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Fatty acid synthase contributes to epithelial-mesenchymal transition and invasion of salivary adenoid cystic carcinoma through PRRX1/Wnt/?-catenin pathway.

ABSTRACT: Fatty acid synthase (FASN) has been shown to be selectively up-regulated in cancer cells to drive the development of cancer. However, the role and associated mechanism of FASN in regulating the malignant progression of salivary adenoid cystic carcinoma (SACC) still remains unclear. In this study, we demonstrated that FASN inhibition attenuated invasion, metastasis and EMT of SACC cells as well as the expression ofPRRX1, ZEB1, Twist, Slug and Snail, among which the level of PRRX1 changed the most obviously. Overexpression of PRRX1 restored migration and invasion in FASN knockdown cells, indicating that PRRX1 is an important downstream target of FASN signalling. Levels of cyclin D1 and c-Myc, targets of Wnt/?-catenin pathway, were significantly decreased by FASN silencing and restored by PRRX1 overexpression. In addition, FASN expression was positively associated with metastasis and poor prognosis of SACC patients as well as with the expression of PRRX1, cyclin D1 and c-Myc in SACC tissues. Our findings revealed that FASN in SACC progression may induce EMT in a PRRX1/Wnt/?-catenin dependent manner.

SUBMITTER: Zhang WL

PROVIDER: S-EPMC7576276 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Fatty acid synthase contributes to epithelial-mesenchymal transition and invasion of salivary adenoid cystic carcinoma through PRRX1/Wnt/β-catenin pathway.

Zhang Wei-Long WL Wang Sha-Sha SS Jiang Ya-Ping YP Liu Yan Y Yu Xiang-Hua XH Wu Jing-Biao JB Wang Ke K Pang Xin X Liao Peng P Liang Xin-Hua XH Liang Xin-Hua XH Tang Ya-Ling YL

Journal of cellular and molecular medicine 20200820 19

Fatty acid synthase (FASN) has been shown to be selectively up-regulated in cancer cells to drive the development of cancer. However, the role and associated mechanism of FASN in regulating the malignant progression of salivary adenoid cystic carcinoma (SACC) still remains unclear. In this study, we demonstrated that FASN inhibition attenuated invasion, metastasis and EMT of SACC cells as well as the expression ofPRRX1, ZEB1, Twist, Slug and Snail, among which the level of PRRX1 changed the most ...[more]

PMID: 32820613

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Project description:Purpose:Perineural invasion (PNI) is reported to correlate with local recurrence and poor prognosis of salivary adenoid cystic carcinoma (SACC). However, the pathogenesis of PNI remains unclear. The aims of this study were to investigate the correlation between sympathetic innervation and SACC PNI and to elucidate how the sympathetic neurotransmitter norepinephrine (NE) regulates the PNI process. Materials and methods:Sympathetic innervation and ?2-adrenergic receptor (?2-AR) expression in SACC tissues were evaluated by immunohistochemistry. The NE concentrations in SACC tissues and dorsal root ganglia (DRG) coculture models were measured by ELISA. ?2-AR expression in SACC cells was detected by performing quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence assay. SACC cells were treated with NE, the nonselective ?-AR blocker phentolamine, the ?2-AR antagonist ICI118,551, or were transfected with ?2-AR small interfering RNA (siRNA). Proliferation was evaluated in methyl thiazolyl tetrazolium assay, and migration was evaluated in Transwell assay and wound-healing assay. PNI was tested through both Transwell assay and a DRG coculture model. The expressions of epithelial-mesenchymal transition (EMT) markers and matrix metalloproteinases (MMPs) were measured by performing qRT-PCR and Western blot assay. Results:Sympathetic innervation and ?2-AR were highly distributed in SACC tissues and correlated positively with PNI (P=0.035 and P=0.003, respectively). The sympathetic neurotransmitter NE was overexpressed in SACC tissues and DRG coculture models. Exogenously added NE promoted proliferation, migration, and PNI of SACC cells via ?2-AR activation. NE/?2-AR signaling may promote proliferation, migration, and PNI by inducing EMT and upregulating MMPs. However, ?2-AR inhibition with either an antagonist or siRNA abrogated NE-induced PNI. Conclusion:Collectively, our findings reveal the supportive role of sympathetic innervation in the pathogenesis of SACC PNI and suggest ?2-AR as a potential therapeutic target for treating PNI in SACC.

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Fatty acid synthase contributes to epithelial-mesenchymal transition and invasion of salivary adenoid cystic carcinoma through PRRX1/Wnt/?-catenin pathway.

Publications

Fatty acid synthase contributes to epithelial-mesenchymal transition and invasion of salivary adenoid cystic carcinoma through PRRX1/Wnt/β-catenin pathway.

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