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Contributions of ADAM12 via HB‑EGF/EGFR signaling cascades to EMT and cancer progression in pancreas

  • Authors:
    • Qiubo Zhang
    • Feng Xu
    • Zetian Gao
    • Xianwen Dong
    • Yanyan Ma
    • Hong Li
    • Kaihong Huang
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang 315000, P.R. China, Department of Emergency, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang 315000, P.R. China, Department of Hepatobiliary Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang 315000, P.R. China, Department of Gastroenterology, Sun Yat‑Sen Memorial Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510000, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 5
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    Published online on: November 7, 2025
       https://doi.org/10.3892/mco.2025.2914
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Abstract

Pancreatic cancer (PC) is among the most aggressive malignancies, with a five‑year survival rate of <7% in China. The substantial stromal component and activation of epithelial‑mesenchymal transition (EMT) in PC contribute to drug resistance and poor outcomes. Between January 2017 and December 2020, 62 pancreatic specimens were obtained via surgical resection from two hospitals. In alignment with the GEPIA database, the expression levels of a disintegrin and metalloproteinase 12 (ADAM12) and heparin‑binding epidermal growth factor (HB‑EGF) were significantly elevated in 43 PC tissues compared with 19 benign pancreatic masses. Furthermore, elevated expression of ADAM12 and HB‑EGF was significantly associated with lymph node metastasis, advanced TNM stage, and reduced survival rates. Additionally, high ADAM12 expression was correlated with the upregulation of EGFR and EMT markers. Collectively, the present findings suggested that ADAM12 is involved in PC progression and may facilitate the shedding of HB‑EGF, thereby inducing EMT through the EGFR pathway. These results suggest that targeting the ADAM12/HB‑EGF/EGFR signaling pathway could represent a potential therapeutic strategy, warranting further in vivo and in vitro investigations to elucidate the underlying mechanisms.
View Figures

Figure 1

Age-standardized incidence and
mortality rates of PC in China. There are age-standardized
incidence and mortality rates for PC in both sexes. Data source:
GLOBOCAN 2022. Graph production: IARC (http://gco.iarc.fr/today.), World Health Organization.
PC, pancreatic cancer.

Figure 2

Activation of pancreatic stellate
cells. Transforming growth factor β, platelet-derived growth factor
and angiotensin II, secreted by pancreatic cancer, can promote
activation of cancer-associated fibroblasts.

Figure 3

Diagram depicts HB-EGF/EGFR mediated
development and migration in PC cells. The binding of HB-EGF to
EGFR promotes the activation of the EGFR signaling pathway, which
plays a critical role in PC cell proliferation, metastasis,
chemoresistance, poor prognosis and EMT through p-ERK. However, the
specific mechanisms remain unclear. HB-EGF, heparin-binding
epidermal growth factor; EGFR, EGF receptor; PC, pancreatic cancer;
EMT, epithelial-mesenchymal transition; p-ERK, phosphorylated
extracellular signal-regulated kinase.

Figure 4

Distinction between PC tissue and
benign pancreatic mass. (A) A disintegrin and metalloproteinase 12,
(C) heparin-binding EGF, (E) EGF receptor and (I) vimentin show
strong staining of the PC tissue, while benign pancreatic mass is
weak (B, D, F and J); by contrast, (G) E-cadherin shows weak
staining of the PC tissue, while benign pancreatic mass is strong
(H). H&E stain, x200 magnification, all images. PC, pancreatic
cancer; EGF, epidermal growth factor.

Figure 5

(A) ADAM12 and (B) HB-EGF are
upregulated in pancreatic cancer. Images were obtained from the
GEPIA online database (http://gepia.cancer-pku.cn). *P<0.01.
ADAM12, a disintegrin and metalloproteinase 12; HB-EGF,
heparin-binding epidermal growth factor; T, tumor; N, normal.

Figure 6

Kaplan-Meier survival analysis of
ADAM12 and HB-EGF and PC survival. (A) Patients with ADAM12 lower
expression showed a superior OS to patients with higher expression
of ADAM12 (P<0.0001). (B) Patients with HB-EGF lower expression
showed a superior OS to patients with higher expression of HB-EGF
(P=0.001). In GEPIA database, (D) HB-EGF was significantly
predicting the prognosis of patients with PC (n=198) by
Kaplan-Meier analysis (P<0.05), while (C) ADAM12 was not.
ADAM12, a disintegrin and metalloproteinase 12; HB-EGF,
heparin-binding epidermal growth factor; OS, overall survival.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang Q, Xu F, Gao Z, Dong X, Ma Y, Li H and Huang K: Contributions of ADAM12 via HB‑EGF/EGFR signaling cascades to EMT and cancer progression in pancreas. Mol Clin Oncol 24: 5, 2026.
APA
Zhang, Q., Xu, F., Gao, Z., Dong, X., Ma, Y., Li, H., & Huang, K. (2026). Contributions of ADAM12 via HB‑EGF/EGFR signaling cascades to EMT and cancer progression in pancreas. Molecular and Clinical Oncology, 24, 5. https://doi.org/10.3892/mco.2025.2914
MLA
Zhang, Q., Xu, F., Gao, Z., Dong, X., Ma, Y., Li, H., Huang, K."Contributions of ADAM12 via HB‑EGF/EGFR signaling cascades to EMT and cancer progression in pancreas". Molecular and Clinical Oncology 24.1 (2026): 5.
Chicago
Zhang, Q., Xu, F., Gao, Z., Dong, X., Ma, Y., Li, H., Huang, K."Contributions of ADAM12 via HB‑EGF/EGFR signaling cascades to EMT and cancer progression in pancreas". Molecular and Clinical Oncology 24, no. 1 (2026): 5. https://doi.org/10.3892/mco.2025.2914
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang Q, Xu F, Gao Z, Dong X, Ma Y, Li H and Huang K: Contributions of ADAM12 via HB‑EGF/EGFR signaling cascades to EMT and cancer progression in pancreas. Mol Clin Oncol 24: 5, 2026.
APA
Zhang, Q., Xu, F., Gao, Z., Dong, X., Ma, Y., Li, H., & Huang, K. (2026). Contributions of ADAM12 via HB‑EGF/EGFR signaling cascades to EMT and cancer progression in pancreas. Molecular and Clinical Oncology, 24, 5. https://doi.org/10.3892/mco.2025.2914
MLA
Zhang, Q., Xu, F., Gao, Z., Dong, X., Ma, Y., Li, H., Huang, K."Contributions of ADAM12 via HB‑EGF/EGFR signaling cascades to EMT and cancer progression in pancreas". Molecular and Clinical Oncology 24.1 (2026): 5.
Chicago
Zhang, Q., Xu, F., Gao, Z., Dong, X., Ma, Y., Li, H., Huang, K."Contributions of ADAM12 via HB‑EGF/EGFR signaling cascades to EMT and cancer progression in pancreas". Molecular and Clinical Oncology 24, no. 1 (2026): 5. https://doi.org/10.3892/mco.2025.2914
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