SHFM1 deficiency suppresses esophageal squamous cell carcinomas progression via modulating NF-κB signaling and enhancing nature killer cell-mediated tumor surveillance

Sep 24, 2026

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Excessive proliferation, metastasis, and immune escape drive tumor progression in esophageal squamous cell carcinomas (ESCC). Split hand and foot malformation 1 (SHFM1) is highly expressed in multiple cancers, yet its function in ESCC remains unclear. Integrated bioinformatics analysis identified SHFM1 as markedly upregulated in ESCC and linked to poor prognosis. Functional assays using SHFM1 depletion or overexpression showed altered ESCC growth, migration, and immune escape. Xenograft experiments supported these findings in vivo. Mechanistically, SHFM1 promoted malignant behavior by activating NF-κB signaling, increasing P65 phosphorylation and nuclear translocation, and by modulating NK-cell sensitivity via targets c-Myc and PD-L1.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

SHFM1 in cancer progression and ESCC context

NF-κB signaling and ESCC regulation

NK cell–mediated immunotherapy background

Study rationale

EXPERIMENTAL AND THERAPEUTIC MEDICINE 25: 195, 2023 SHFM1 deficiency suppresses esophageal squamous cell carcinomas progression via modulating NF‑κB signaling and enhancing nature killer cell‑mediated tumor surveillance YIJUAN WU 1,2 , ZHIYU WANG 1 , SHENGMIAN LI3 , XIANLIANG CHEN4 and SHENGYUN ZHOU2 1Department of Oncology and Immunology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050010; 2Endoscopy Center, Xingtai People's Hospital, Xingtai, Hebei 054031; 3Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050010; 4Department of Gastroenterology, Xingtai People's Hospital, Xingtai, Hebei 054031, P.R. China Received October 27, 2022; Accepted February 28, 2023 DOI: 10. 3892/etm.2023.11894 Abstract. Excessive proliferation, metastasis and immune escape are considered to be hallmarks of cancer contributing to tumor progression . Split hand and foot malformation 1 (SHFM1) is highly expressed in various cancers and has been reported to increase malignant behaviors. However, the biological functions of SHFM1 in esophageal squamous cell carcinomas (ESCC) progression remain to be elucidated. An integrated bioinformatics analysis was performed to identify candidate genes in ESCC progression based on GSE micro‑ arrays. SHFM1 was found to be profoundly upregulated in ESCC tissues compared with normal tissues and SHFM1 expression was positively associated with poor prognosis . The biological effects of SHFM1 on cell growth, metastasis and immune escape were investigated following depletion or overexpression of SHFM1 in vitro. A xenograft mouse model was established to investigate the effect of SHFM1 on ESCC progression in vivo. SHFM1 overexpression promoted ESCC cell proliferation and migration in vitro as well as tumori‑ genesis in vivo, while SHFM1 knockdown restored those phenotype changes. Additionally, the present study demon‑ strated that the effects of SHFM1 on malignant behaviors of ESCC cells were achieved by activating the NF‑κB signaling accompanied by increased P65 phosphorylation and nuclear translocation. Furthermore, SHFM1 was also found to regu‑ late the sensitivity of cancer cells to natural killer (NK) cells. Specifically, inhibition of SHFM1 enhanced cell‑mediated cell apoptosis and increased NK toxicity, which might involve the Correspondence to: Dr Zhiyu Wang, Department of Oncology and Immunology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei 050010, P.R. China E‑[mail: wangzhiyudo2020@163.com](mail: wangzhiyudo2020@163.com) Key words: split hand and foot malformation 1, esophageal squamous cell carcinomas, NF‑κB signaling pathway, immune response, malignant behaviors downregulation of c‑Myc and programmed death‑ligand 1, key targets in cancer immunotherapy. In conclusion, these findings suggested that SHFM1 probably promoted ESCC progression by activating the NF‑κB pathway and enhancing the resistance of ESCC cells to NK cell cytotoxicity, indicating that SHFM1 may be a promising target for ESCC treatment. Introduction Esophageal cancer (ESCA) is one of the most prevalent malig‑ nant cancers worldwide and ranks as the sixth commonest cause of death (1) . Esophageal squamous cell carcinomas (ESCC) and adenocarcinoma are two major subtypes of ESCA with broad pathological heterogeneity and together comprise the majority of diagnosed ESCA cases (2) . ESCCis the primary histologic type and accounts for >90% of ESCA (3) . Currently, the primary clinical therapies have focused on the improvement of patient outcomes, including chemotherapy and surgical resection (4) . Extensive tumor cell metastasis remains the primary cause of high mortality and poor prognosis of ESCC (5) . Previous reports demonstrate that cancer immunotherapies have been considered a central tool against cancer in the past few decades (6,7) . Therefore, it is urgent to elucidate the more specific detection indic

FAQs

What role does SHFM1 play in ESCC progression according to the study?

SHFM1 promotes ESCC malignant behaviors, including increased proliferation and migration, and contributes to tumor progression in vitro and in vivo.

How does SHFM1 regulate NF-κB signaling in ESCC cells?

SHFM1 activates NF-κB signaling, evidenced by increased P65 phosphorylation and nuclear translocation.

What is the relationship between SHFM1 and natural killer (NK) cell–mediated tumor surveillance?

SHFM1 modulates ESCC sensitivity to NK cells; inhibiting SHFM1 enhances apoptosis and increases NK toxicity, involving changes in c-Myc and PD-L1.

Sep 24, 2026

Uploaded by Hazel