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Patients with glycogen storage disease type Ib (GSD‐Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD‐Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo‐polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single‐cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper‐activation of the CCL4L2‐VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD‐Ib. Collectively, the microbiota‐driven pathomechanism of IBD is demonstrated in GSD‐Ib and revealed the active role of the CCL4L2‐VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2‐VISR axis may represent a potential therapy for GSD‐associated IBD. [ABSTRACT FROM AUTHOR]

Background: N6‐methyladenosine (m6A) modification is essential for modulating RNA processing as well as expression, particularly in the context of malignant tumour progression. However, the exploration of m6A modification in nasopharyngeal carcinoma (NPC) remains very limited. Methods: RNA m6A levels were analysed in NPC using m6A dot blot assay. The expression level of methyltransferase‐like 14 (METTL14) within NPC tissues was analysed from public databases as well as RT‐qPCR and immunohistochemistry. The influences on METTL14 expression on NPC proliferation and metastasis were explored via in vitro as well as in vivo functional assays. Targeted genes of METTL14 were screened using the m6A and gene expression profiling microarray data. Actinomycin D treatment and polysome analysis were used to detect the half‐life and translational efficiency of ANKRD22. Flow cytometry, immunofluorescence and immunoprecipitation were used to validate the role of ANKRD22 on lipid metabolism in NPC cells. ChIP‐qPCR analysis of H3K27AC signalling near the promoters of METTL14, GINS3, POLE2, PLEK2 and FERMT1 genes. Results: We revealed METTL14, in NPC, correlating with poor patient prognosis. In vitro and in vivo assays indicated METTL14 actively promoted NPC cells proliferation and metastasis. METTL14 catalysed m6A modification on ANKRD22 messenger ribonucleic acid (mRNA), recognized by the reader IGF2BP2, leading to increased mRNA stability and higher translational efficiency. Moreover, ANKRD22, a metabolism‐related protein on mitochondria, interacted with SLC25A1 to enhance citrate transport, elevating intracellular acetyl‐CoA content. This dual impact of ANKRD22 promoted lipid metabolism reprogramming and cellular lipid synthesis while upregulating the expression of genes associated with the cell cycle (GINS3 and POLE2) and the cytoskeleton (PLEK2 and FERMT1) through heightened epigenetic histone acetylation levels in the nucleus. Intriguingly, our findings highlighted elevated ANKRD22‐mediated histone H3 lysine 27 acetylation (H3K27AC) signals near the METTL14 promoter, which contributes to a positive feedback loop perpetuating malignant progression in NPC. Conclusions: The identified METTL14‐ANKRD22‐SLC25A1 axis emerges as a promising therapeutic target for NPC, and also these molecules may serve as novel diagnostic biomarkers. [ABSTRACT FROM AUTHOR]

Soil moisture flash droughts often pose significant challenges to humans and ecosystems, with wide‐ranging socioeconomic consequences. However, the underlying mechanisms of flash droughts and their changes remain unquantified. Taking China as a case study, we present a novel framework that combines machine learning with interpretable and cluster techniques to investigate flash drought mechanisms from 1980 to 2018. We first quantified the temporal contribution of drivers and further identified different mechanisms during drought onsets. We subsequently investigated the temporal changes in different mechanisms and classified drought event types. We identified four driving mechanism types triggering drought: Concurrent precipitation, Antecedent‐concurrent precipitation, Antecedent temperature‐concurrent precipitation, and Antecedent transpiration‐concurrent precipitation. The total effects from vegetation transpiration contributed to around 50% of the impacts for mechanisms involving antecedent transpiration and concurrent precipitation, highlighting the non‐neglectable role of vegetation water consumption in drought occurrences. Remarkably, about 60% of flash drought onsets exhibited close association with the antecedent anomalies, which contribute approximately 50% of overall effects, emphasizing the importance of the cumulative effects of drivers. Moreover, driving mechanisms associated with temperature and transpiration increased significantly over time, implying an elevated influence of these factors on droughts. Our classification of drought events reveals that nearly 70% of events were driven by at least two mechanisms, underscoring a complex time‐varying pattern of driving factors during drought events. The proposed holistic framework not only sheds insight into the multifaceted mechanisms driving flash droughts within China but also extends its potential applicability to broader geographical contexts. Key Points: A novel framework combining interpretable machine learning and cluster techniques was proposed to investigate flash drought mechanismFour distinct types of driving mechanisms of flash drought onset in eastern China were discoveredNearly 70% of flash drought events involve multiple mechanisms, emphasizing the time‐varying feature of drought drivers [ABSTRACT FROM AUTHOR]

In South and Southeast Asia, the habit of chewing betel nuts is prevalent, which leads to oral submucous fibrosis (OSF). OSF is a well‐established precancerous lesion, and a portion of OSF cases eventually progress to oral squamous cell carcinoma (OSCC). However, the specific molecular mechanisms underlying the malignant transformation of OSCC from OSF are poorly understood. In this study, the leading‐edge techniques of Spatial Transcriptomics (ST) and Spatial Metabolomics (SM) are integrated to obtain spatial location information of cancer cells, fibroblasts, and immune cells, as well as the transcriptomic and metabolomic landscapes in OSF‐derived OSCC tissues. This work reveals for the first time that some OSF‐derived OSCC cells undergo partial epithelial–mesenchymal transition (pEMT) within the in situ carcinoma (ISC) region, eventually acquiring fibroblast‐like phenotypes and participating in collagen deposition. Complex interactions among epithelial cells, fibroblasts, and immune cells in the tumor microenvironment are demonstrated. Most importantly, significant metabolic reprogramming in OSF‐derived OSCC, including abnormal polyamine metabolism, potentially playing a pivotal role in promoting tumorigenesis and immune evasion is discovered. The ST and SM data in this study shed new light on deciphering the mechanisms of OSF‐derived OSCC. The work also offers invaluable clues for the prevention and treatment of OSCC. [ABSTRACT FROM AUTHOR]

Single cell RNA sequencing (scRNA‐seq) provides a great convenience for studying tumor occurrence and development for its ability to study gene expression at the individual cell level. However, patient‐derived tumor tissues are composed of multiple types of cells including tumor cells and adjacent non‐malignant cells such as stromal cells and immune cells. The spatial locations of various cells in situ tissues plays a pivotal role in the occurrence and development of tumors, which cannot be elucidated by scRNA‐seq alone. Spatially resolved transcriptomics (SRT) technology emerges timely to explore the unrecognized relationship between the spatial background of a particular cell and its functions, and is increasingly used in cancer research. This review provides a systematic overview of the SRT technologies that are developed, in particular the more widely used cutting‐edge SRT technologies based on next‐generation sequencing (NGS). In addition, the main achievements by SRT technologies in precisely unveiling the underappreciated spatial locations on gene expression and cell function with unprecedented high‐resolution in cancer research are emphasized, with the aim of developing more effective clinical therapeutics oriented to a deeper understanding of the interaction between tumor cells and surrounding non‐malignant cells. [ABSTRACT FROM AUTHOR]

The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non‐muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co‐immunoprecipitation, GST pull‐down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non‐muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin‐specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co‐expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10‐MYH9‐snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention. [ABSTRACT FROM AUTHOR]

Cancer cells prefer glycolysis to support their proliferation. Our previous studies have shown that the long palate, lung, and nasal epithelial cell clone 1 (LPLUNC1) can upregulate prohibitin 1 (PHB1) expression to inhibit the proliferation of nasopharyngeal carcinoma (NPC) cells. Given that PHB1 is an important regulator of cell energy metabolism, we explored whether and how LPLUNC1 regulated glucose glycolysis in NPC cells. LPLUNC1 or PHB1 overexpression decreased glycolysis and increased oxidative phosphorylation (OXPHOS)‐related protein expression in NPC cells, promoting phosphorylated PHB1 nuclear translocation through 14‐3‐3σ. LPLUNC1 overexpression also increased p53 but decreased c‐Myc expression in NPC cells, which were crucial for the decrease in glycolysis and increase in OXPHOS‐related protein expression induced by LPLUNC1 overexpression. Finally, we found that treatment with all‐trans retinoic acid (ATRA) reduced the viability and clonogenicity of NPC cells, decreased glycolysis, and increased OXPHOS‐related protein expression by enhancing LPLUNC1 expression in NPC cells. Therefore, the LPLUNC1‐PHB1‐p53/c‐Myc axis decreased glycolysis in NPC cells, and ATRA upregulated LPLUNC1 expression, ATRA maybe a promising drug for the treatment of NPC. [ABSTRACT FROM AUTHOR]

The pathogenesis and cisplatin chemoresistance of ovarian cancer (OC) are still unclear. Vacuolar protein sorting‐associated 33B (VPS33B) has not been reported in OC to date. In this study, immunohistochemistry was used to detect VPS33B protein expression between OC and ovarian tissues. MTT, EdU, colony formation, cell cycle, in vivo tumorigenesis, western blot, ChIP, EMSA, co‐immunoprecipitation (CoIP), qRT‐PCR, and microconfocal microscopy were used to explore the function and molecular mechanisms of VPS33B in OC cells. The results of the present study demonstrated that VPS33B protein expression was obviously reduced in OC compared with that in ovarian tissues. Overexpressed VPS33B suppressed cell cycle transition, cell growth, and chemoresistance to cisplatin in vitro and in vivo. Analysis of the mechanism indicated that overexpressed VPS33B regulated the epidermal growth factor receptor (EGFR)/PI3K/AKT/c‐Myc/p53/miR‐133a‐3p feedback loop and reduced the expression of the cell cycle factor CDK4. Nasopharyngeal epithelium‐specific protein 1 (NESG1) as a tumor suppressor not only interacted with VPS33B, but was also induced by VPS33B by the attenuation of PI3K/AKT/c‐Jun‐mediated transcription inhibition. Overexpressed NESG1 further suppressed cell growth by mediating VPS33B‐modulated signals in VPS33B‐overexpressing OC cells. Finally, NESG1 induced VPS33B expression by reducing the inhibition of PI3K/AKT/c‐Jun‐mediated transcription. Our study is the first to demonstrate that VPS33B serves as a tumor suppressor, and VPS33B can interact with NESG1 to suppress cell growth and promote cisplatin sensitivity by regulating the EGFR/PI3K/AKT/c‐Myc/p53/miR‐133a‐3p feedback loop in OC cells. [ABSTRACT FROM AUTHOR]

Long noncoding RNA (lncRNA) have emerged as crucial regulators for a myriad of biological processes, and perturbations in their cellular expression levels have often been associated with cancer pathogenesis. In this study, we identified AATBC (apoptosis‐associated transcript in bladder cancer, LOC284837) as a novel lncRNA. AATBC was found to be highly expressed in nasopharyngeal carcinoma (NPC), and increased AATBC expression was associated with poor survival in patients with NPC. Furthermore, AATBC promoted migration and invasion of NPC cells in vitro, as well as metastasis in vivo. AATBC upregulated the expression of the desmosome‐associated protein pinin (PNN) through miR‐1237‐3p sponging. In turn, PNN interacted with the epithelial–mesenchymal transition (EMT) activator ZEB1 and upregulated ZEB1 expression to promote EMT in NPC cells. Collectively, our results indicate that AATBC promotes NPC progression through the miR‐1237‐3p–PNN–ZEB1 axis. Our findings indicate AATBC as a potential prognostic biomarker or therapeutic target in NPC. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) constitute approximately 4% of all cancers worldwide. In this study, we analyzed the expression profile of the long noncoding RNA (lncRNA) of 502 HNSCC patients from The Cancer Genome Atlas database. Among the differentially expressed lncRNAs between HNSCC and normal samples, LNCAROD is overexpressed in HNSCC and associated with advanced T stage and shortened overall survival. The N6‐methyladenosine (m6A) modification mediated by METTL3 and METTL14 enhanced the stability of LNCAROD in HNSCC cells. Depletion of LNCAROD attenuated cell proliferation, mobility in vitro, and tumorigenicity in vivo, whereas overexpression of LNCAROD exerted opposite effects. LNCAROD is mainly distributed in nucleus and binds with YBX1 and HSPA1A proteins. Silencing either YBX1 or HSPA1A did not affect the level of LNCAROD. However, loss of LNCAROD led to shortened half‐life of YBX1 protein. Mechanistically, LNCAROD protected YBX1 from proteasomal degradation by facilitating YBX1‐HSPA1A protein–protein interaction. Depletion of HSPA1A in LNCAROD‐overexpressing cells resulted in accelerated proteasomal degradation of YBX1 protein. Moreover, re‐expression of Flag‐YBX1 in LNCAROD‐silenced cells rescued malignant behavior of HNSCC cells. Our study indicates that LNCAROD is an oncogenic lncRNA and dysregulation of m6A modification might account for aberrant expression of LNCAROD in HNSCC. LNCAROD acts as a scaffold for the interaction between YBX1 and HSPA1A, preventing proteasomal degradation of YBX1 in HNSCC cells. [ABSTRACT FROM AUTHOR]

Inhibin B (INHBB), a heterodimer of a common α‐subunit and a βB‐subunit, is a glycoprotein belonging to the transforming growth factor‐β (TGF‐β) family. In this study, we observed INHBB expression was reduced in nasopharyngeal carcinoma (NPC) tissues compared to non‐tumor nasopharyngeal epithelium tissues, and INHBB was associated with lymph node metastasis, stage of disease, and clinical progress. Positive expression of INHBB in NPC predicted a better prognosis (overall survival, P = 0.038). However, the molecular mechanisms of INHBB have not been addressed in NPC. We induced anoikis‐resistant cells in NPC cell lines under anchorage‐independent conditions, then found epithelial‐mesenchymal transition markers changed, cell apoptosis decreased, cell cycle was modified, and invasion strengthened in anoikis‐resistant NPC cells. These anoikis‐resistant NPC cells showed decreased expression of INHBB compared with adhesion cells. Furthermore, INHBB was found to influence the above‐mentioned changes. In the anoikis‐resistant NPC cells with INHBB overexpression, apoptotic cells increased, S phase cells weakened, vimentin, matrix metallopeptidase‐9, and vascular endothelial growth factor A expression were downregulated, and E‐cadherin expression was upregulated, and vice versa in knockdown of INHBB (INHBB shRNA) anoikis‐resistant NPC cells. Diminished INHBB expression could activate the TGF‐β pathway to phosphorylate Smad2/3 and form complexes in the nucleus, which resulted in the above changes. Thus, our results revealed for the first time that INHBB could suppress anoikis resistance and migration of NPC cells by the TGF‐β signaling pathway, decrease p53 overexpression, and could serve as a potential biomarker for NPC metastasis and prognosis as well as a therapeutic application. Our results showed for the first time that inhibin B could suppress anoikis resistance and migration of nasopharyngeal carcinoma cells by the transforming growth factor‐β signaling pathway, and decrease p53 overexpression. Inhibin B could serve as a potential biomarker for nasopharyngeal carcinoma metastasis and prognosis, as well as a therapeutic application. [ABSTRACT FROM AUTHOR]

Human SPLUNC1 can suppress nasopharyngeal carcinoma ( NPC) tumor formation; however, the correlation between SPLUNC1expression and NPC patient prognosis has not been reported. In the present study, we used a large-scale sample of 1015 tissue cores to detect SPLUNC1 expression and its association with patient prognosis. SPLUNC1 expression was reduced in NPC samples compared to nontumor nasopharyngeal epithelium tissues. Positive expression of SPLUNC1 in NPC predicted a better prognosis (disease-free survival, P = 0.034; overall survival, P = 0.048). Cox's proportional hazards model revealed that SPLUNC1 could be a significant prognostic factor affecting disease-free survival ( P = 0.027). A c DNA micro-array analyzed by significant analysis of micro-array (SAM) and ingenuity pathway analysis (IPA) revealed that an indirect interaction existed between SPLUNC1 and retinoic acid (RA) in the cancer regulatory network. To further investigate the molecular mechanisms involved, we utilized several bioinformatics tools and identified 12 retinoid X receptors heterodimer binding sites in the promoter region of the SPLUNC1 gene. The transcriptional activity of the SPLUNC1 promoter was up-regulated significantly by all-trans-retinoic acid ( ATRA). SPLUNC1 and retinoic acid receptor expression were induced significantly by ATRA, and removal of ATRA led to a progressive loss of SPLUNC1 and retinoic acid receptor expression. ATRA inhibited proliferation and induced the differentiation of NPC cells. Interestingly, over-expression of SPLUNC1 sensitized NPC cells to ATRA, whereas knockdown of SPLUNC1 in HNE1 cells increased cell viability. Under SPLUNC1 knockdown conditions, differentiation was reversed by ATRA treatment. We concluded that SPLUNC1 could potentially predict prognosis for NPC patients and play an important role in ATRA-induced growth inhibition and differentiation in NPC cells. [ABSTRACT FROM AUTHOR]