optimal receiver operating curve cut-off value of 51,100 U/L for predicting salivary fistula development. Cases wherein the parotid–masseteric fascia remained intact were associated with a lower risk of salivary fistula development (
p
= 0.006).
Conclusion
Drain fluid amylase concentration may be a valuable predictor of postoperative salivary fistula in cases with benign parotid tumours.
Programmed death ligand 1 (PD-L1) functions as a key immune inhibitory factor by binding with its receptor, programmed death 1 (PD-1), to induce immune cell dysfunction and escape of the immune ...system. However, the mechanisms of PD-L1 expression under growth factor stimulation are not well characterized. Here, we demonstrate a novel role for glial cell line-derived neurotrophic factor (GDNF) in upregulating PD-L1 expression in head and neck squamous cell carcinoma (HNSCC). The expression and correlation of PD-L1, GDNF and perineural invasion (PNI) status were evaluated by bioinformatics analysis of TCGA database and IHC assays from 145 HNSCC patients. PD-L1 expression was investigated by flow cytometry, Western blot and real-time PCR analyses in HNSCC cells after GNDF incubation. The cell signaling pathways activated by GDNF were analyzed with an antibody array and blocked by specific signaling inhibitors in cancer cell lines. PD-L1 expression was significantly higher in cancer cells that exhibited PNI in the HNSCC specimens, and elevated PD-L1 expression was significantly correlated with GDNF levels. GDNF not only enhanced cancer cell PNI in a co-culture of dorsal root ganglions and cancer cells but also had a potent role in inducing PD-L1 expression through the JAK2-STAT1 signaling pathway. Moreover, a JAK2 inhibitor attenuated GDNF-induced PD-L1 and enhanced tumor cell susceptibility to NK cell killing. Our findings provide clinically novel evidence that nerve-derived GDNF can increase PD-L1 levels in cancer cells around the perineural niche and that regulatory signaling is critical for cancer cell escape from immune surveillance in the nerve-cancer microenvironment.
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