PTPN23[Thr] variant reduces susceptibility and tumorigenesis in esophageal squamous cell carcinoma through dephosphorylation of EGFR.

Post-translational modifications (PTMs) have emerged as pivotal regulators of the development of cancers, including esophageal squamous cell carcinoma (ESCC). Here, we conducted a comprehensive analysis of PTM-related genetic variants associated with ESCC risk using large-scale genome-wide and exome-wide association datasets. We observed significant enrichment of PTM-related variants in the ESCC risk loci and identified five variants that were significantly associated with ESCC risk. Among them, rs6780013 in PTPN23 exhibited the highest level of significance in ESCC susceptibility in 9,728 ESCC cases and 10,977 controls (odds ratio [OR] = 0.85, 95 % confidence interval [CI] = 0.81- 0.89, P = 9.77 × 10-14). Further functional investigations revealed that PTPN23[Thr] variant binds to EGFR and modulates its phosphorylation at Thr699. PTPN23[Thr] variant substantially inhibited ESCC cell proliferation both in vitro and in vivo. Our findings underscore the critical role of PTPN23[Thr]-EGFR interaction in ESCC development, providing more insights into the pathogenesis of this cancer.

Flexible Chitosan-Based Capacitive Humidity Sensors for Respiratory Monitoring.

As one of the most important human health indicators, respiratory status is an important basis for the diagnosis of many diseases. However, the high cost of respiratory monitoring makes its use uncommon. This study introduces a low-cost, wearable, flexible humidity sensor for respiratory monitoring. Solution-processed chitosan (CS) placed on a polyethylene terephthalate substrate was used as the sensing layer. An Arduino circuit board was used to read humidity-sensitive voltage changes. The CS-based sensor demonstrated capacitive humidity sensitivity, whereby the capacitance instantly increased from 10-2 to 30 nF when the environmental humidity changed from 43% to 97%. The capacitance logarithm sensitivity and response voltage change was 35.9 pF/%RH and 0.8 V in the RH range from 56% to 97%. And the voltage variation between inhalation and exhalation was ~0.5 V during normal breathing. A rapid response time of ~0.7 s and a recovery time of ~2 s were achieved during respiration testing. Breathing modes (i.e., normal breathing, rest breathing, deep breathing, and fast breathing) and tonal changes during speech could be clearly distinguished. Therefore, such sensors provide a means for economical and convenient wearable respiratory monitoring, and they have the potential to be used for daily health examinations and professional medical diagnoses.

Single-cell analysis identified POSTN+ cells associated with the aggressive phenotype and risk of esophageal squamous cell carcinoma.

Tumors are intricate and heterogeneous systems characterized by mosaic cancer cell populations with diverse expression profiles. Leveraging single-cell technologies, we employed the Scissor algorithm to delineate an epithelial subpopulation associated with the aggressive phenotype in esophageal squamous cell carcinoma (ESCC). This identified subpopulation exhibited elevated expression of genes involved in critical pathways, such as epithelial-mesenchymal transition and PI3K-Akt. Key signature genes within this subpopulation, namely CAV1, COL3A1, COL6A1, POSTN, and TAGLN, demonstrated significant upregulation concomitant with both tumorigenesis and tumor progression across independent single-cell datasets. Furthermore, we selected 1,450 expression quantitative trait loci of the top 62 signature genes of this cell subpopulation to investigate their potential in predicting ESCC risk. The results showed that the POSTN loci were predominantly associated with ESCC susceptibility. Through functional annotation and replication analyses, we identified that the rs1028728 in the POSTN promoter was significantly associated with increased ESCC risk in 7,049 ESCC cases and 8,063 controls (odds ratio = 1.29, 95% confidence interval: 1.18-1.42, p = 4.03 × 10-8). Subsequent biochemical experiments showed that the rs1028728[T] allele enhanced POSTN expression by affecting the binding of PRRX1 in the POSTN promoter. In summary, our meticulous single-cell analysis delineates an invasive epithelial subpopulation in ESCC, with POSTN emerging as an important marker for the aggressive phenotype. These findings offer more insights into potential strategies for the prevention and intervention of ESCC, enriching our understanding of this complex cancer landscape.

Systematical identification of key genes and regulatory genetic variants associated with prognosis of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) stands as a highly lethal malignancy characterized by pronounced recurrence and metastasis, resulting in a bleak 5-year survival rate. Despite extensive investigations, encompassing genome-wide association studies, the identification of robust prognostic markers has remained elusive. In this study, leveraging four independent data sets comprising 404 ESCC patients, we conducted a systematic analysis to unveil pivotal genes influencing overall survival. our meta-analysis identified 278 genes significantly associated with ESCC prognosis. Further exploration of the prognostic landscape involved an examination of expression quantitative trait loci for these genes, leading to the identification of six tag single nucleotide polymorphisms predictive of overall survival in a cohort of 904 ESCC patients. Notably, functional annotation spotlighted rs11227223, residing in the enhancer region of nuclear paraspeckle assembly transcript 1 (NEAT1), as a crucial variant likely exerting a substantive biological role. Through a series of biochemistry experiments, we conclusively demonstrated that the rs11227223-T allele, indicative of a poorer prognosis, augmented NEAT1 expression. Our results underscore the substantive role of NEAT1 and its regulatory variant in prognostic predictions for ESCC. This comprehensive analysis not only advances our comprehension of ESCC prognosis but also unveils a potential avenue for targeted interventions, offering promise for enhanced clinical outcomes.

A variant in CYP26B1 associated with esophageal squamous cell carcinoma risk by affecting retinoic acid metabolism.

All-trans retinoic acid (ATRA) is the natural and synthetic analogue of vitamin A, playing an essential tumor suppressive role in multiple cancers including the esophageal squamous cell carcinoma (ESCC). Cytochrome P450 family 26 subfamily B member 1 (CYP26B1) exerts a critical regulator of ATRA levels through specific inactivation of ATRA to hydroxylated forms. Our previous exome-wide analyses revealed a rare missense variant in CYP26B1 significantly associated with ESCC risk in the Chinese population. However, it is still unclear whether there are common variants in CYP26B1 affect the susceptibility of ESCC and the tumor promotion role of CYP26B1 in vivo. In this research, we conducted a two-stage case-control study comprised of 5057 ESCC cases and 5397 controls, followed by a series of biochemical experiments to explore the function of CYP26B1 and its common variants in the tumorigenesis of ESCC. Intriguingly, we identified a missense variant rs2241057[A>G] in the fourth exon of CYP26B1 significantly associated with the ESCC risk (combined odds ratio = 1.28; 95% confidence interval = 1.15-1.42; p = 2.96 × 10-6 ). Through further functional analysis, we demonstrated that ESCC cells with the overexpression of rs2241057[G] had a significant lower level of retinoic acid, compared with the overexpression of rs2241057[A] or the control vector. In addition, the CYP26B1 overexpression and knock-out ESCC cells affected cell proliferation rate both in vitro and in vivo. These results highlighted the carcinogenicity of CYP26B1 related to the ATRA metabolism in ESCC risk.