Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, MD 21201, USA; Department of Basic and Clinical Oral Sciences, College of Dentistry, Umm Al Qura University, Makkah, Saudi Arabia.
Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, MD 21201, USA.
Cell Signal. 2023 Aug;108:110697. doi: 10.1016/j.cellsig.2023.110697. Epub 2023 May 9.
The molecular mechanisms whereby angiopoietin-like 4 (ANGPTL4), a pluripotent protein implicated in cancer development, contributes to head and neck squamous cell carcinoma (HNSCC) growth and dissemination are unclear.
We investigated ANGPTL4 expression in human normal oral keratinocytes (NOKs), dysplastic oral keratinocytes (DOKs), oral leukoplakia cells (LEUK1), and HNSCC cell lines, as well as in tissue biopsies from patients with oral dysplasia, and primary and metastatic HNSCC. We further examined the contribution of ANGPTL4 cancer progression in an HNSCC orthotopic floor-of mouth tumor model and the signaling pathways linking ANGPTL4 to cancer cell migration.
ANGPTL4 expression was upregulated in premalignant DOKs and HNSCC cell lines compared to NOKs and was increased in tissue biopsies from patients with oral dysplasia, as well as in primary and metastatic HNSCC. We also observed that downregulation of ANGPTL4 expression inhibited primary and metastatic cancer growth in an HNSCC orthotopic tumor model. Interestingly, ANGPTL4 binding to the neuropilin1 (NRP1) receptor led to phosphorylation of the focal adhesion protein, paxillin (PXN), and tumor cell migration; this was dependent on the tyrosine kinase ABL1. Treatment with the ABL1 inhibitor, dasatinib and small interfering RNA silencing of NRP1 or ABL1 expression blocked PXN phosphorylation and tumor cell migration.
Our findings suggest an early, sustained, and angiogenesis-independent autocrine role for ANGPTL4 in HNSCC progression and expose ANGPTL4/NRP1/ABL1/PXN as an early molecular marker and vulnerable target for the prevention of HNSCC growth and metastasis.
血管生成素样蛋白 4（ANGPTL4）是一种多能蛋白，与癌症的发展有关，但其促进头颈部鳞状细胞癌（HNSCC）生长和扩散的分子机制尚不清楚。
我们研究了 ANGPTL4 在人正常口腔角质形成细胞（NOK）、发育不良的口腔角质形成细胞（DOK）、口腔白斑细胞（LEUK1）和 HNSCC 细胞系中的表达，以及口腔发育不良、原发性和转移性 HNSCC 患者的组织活检。我们进一步研究了 ANGPTL4 在 HNSCC 原位口腔底肿瘤模型中的癌症进展作用，以及将 ANGPTL4 与癌细胞迁移联系起来的信号通路。
ANGPTL4 的表达在癌前的 DOK 和 HNSCC 细胞系中上调，与 NOK 相比，在口腔发育不良患者的组织活检中，以及在原发性和转移性 HNSCC 中，ANGPTL4 的表达增加。我们还观察到，下调 ANGPTL4 的表达抑制了 HNSCC 原位肿瘤模型中的原发性和转移性癌症生长。有趣的是，ANGPTL4 与神经纤毛蛋白 1（NRP1）受体结合导致粘着斑蛋白 paxillin（PXN）的磷酸化和肿瘤细胞迁移；这依赖于酪氨酸激酶 ABL1。用 ABL1 抑制剂达沙替尼和 NRP1 或 ABL1 表达的小干扰 RNA 沉默治疗阻断了 PXN 磷酸化和肿瘤细胞迁移。
我们的研究结果表明，ANGPTL4 在 HNSCC 进展中具有早期、持续和血管生成非依赖性的自分泌作用，并揭示了 ANGPTL4/NRP1/ABL1/PXN 作为预防 HNSCC 生长和转移的早期分子标志物和脆弱靶点。
