Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA.
Department of Basic and Clinical Oral Sciences, College of Dental Medicine, Umm Al Qura University, Makkah, Saudi Arabia.
J Oral Pathol Med. 2024 Jul;53(6):366-375. doi: 10.1111/jop.13545. Epub 2024 May 19.
Angiopoietin-like 4 is a molecular hallmark that correlates with the growth and metastasis of head and neck squamous cell carcinoma, one of the most prevalent cancers worldwide. However, the molecular mechanisms by which angiopoietin-like 4 promotes head and neck squamous cell carcinoma tumorigenesis are unclear.
Using well-characterized cell lines of head and neck squamous cell carcinoma development, including human normal oral keratinocytes, dysplastic oral keratinocytes, oral leukoplakia-derived oral keratinocytes, and head and neck squamous cell carcinoma cell lines, HN13, HN6, HN4, HN12, and CAL27, we investigated the signaling pathways upstream and downstream of angiopoietin-like 4-induced head and neck squamous cell carcinoma tumorigenesis.
We found that both epidermal growth factor receptor ligands, epithelial growth factor, and amphiregulin led to angiopoietin-like 4 upregulation in normal oral keratinocytes and dysplastic oral keratinocytes and cooperated with the activation of hypoxia-inducible factor-1 in this effect. Interestingly, amphiregulin and angiopoietin-like 4 were increased in dysplastic oral keratinocytes and head and neck squamous cell carcinoma cell lines, and amphiregulin-induced activation of cell proliferation was dependent on angiopoietin-like 4. Although both p38 mitogen-activated protein kinases (p38 MAPK) and protein kinase B (AKT) were activated by angiopoietin-like 4, only pharmacological inhibition of p38 MAPK was sufficient to prevent head and neck squamous cell carcinoma cell proliferation and migration. We further observed that angiopoietin-like 4 promoted the secretion of interleukin 11 (IL-11), interleukin 12 (IL-12), interleukin-1 alpha (IL-1α), vascular endothelial growth factor, platelet-derived growth factor (PDGF), and tumour necrosis factor alpha (TNF-α), cytokines and chemokines previously implicated in head and neck squamous cell carcinoma pathogenesis.
Our results demonstrate that angiopoietin-like 4 is a downstream effector of amphiregulin and promotes head and neck squamous cell carcinoma development both through direct activation of p38 kinase as well as paracrine mechanisms.
血管生成素样 4 是一种分子标志，与头颈部鳞状细胞癌（全球最常见的癌症之一）的生长和转移相关。然而，血管生成素样 4 促进头颈部鳞状细胞癌肿瘤发生的分子机制尚不清楚。
我们使用了头颈部鳞状细胞癌发展的特征明确的细胞系，包括人正常口腔角质细胞、发育不良的口腔角质细胞、口腔白斑衍生的口腔角质细胞和头颈部鳞状细胞癌细胞系 HN13、HN6、HN4、HN12 和 CAL27，研究了血管生成素样 4 诱导的头颈部鳞状细胞癌肿瘤发生的上下游信号通路。
我们发现，表皮生长因子受体配体表皮生长因子和 Amphiregulin 都导致正常口腔角质细胞和发育不良的口腔角质细胞中血管生成素样 4 的上调，并在这种效应中与缺氧诱导因子-1 的激活合作。有趣的是，Amphiregulin 和血管生成素样 4 在发育不良的口腔角质细胞和头颈部鳞状细胞癌细胞系中增加，Amphiregulin 诱导的细胞增殖激活依赖于血管生成素样 4。虽然血管生成素样 4 激活了丝裂原活化蛋白激酶（p38 MAPK）和蛋白激酶 B（AKT），但仅药理学抑制 p38 MAPK 就足以阻止头颈部鳞状细胞癌的增殖和迁移。我们进一步观察到，血管生成素样 4 促进白细胞介素 11（IL-11）、白细胞介素 12（IL-12）、白细胞介素 1 阿尔法（IL-1α）、血管内皮生长因子、血小板衍生生长因子（PDGF）和肿瘤坏死因子-α（TNF-α）的分泌，这些细胞因子和趋化因子以前被认为与头颈部鳞状细胞癌的发病机制有关。
我们的结果表明，血管生成素样 4 是 Amphiregulin 的下游效应物，通过直接激活 p38 激酶以及旁分泌机制促进头颈部鳞状细胞癌的发展。
