Kim Shihyun, Park Suyeon, Moon Eun-Hye, Kim Gi Jin, Choi Jongho
Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea.
Institute of Lee Gil Ya Cancer and Diabetes, Gachon University, Incheon, 21999, Republic of Korea.
Cancer Cell Int. 2023 Apr 24;23(1):79. doi: 10.1186/s12935-023-02924-8.
Oral squamous cell carcinoma (OSCC) is a highly malignant tumor that is frequently associated with lymph node metastasis, resulting in poor prognosis and survival in patients. In the tumor microenvironment, hypoxia plays an important role in regulating cellular responses such as progressive and rapid growth and metastasis. In these processes, tumor cells autonomously undergo diverse transitions and acquire functions. However, hypoxia-induced transition of OSCC and the involvement of hypoxia in OSCC metastasis remain unclear. Therefore, in this study, we aimed to elucidate the mechanism of hypoxia-induced OSCC metastasis and particularly, its impact on tight junctions (TJs).
The expression of hypoxia-inducible factor 1-alpha (HIF-1α) was detected in tumor tissues and adjacent normal tissues from 29 patients with OSCC using reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC). The migration and invasion abilities of OSCC cell lines treated with small interfering (si)RNA targeting HIF-1α or cultured in hypoxic conditions were analyzed using Transwell assays. The effect of HIF-1α expression on in vivo tumor metastasis of OSCC cells was evaluated using lung metastasis model.
HIF-1α was overexpressed in patients with OSCC. OSCC metastasis was correlated with HIF-1α expression in OSCC tissues. Hypoxia increased the migration and invasion abilities of OSCC cell lines by regulating the expression and localization of partitioning-defective protein 3 (Par3) and TJs. Furthermore, HIF-1α silencing effectively decreased the invasion and migration abilities of OSCC cell lines and restored TJ expression and localization via Par3. The expression of HIF-1α was positively regulated the OSCC metastasis in vivo.
Hypoxia promotes OSCC metastasis by regulating the expression and localization of Par3 and TJ proteins. HIF-1α positively correlates to OSCC metastasis. Lastly, HIF-1α expression could regulate the expression of Par3 and TJs in OSCC. This finding may aid in elucidating the molecular mechanisms of OSCC metastasis and progression and developing new diagnostic and therapeutic approaches for OSCC metastasis.
口腔鳞状细胞癌（OSCC）是一种高度恶性肿瘤，常伴有淋巴结转移，导致患者预后不良和生存率降低。在肿瘤微环境中，缺氧在调节细胞反应（如进行性快速生长和转移）中起重要作用。在这些过程中，肿瘤细胞自主经历多种转变并获得功能。然而，缺氧诱导的OSCC转变以及缺氧在OSCC转移中的作用仍不清楚。因此，在本研究中，我们旨在阐明缺氧诱导OSCC转移的机制，特别是其对紧密连接（TJ）的影响。
采用逆转录定量实时聚合酶链反应（qRT-PCR）、蛋白质印迹法和免疫组织化学（IHC）检测29例OSCC患者肿瘤组织和癌旁正常组织中缺氧诱导因子1α（HIF-1α）的表达。使用Transwell实验分析用靶向HIF-1α的小干扰（si）RNA处理或在缺氧条件下培养的OSCC细胞系的迁移和侵袭能力。使用肺转移模型评估HIF-1α表达对OSCC细胞体内肿瘤转移的影响。
HIF-1α在OSCC患者中过表达。OSCC转移与OSCC组织中HIF-1α表达相关。缺氧通过调节分隔缺陷蛋白3（Par3）和紧密连接的表达及定位增加OSCC细胞系的迁移和侵袭能力。此外，HIF-1α沉默有效降低OSCC细胞系的侵袭和迁移能力，并通过Par3恢复紧密连接的表达和定位。HIF-1α的表达在体内正向调节OSCC转移。
缺氧通过调节Par3和紧密连接蛋白的表达及定位促进OSCC转移。HIF-1α与OSCC转移呈正相关。最后，HIF-1α表达可调节OSCC中Par3和紧密连接的表达。这一发现可能有助于阐明OSCC转移和进展的分子机制，并开发针对OSCC转移的新诊断和治疗方法。
