1. Academic Validation
  2. Programmed death-ligand 1 signaling and expression are reversible by lycopene via PI3K/AKT and Raf/MEK/ERK pathways in tongue squamous cell carcinoma

Programmed death-ligand 1 signaling and expression are reversible by lycopene via PI3K/AKT and Raf/MEK/ERK pathways in tongue squamous cell carcinoma

  • Genes Nutr. 2022 Feb 14;17(1):3. doi: 10.1186/s12263-022-00705-y.
Mingjing Peng 1 2 Songqing Fan 3 Junjun Li 4 Xiao Zhou 4 Qianjin Liao 4 Faqing Tang 4 Wei Liu 5 6
Affiliations

Affiliations

  • 1 Central South University, Xiangya Medical School affiliated Cancer Hospital, Hunan Cancer Hospital, Changsha, 410073, Hunan, People's Republic of China.
  • 2 Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, Hunan, People's Republic of China.
  • 3 Department of Pathology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
  • 4 Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410073, Changsha, People's Republic of China.
  • 5 Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410073, Changsha, People's Republic of China. [email protected].
  • 6 Post-doctorate of Pathology,Second Xiangya Hospital, Central South University, Hunan, Changsha, People's Republic of China. [email protected].
Abstract

Background: Cancer therapy targeting programmed death receptor-1 (PD-1 or CD279) or programmed death-ligand 1 (PD-L1 or CD274) gives hope to Tongue Squamous Cell Carcinoma (TSCC) treatment. However, the tumor-intrinsic mechanism of PD-L1 is not fully elucidated in TSCC. On the other hand, lycopene showed antitumor effects and chemotherapy/radiotherapy-enhancing effects by mechanisms closely correlated with PD-L1.

Purpose: We aimed to explore whether the mechanisms of PD-L1 signaling and regulation are reversible by lycopene treatment in TSCC.

Methods: We collected TSCC tissues and normal tissues for assessment of PD-L1 expression by immunohistochemical technique and western blotting. We measured the expression of PD-L1 in three TSCC cell lines and constructed cell lines with knockdown and overexpression of PD-L1. Then, we measured the proliferation by CCK-8 assay, migration and invasion by Transwell assay, and Apoptosis by TUNEL assay in five groups with treatment of blank control, negative control with vector transfection, PD-L1 knockdown/overexpression, 4 μM lycopene, and combined 4 μM lycopene and PD-L1 knockdown/overexpression. We also systematically analyzed the PD-L1 constitutive signaling pathways and their effect EMT pathways. In order to bring out the mechanism underlying PI3K/Akt depressing Raf/MEK/ERK, we used PI3K Inhibitor LY294002.

Results: We detected significant PD-L1 upregulation in biopsies by western blot and immunohistochemistry. Our study demonstrated that PD-L1 upregulation elevated IGF-1R to activate the PI3K/Akt pathway but inactivated the Raf/MEK/ERK pathway in TSCC cell line CAL27, while PD-L1 knockdown decreased IGF-1R to inactivate both PI3K/Akt and Raf/MEK/ERK pathways in cell line SCC9, to increase/decrease p-FOXOs and decrease/increase p-GSK-3β, producing further changes in EMT, proliferation, migration, invasion, and Apoptosis. Lycopene reversed PD-L1 signaling and expression by mechanisms opposite to PD-L1 upregulation but similar to PD-L1 knockdown.

Conclusion: Taken together, this study firstly confirmed PD-L1 expression and signaling are reversible by lycopene via PI3K/Akt and Raf/MEK/ERK pathways in TSCC. Our study provides a sounder basis for comprehending PD-L1 signaling and expression and prevention and treatment of TSCC.

Keywords

Apoptosis; EMT; Lycopene; PD-L1; Proliferation; TSCC.

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