BHLHE40, a potential immune therapy target, regulated by FGD5‑AS1/miR‑15a‑5p in pancreatic cancer

Sep 24, 2026

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Pancreatic cancer is an aggressive malignancy with poor outcomes largely driven by delayed diagnosis and immunosuppressive tumor microenvironment features. This work identifies BHLHE40 as a transcription factor elevated in pancreatic cancer tissues and links lower BHLHE40 expression with improved patient survival. Bioinformatics and in vitro/in vivo experiments show BHLHE40 promotes proliferation and invasion while impairing apoptosis, consistent with an immunosuppression-related role. The study further validates the FGD5-AS1/miR-15a-5p axis as an upstream regulatory mechanism and proposes the BHLHE40 ceRNA network as a diagnostic marker and immunotherapeutic target.

LanguageEnglish

CategoryHealthcare

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Pages21

Reading Time53 min

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BHLHE40 and pancreatic cancer background

Tumor immune microenvironment and immunosuppression

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN BHLHE40, a potential immune therapy target, regulated by FGD5‑AS1/miR‑15a‑5pin pancreatic cancer Wenxin Qi1, Qian Liu1, Wenjun Fu1, Jiaming Shi1, Minmin Shi2, Songqi Duan3, Zhe Li1*, Shaohua Song2*, Jiao Wang1* & Yihao Liu2* Pancreatic cancer, as one of the neoplasms with the highest degree of malignancy, has become a main disease of concerns in recent years. BHLHE40, a critical transcription factor for remodeling of the tumor immune microenvironment, has been described to be substantially increased in a variety of tumor‑associated immune cells. Nevertheless, the pro‑cancer biological functions and underlying molecular mechanisms of BHLHE40 for pancreatic cancer and its unique microenvironment are unclear. Hereby, we investigated the pro‑oncogenic role of BHLHE40 in the pancreatic cancer microenvironment by bioinformatics analysis and cell biology experiments and determined that the expression of BHLHE40 was obviously elevated in pancreatic cancer tissues than in adjacent normal tissues. In parallel, Kaplan–Meier survival analysis unveiled that lower expression of BHLHE40 was strongly associated with better prognosis of patients. Receiver operating characteristic (ROC) curve analysis confirmed the accuracy of the BHLHE40‑related prediction model. Subsequent, spearman correlation analysis observed that higher expression of BHLHE40 might be involved in immunosuppression of pancreatic cancer. Silencing of BHLHE40 could inhibit proliferation, invasion, and apoptosis of pancreatic cancer in vitro and in vivo, implying that BHLHE40 is expected to bea potential therapeutic target for pancreatic cancer. In addition, we explored and validated the FGD5‑AS1/miR‑15a‑5p axis as a potential upstream regulatory mode for high expression of BHLHE40 in pancreatic cancer. In summary, our data showed that ceRNA involved in the regulation of BHLHE40 contributes to the promotion of immunosuppressive response in pancreatic and is expected to be a diagnostic marker and potential immunotherapeutic target for pancreatic cancer. Pancreatic cancer is a devastating malignant tumor, and with the rapid growth of incidence and mortality, it is expected to be the second leading cause of cancer-related mortality in the United States before 20301,2. The poor prognosis is due to difficulty in early diagnosis, the lesion sites are prone to liver or blood metastasis and immunosuppressive components in microenvironment3,4. Pancreatic cancer is most common in the United States, Europe and Australia, and pancreatic cancer involves genetics, diabetes, diet and smoking5–7. Remarkable progress has been made in treatment of pancreatic cancer, including the introduction of surgical techniques and medical therapies such as laparoscopic techniques and neo-adjuvant chemoradiotherapy8,9. However, 85% of patients present with metastatic unresectable pancreatic cancer and pancreatic cancer responds poorly to most chemotherapeutic agents10. Hence, it is essential to dig deeper into the molecular pathways that are contained in the process of pancreatic cancer to find novel biomarkers to improve the prognosis of pancreatic cancer patients11, 12. Transcripts of Long non-coding RNAs (LncRNA) specifically bind to transcription factors (TF) or form scaffold structures for transcription initiation to control disease genesis and progression, e.g. ZEB1 may emerge asa mediator oflinc-ROR-induced epithelial-mesenchymal transition (EMT) to promote invasion and metastasis in pancreatic cancer13, 14, TF-LncRNA-mediated feed-forward loop networks are involved in prognostic motifs in different cancers15. As a TF, BHLHE40 can be expressed in both nucleus and cytoplasm, regulating different targets in variant organs. Besides, BHLHE40 is a helix-loop-helix transcription factor that has been emerged as a 1School of Life Sciences, Shanghai University, Shanghai, China. 2Department of General Surgery, Ruijin Hosp

FAQs

What is BHLHE40’s role in pancreatic cancer according to the study?

BHLHE40 is elevated in pancreatic cancer tissues and is associated with poorer patient prognosis. Functional experiments indicate it promotes proliferation and invasion while affecting apoptosis and immunosuppressive processes.

How is BHLHE40 expression regulated upstream in pancreatic cancer?

The study explores and validates an FGD5-AS1/miR-15a-5p axis as an upstream regulatory mode underlying high BHLHE40 expression.

Why is the BHLHE40 network considered a potential therapeutic target?

Silencing BHLHE40 inhibits pancreatic cancer growth-related behaviors in vitro and in vivo. The findings also connect higher BHLHE40 with immunosuppression, supporting its use as an immunotherapeutic target.

Sep 24, 2026

Uploaded by Cipher