Hypoxia disrupt tight junctions and promote metastasis of oral squamous cell carcinoma via loss of par3

Shihyun Kim; Suyeon Park; Eun-Hye Moon; Gi Jin Kim; Jongho Choi

doi:10.1186/s12935-023-02924-8

Hypoxia disrupt tight junctions and promote metastasis of oral squamous cell carcinoma via loss of par3

Cancer Cell Int. 2023 Apr 24;23(1):79. doi: 10.1186/s12935-023-02924-8.

Authors

Shihyun Kim¹, Suyeon Park¹, Eun-Hye Moon², Gi Jin Kim³, Jongho Choi⁴

Affiliations

¹ Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea.
² Institute of Lee Gil Ya Cancer and Diabetes, Gachon University, Incheon, 21999, Republic of Korea.
³ Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea.
⁴ Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea. jhchoi@gwnu.ac.kr.

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: HIF-1α; Hypoxia; Oral squamous cell carcinoma; Par3; TJs.

Abstract

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