Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer.
Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer.
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DOI：
10.1002/adbi.202200190
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发表时间：
2022-09
期刊：
影响因子：
3.7
通讯作者：
Viet, Chi T.
中科院分区：
文献类型：
--
作者：
Doan, Coleen;Aouizerat, Bradley E.;Ye, Yi;Dang, Dongmin;Asam, Kesava;Bhattacharya, Aditi;Howard, Timothy;Patel, Yogin K.;Viet, Dan T.;Figueroa, Johnny D.;Zhong, Jiang F.;Thomas, Carissa M.;Morlandt, Anthony B.;Yu, Gary;Callahan, Nicholas F.;Allen, Clint T.;Grandhi, Anupama;Herford, Alan S.;Walker, Paul C.;Nguyen, Khanh;Kidd, Stephanie C.;Lee, Steve C.;Inman, Jared C.;Slater, Jason M.;Viet, Chi T.
口腔鳞状细胞癌（OSCC）患者由于转移或局部复发而生存率低，这两个过程都是由神经浸润（PNI）促进的。OSCC的PNI发生率高于其他癌症亚型，PNI存在于80%的肿瘤中。尽管PNI对口腔癌预后和疼痛有影响，但我们对驱动PNI的基因知之甚少，而PNI反过来又驱动疼痛、侵袭和转移。在这项研究中，我们利用临床数据，临床前和体外模型来阐明神经营养因子在口腔鳞癌转移，PNI和疼痛中的作用。我们在伴有转移、PNI或疼痛的OSCC患者中的表达数据表明神经营养因子基因失调。我们专注于TrkA和NGFR，这两种受体被神经生长因子（NGF）激活，神经生长因子是一种在口腔鳞癌中高水平表达的神经营养因子。我们证明，有针对性地敲低这两种受体抑制增殖和侵袭在体外和临床前模型的口腔鳞状细胞癌，转移，PNI和疼痛。我们进一步确定单独的TrkA敲低抑制热痛觉过敏，而单独的NGFR敲低抑制机械性异常性疼痛。总的来说，我们的研究结果强调了口腔鳞癌在转移、PNI和疼痛中吸收神经营养因子通路的不同成分的能力。在这项研究中，我们证明了神经营养因子基因通路在口腔鳞状细胞癌（OSCC）转移，神经浸润（PNI）和疼痛患者中失调。shRNA介导的神经营养因子受体TrkA和NGFR的敲低抑制体外OSCC增殖，以及临床前OSCC模型中的转移、PNI和疼痛。
Oral squamous cell carcinoma (OSCC) patients suffer from poor survival due to metastasis or locoregional recurrence, processes that are both facilitated by perineural invasion (PNI). OSCC has higher rates of PNI than other cancer subtypes, with PNI present in 80% of tumors. Despite the impact of PNI on oral cancer prognosis and pain we know little about the genes that drive PNI, which in turn drive pain, invasion and metastasis. In this study we leverage clinical data, preclinical and in vitro models to elucidate the role of neurotrophins in OSCC metastasis, PNI, and pain. Our expression data in OSCC patients with metastasis, PNI, or pain demonstrate dysregulation of neurotrophin genes. We focus on TrkA and NGFR, two receptors that are activated by nerve growth factor (NGF), a neurotrophin expressed at high levels in OSCC. We demonstrate that targeted knockdown of these two receptors inhibits proliferation and invasion in an in vitro and preclinical model of OSCC, and metastasis, PNI and pain. We further determine that TrkA knockdown alone inhibits thermal hyperalgesia, whereas NGFR knockdown alone inhibits mechanical allodynia. Collectively our results highlight the ability of OSCC to co-opt different components of the neurotrophin pathway in metastasis, PNI, and pain. In this study, we demonstrate that the neurotrophin gene pathway is dysregulated in oral squamous cell carcinoma (OSCC) patients with metastasis, perineural invasion (PNI), and pain. shRNA-mediated knockdown of the neurotrophin receptors, TrkA and NGFR, inhibits OSCC proliferation in vitro, and metastasis, PNI and pain in a preclinical OSCC model.
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