Down-regulation of YAP prevents smoking-and alcohol-induced carcinogenesis of esophageal paracancerous tissue by promoting cellular pyroptosis

Sep 23, 2026

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Down-regulation of YAP is investigated as a mechanism linking smoking and alcohol exposure to carcinogenesis in esophageal paracancerous tissues. The study analyzes Hippo-pathway and pyroptosis-related gene alterations across esophageal cancer tissues, paracancerous tissues, and distal normal tissues using molecular epidemiological methods. In vitro exposure with 4.0% alcohol plus cigarette smoke extract induces heterogeneity and cancerous transformation while suppressing Hippo signaling and pyroptosis. Verteporfin blocks these effects by inhibiting YAP and promoting pyroptosis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Methods

Study design and participants

Molecular epidemiological analysis

In vitro exposure and treatments

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Down-regulation of YAP prevents smoking-and alcohol-induced carcinogenesis of esophageal paracancerous tissue by promoting cellular pyroptosis Xinyu Ding1,5, Ying Li2,5, Xuning Wang3, Fan Li3, Zhifei Xu4, Yongfei Zhu3􀀍 & Zihao Chen4􀀍 Paracancerous tissues (PCTs) were previously considered benign regions, but recent findings reveal genomic instability in these areas. Smoking and alcohol consumption are closely associated with esophageal cancer (EC) development. This study explored the interplay between the Hippo pathway and pyroptosis in EC, PCTs, and distal normal tissues (DNTs). We used molecular epidemiological methods to analyze the effects of smoking and alcohol on these pathways. We found that key genes in both pathways were more altered in smokers and/or drinkers compared to non-smokers and nondrinkers. Additionally, we observed changes in some genes and proteins in PCTs, while the Hippo pathway and pyroptosis had not yet been influenced. We applied 4.0% alcohol combined with various concentrations of cigarette smoke extract (CSE) to PCTs cultured in vitro to observe carcinogenesis and changes in these pathways. Verteporfin, as an inhibitor of YAP, was also used in vitro culture experiments to observe its effects on cellular carcinogenesis. Among 56 EC patients, 41 had a history of smoking and/or alcohol consumption in this study. Compared to DNTs, Hippo pathway genes (Lats1, Yap, and Taz) and pyroptosis genes (Nlrp3, Asc, Gsdmd, and Caspase-1) were altered in 49 EC tissues, while changes ofLats1, Nlrp3, andAsc were observed in 47 PCTs. Additionally, 4.0% alcohol combined with 3.2%, 4.0%, and 5.8% CSE, respectively, not only induced cellular heterogeneity and even cancerous transformation, but also suppressed the Hippo pathway and pyroptosis in the PCTs culturedin vitro. Furthermore, in vitro, 9 μM verteporfin inhibited cellular heterogeneity/carcinogenesis in PCTs induced by 4.0% alcohol combined with 5.8% CSE through inhibiting YAP and promoting pyroptosis. It is speculated that the downregulation of YAP could prevent smoking-and alcohol-induced carcinogenesis in esophageal PCTs by promoting pyroptosis, which may offer new insights for the treatment of esophageal squamous carcinoma. Keywords Esophageal cancer, Paracancerous tissues, Hippo pathway, Pyroptosis The etiological evidence suggests that alcohol, cigarettes, and hot drinks play a crucial role in esophageal cancer (EC)1. Despite improvements in detection, staging, and proactive multimodal interventions for EC, overall survival has not changed significantly over the last few decades2. The main reason is that the mechanism of its occurrence and development remains unclear, resulting in poor treatment outcomes. The Hippo pathway plays a unique regulatory role in biological processes, such as organ size and tissue regeneration, and is closely related to the occurrence and development of tumours3. It is also commonly recognized as a conspicuous cancer signalling pathway and is frequently dysregulated in human cancers, making it an ideal molecular target for cancer therapy4. Inhibition of Hippo pathway activity promotes the proliferation and migration of esophageal squamous cell carcinoma (ESCC) cells cultured in vitro5. Pyroptosis is a type of 1Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. 2Department of Pathology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China. 3Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Medical School, Hunan Normal University, Changsha 410013, China. 4Department of Thoracic Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China. 5These authors contributed equally: Xinyu Ding and Ying Li. 􀀍 email: [njzhu70@126.com](njzhu70@126.com); [giochan@163.com](giochan@163.com) [www. na

FAQs

What is the main hypothesis regarding YAP and esophageal paracancerous tissues?

Down-regulating YAP could prevent smoking- and alcohol-induced carcinogenesis in esophageal paracancerous tissues by promoting cellular pyroptosis.

How did the study model smoking and alcohol exposure in vitro?

Paracancerous tissues were cultured with 4.0% alcohol combined with different concentrations of cigarette smoke extract (CSE) to observe carcinogenesis and pathway changes.

What role did verteporfin play in the experiments?

Verteporfin, used as a YAP inhibitor, suppressed cellular heterogeneity and carcinogenesis in vitro and promoted pyroptosis.

Sep 23, 2026

Upload by Jake