MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma.
MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma.
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DOI：
10.18632/oncoscience.99
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Dasgupta S
中科院分区：
文献类型：
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作者：
Oyesanya RA;Bhatia S;Menezes ME;Dumur CI;Singh KP;Bae S;Troyer DA;Wells RB;Sauter ER;Sidransky D;Fisher PB;Semmes OJ;Dasgupta S
头颈部鳞状细胞癌（HNSCC）分化不良和侵袭的分子调控机制尚不清楚。在本研究中，我们的目的是确定MDA-9/Syntenin，转移相关分子在HNSCC肿瘤发生中的作用。MDA-9/Syntenin表达升高在67%（54/81）的原发性HNSCC肿瘤（p=0.001-0.002）和69%（9/13）的肿瘤前组织（p=0.02-0.03）中是明显的。MDA-9/Syntenin过表达与肿瘤分期（p=0.001）、分级（p=0.001）和淋巴结转移（p=0.0001）相关。在3个低分化HNSCC细胞系中沉默MDA-9/Syntenin诱导鳞状上皮细胞分化，破坏血管生成，并在体外和体内减少肿瘤生长。我们证实SPRR 1B和VEGFR 1分别是MDA-9/Syntenin影响HNSCC分化和血管生成的关键分子靶点。MDA-9/Syntenin通过PDZ 1结构域破坏SPRR 1B表达相互作用，并在体外和体内改变VEGFR 1表达。VEGFR 1与MDA-9/Syntenin共定位于HNSCC细胞系和原发性肿瘤中。在MDA-9/Syntenin耗尽的细胞中，生长调节分子CyclinD 1、CDK 4、STAT 3、PI 3 K和CTNNB 1的下调也是明显的，在永生化口腔上皮细胞中MDA-9/Syntenin过表达后，这种下调被逆转。我们的研究结果表明，早期诱导MDA-9/Syntenin表达影响HNSCC的进展，并应进一步评估潜在的生物标志物的发展。
Little is known about the molecular pathways regulating poor differentiation and invasion of head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to determine the role of MDA-9/Syntenin, a metastasis associated molecule in HNSCC tumorigenesis. Elevated MDA-9/Syntenin expression was evident in 67% (54/81) primary HNSCC tumors (p=0.001-0.002) and 69% (9/13) pre-neoplastic tissues (p=0.02-0.03). MDA-9/Syntenin overexpression was associated with the stage (p=0.001), grade (p=0.001) and lymph node metastasis (p=0.0001). Silencing of MDA-9/Syntenin in 3 poorly differentiated HNSCC cell lines induced squamous epithelial cell differentiation, disrupted angiogenesis and reduced tumor growth in vitro and in vivo. We confirmed SPRR1B and VEGFR1 as the key molecular targets of MDA-9/Syntenin on influencing HNSCC differentiation and angiogenesis respectively. MDA-9/Syntenin disrupted SPRR1B expression interacting through its PDZ1 domain and altered VEGFR1 expression in vitro and in vivo. VEGFR1 co-localized with MDA-9/Syntenin in HNSCC cell lines and primary tumor. Downregulation of growth regulatory molecules CyclinD1, CDK4, STAT3, PI3K and CTNNB1 was also evident in the MDA-9/Syntenin depleted cells, which was reversed following over-expression of MDA-9/Syntenin in immortalized oral epithelial cells. Our results suggest that early induction of MDA-9/Syntenin expression influences HNSCC progression and should be further evaluated for potential biomarker development.