轉譯因子GATA3在頭頸癌中的角色

Abstract

GATA3對於T細胞及許多人體器官的分化佔有重要的地位，但是在人類癌症的角色尚未被研究。本研究發現，GATA3在頭頸部鱗狀上皮癌有過量的表現，並且和病人較差的存活率及臨床預後因子有關。在小鼠實驗中，GATA3的表現會促進腫瘤生長及轉移。在頭頸癌及黑色素瘤細胞中，GATA3會促進細胞爬行及侵犯，在低氧環境中，這些惡行表型會更明顯。機轉上，GATA3和HIF-1α 有相互作用，並藉此競爭掉RACK1，此種作用，會使HIF-1α不被蛋白酶體代謝而更穩定。GATA3所造成的細胞侵入，可以藉由減少HIF-1α的表現或是過度表現N-HIF-1α (第1-401胺基酸) 而被抑制。這些研究指出，GATA3除了作為轉錄因子，也可藉由調控其HIF-1α穩定性，進而影響癌細胞的侵入。

GATA3 is pivotal in maturation and differentiation of T helper 2 cells as well as many human organs. However, the clinical significance and roles of transcription factor GATA3 in human cancers remain elusive. Here, we report that GATA3 is overexpressed in head and neck squamous cell carcinoma (HNSCC) compared with adjacent non-tumor mucosa. GATA3 expression positively correlates with metastasis and is an independent predictor for poor disease-free survival. In murine models, GATA3 promotes tumor growth and metastasis. In HNSCC cells, GATA3 enhances migration and invasion under normoxia and these invasive behaviors are further increased by hypoxia. Mechanistically, GATA3 physically interacts with and stabilizes hypoxia inducible factor (HIF)-1α by competing activated protein kinase C 1 (RACK1) binding, hence regulating HIF-1 target genes under hypoxia. Moreover, the GATA3-mediated invasiveness can be significantly reversed by HIF-1α knockdown or expression of the N-terminal part of HIF-1α (aa 1-401), suggesting a critical role of HIF-1α in the underlying mechanism. These findings demonstrate a novel function of GATA3 as a HIF-1α regulator to enhance cancer invasiveness and support the GATA3/HIF-1α axis as a new therapeutic target for HNSCC treatment.