Dataset Information

Bidirectional regulation between tumor cell-intrinsic PD-L1 and TGF-β1 in epithelial-to-mesenchymal transition in melanoma.

ABSTRACT:

Background

Transforming growth factor-β1 (TGF-β1) is the predominant form of TGF-β and induces epithelial-to-mesenchymal transition (EMT) in melanoma. Tumor cell-intrinsic programmed death ligand-1 (PD-L1) plays a crucial role in maintenance of the EMT in melanoma. However, the relationship among tumor cell-intrinsic PD-L1, TGF-β1 and EMT is very complicated.

Methods

We investigated the bidirectional regulation between cell-intrinsic PD-L1 and TGF-β1 in melanoma, and explored the role of PD-L1 in TGF-β1-induced EMT and tumor progression.

Results

We found that TGF-β1 upregulated PD-L1 expression in B16-F0 and B16-F10 melanoma cells. Interestingly, PD-L1 also enhanced the intracellular TGF-β1 mRNA levels and induced the secretion of TGF-β1. Immunohistochemical staining revealed that PD-L1 protein expression was co-localized with α-smooth muscle actin (SMA) protein expression in melanoma, suggesting that PD-L1 was associated with EMT. By using shRNA lentivirus to knockdown PD-L1 (PD-L1-shRNA) in melanoma cell lines, we showed that TGF-β1-induced EMT was significantly inhibited in PD-L1-shRNA melanoma cells, which was characterized by the lower fibronectin (FN1) mRNA and higher E-cadherin (CDH1) mRNA levels (both are EMT markers) than that in control. TGF-β1-induced melanoma cell proliferation and migration were also markedly inhibited in PD-L1-shRNA cells. Consistent with the observation in vitro, PD-L1 knockdown inhibited tumor growth and repressed TGF-β1-induced EMT characterized by reduction of FN1 and increase of CDH1 in mouse model.

Conclusions

The present study demonstrated a bidirectional regulation between cell-intrinsic PD-L1 and TGF-β1 in melanoma, which may help in designing promising combinations which include targeting TGF-β1 signaling along with PD-L1.

SUBMITTER: Li Z

PROVIDER: S-EPMC9641118 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Bidirectional regulation between tumor cell-intrinsic PD-L1 and TGF-β1 in epithelial-to-mesenchymal transition in melanoma.

Li Zhen Z Wang Fengdi F Dang Jianzhong J Cheng Fanjun F Zheng Fang F

Translational cancer research 20221001 10

<h4>Background</h4>Transforming growth factor-β1 (TGF-β1) is the predominant form of TGF-β and induces epithelial-to-mesenchymal transition (EMT) in melanoma. Tumor cell-intrinsic programmed death ligand-1 (PD-L1) plays a crucial role in maintenance of the EMT in melanoma. However, the relationship among tumor cell-intrinsic PD-L1, TGF-β1 and EMT is very complicated.<h4>Methods</h4>We investigated the bidirectional regulation between cell-intrinsic PD-L1 and TGF-β1 in melanoma, and explored the ...[more]

PMID: 36388018

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Project description:Epithelial-to-mesenchymal transition (EMT) plays a role in chronic obstructive pulmonary diseases (COPD). Cyclic adenosine monophosphate (cAMP) can inhibit transforming growth factor-β1 (TGF-β1) mediated EMT. Although compartmentalization via A-kinase anchoring proteins (AKAPs) is central to cAMP signaling, functional studies regarding their therapeutic value in the lung EMT process are lacking. The human bronchial epithelial cell line (BEAS-2B) and primary human airway epithelial (pHAE) cells were exposed to TGF-β1. Epithelial (E-cadherin, ZO-1) and mesenchymal markers (collagen Ӏ, α-SMA, fibronectin) were analyzed (mRNA, protein). ELISA measured TGF-β1 release. TGF-β1-sensitive AKAPs Ezrin, AKAP95 and Yotiao were silenced while using siRNA. Cell migration was analyzed by wound healing assay, xCELLigence, Incucyte. Prior to TGF-β1, dibutyryl-cAMP (dbcAMP), fenoterol, rolipram, cilostamide, and forskolin were used to elevate intracellular cAMP. TGF-β1 induced morphological changes, decreased E-cadherin, but increased collagen Ӏ and cell migration, a process that was reversed by the inhibitor of δ/epsilon casein kinase I, PF-670462. TGF-β1 altered (mRNA, protein) expression of Ezrin, AKAP95, and Yotiao. St-Ht31, the AKAP antagonist, decreased E-cadherin (mRNA, protein), but counteracted TGF-β1-induced collagen Ӏ upregulation. Cigarette smoke (CS) increased TGF-β1 release, activated TGF signaling, augmented cell migration, and reduced E-cadherin expression, a process that was blocked by TGF-β1 neutralizing antibody. The silencing of Ezrin, AKAP95, and Yotiao diminished TGF-β1-induced collagen Ӏ expression, as well as TGF-β1-induced cell migration. Fenoterol, rolipram, and cilostamide, in AKAP silenced cells, pointed to distinct cAMP compartments. We conclude that Ezrin, AKAP95, and Yotiao promote TGF-β1-mediated EMT, linked to a TGF-β1 release by CS. AKAP members might define the ability of fenoterol, rolipram, and cilostamide to modulate the EMT process, and they might represent potential relevant targets in the treatment of COPD.

Dataset Information

Bidirectional regulation between tumor cell-intrinsic PD-L1 and TGF-β1 in epithelial-to-mesenchymal transition in melanoma.

Background

Methods

Results

Conclusions

Publications

Bidirectional regulation between tumor cell-intrinsic PD-L1 and TGF-β1 in epithelial-to-mesenchymal transition in melanoma.

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