Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin, 300060, China.
Department of Thyroid and Breast Surgery, The Second Hospital of Anhui Medical University, Anhui, 230601, China.
Cell Death Dis. 2024 Mar 14;15(3):215. doi: 10.1038/s41419-024-06587-9.
The invasion-metastasis cascade in head and neck squamous cell carcinoma (HNSCC) is predominantly caused by the interaction between tumor cells and tumor microenvironment, including hypoxia as well as stromal cells. However, the mechanism of hypoxia-activated tumor-stroma crosstalk in HNSCC metastasis remains to be deciphered. Here, we demonstrated that HIF1α was upregulated in HNSCC specimens compared with adjacent normal tissues, whose overexpression was associated with lymph node metastasis and predicted unfavorable prognosis. HIF1α expression correlated positively with the levels of miR-5100 as well as α-SMA, the marker of CAFs. Hypoxia/HIF1α regulated transcriptionally miR-5100 to promote the degradation of its target gene QKI, which acts as a tumor suppressor in HNSCC. Hypoxic HNSCC-derived exosomal miR-5100 promoted the activation of CAFs by orchestrating QKI/AKT/STAT3 axis, which further facilitated HNSCC metastasis. Additionally, miR-5100 derived from plasma exosomes indicated HNSCC malignant progression. In conclusion, our findings illuminate a novel HIF1α/miR-5100/QKI pathway in HNSCC metastasis, and suggest that miR-5100 might be a potential biomarker and therapeutic target for HNSCC.
头颈部鳞状细胞癌（HNSCC）中的侵袭-转移级联反应主要是由肿瘤细胞与肿瘤微环境之间的相互作用引起的，包括缺氧以及基质细胞。然而，HNSCC 转移中缺氧激活的肿瘤-基质细胞串扰的机制仍有待破译。在这里，我们证明与相邻正常组织相比，HIF1α 在 HNSCC 标本中上调，其过表达与淋巴结转移有关，并预测预后不良。HIF1α 的表达与 miR-5100 的水平以及 CAFs 的标志物 α-SMA 呈正相关。缺氧/HIF1α 转录调控 miR-5100 促进其靶基因 QKI 的降解，QKI 在 HNSCC 中作为一种肿瘤抑制因子发挥作用。缺氧 HNSCC 衍生的外泌体 miR-5100 通过协调 QKI/AKT/STAT3 轴促进 CAFs 的激活，从而进一步促进 HNSCC 转移。此外，来自血浆外泌体的 miR-5100 表明 HNSCC 恶性进展。总之，我们的研究结果阐明了 HNSCC 转移中的一个新的 HIF1α/miR-5100/QKI 通路，并表明 miR-5100 可能是 HNSCC 的一个潜在的生物标志物和治疗靶点。
