RESUMO
Our previous studies have shown that upregulation of SLC7A1 in epithelial ovarian cancer (EOC) tumor cells significantly increases cancer cell proliferation, migration, and cisplatin resistance; however, the molecular mechanism by which SLC7A1 functions in EOC remains unknown. In later studies, we found that SLC7A1 is also highly expressed in the interstitial portion of high-grade serous ovarian cancer (HGSOC), but the significance of this high expression in the interstitial remains unclear. Here, we showed the Interstitial high expression of SLC7A1 in HGSOC by immunohistochemistry. SLC7A1 enriched in cancer-associated fibroblasts (CAFs) was upregulated by TGF-ß1. Transwell assay, scratch assay, cck8 assay and cell adhesion assay showed that SLC7A1 highly expressed in CAFs promoted tumor cells invasion, migration and metastasis in vitro. The effect of SLC7A1 on MAPK and EMT pathway proteins in ovarian cancer (OC) was verified by RNA sequencing and western blotting. Overexpression of SLC7A1 in OC is involved in MAPK/ ERK pathway and EMT. In general, in HGSOC, CAFs overexpressing SLC7A1 supported the migration and invasion of tumor cells; SLC7A1 is highly expressed in ovarian cancer and is involved in ERK phosphorylation and EMT signaling in MAPK signaling pathway. This suggests that SLC7A1 may be a potential therapeutic target for OC metastasis.
Assuntos
Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Transportador 1 de Aminoácidos Neutros Grandes , Neoplasias Ovarianas , Feminino , Humanos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/genética , Progressão da Doença , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/genética , Sistema de Sinalização das MAP Quinases , Gradação de Tumores , Invasividade Neoplásica , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The recent use of PARP inhibitors (PARPi) in the maintenance treatment of ovarian tumor has significantly improved the survival rates of cancer patients. However, the current oral administration of PARP inhibitors fails to realize optimal therapeutic effects due to the low bioavailability in cancerous tissues, and often leads to a range of systemic adverse effects including hematologic toxicities, digestive system reactions, and neurotoxicities. Therefore, the demand for an advanced drug delivery system that can ensure effective drug administration while minimizing these unfavorable reactions is pressing. Injectable hydrogel emerges as a promising solution for local administration with the capability of sustainable drug release. In this study, we developed an injectable hydrogel made from aminated hyaluronic acid and aldehyde-functionalized pluronic127 via Schiff base reaction. This hydrogel exhibits excellent injectability with short gelation time and remarkable self-healing ability, and is applied to load niraparib. The drug-loaded hydrogel (HP@Nir hydrogel) releases drugs sustainably as tested in vitro as well as displays significant anti-proliferation and anti-migratory properties on human epithelial ovarian cancer cell line. Notably, HP@Nir hydrogel effectively suppresses the growth of ovarian cancer, without significant adverse reactions as demonstrated in animal studies. Additionally, the developed hydrogel is gradually degraded in vivo for around 20 d, while maintaining good biocompatibility. Overall, the injectable hydrogel loaded with niraparib provides a secure and efficient strategy for the treatment and management of ovarian cancer.
Assuntos
Ácido Hialurônico , Hidrogéis , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Feminino , Hidrogéis/química , Ácido Hialurônico/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Humanos , Animais , Linhagem Celular Tumoral , Camundongos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Proliferação de Células/efeitos dos fármacos , Injeções , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Movimento Celular/efeitos dos fármacosRESUMO
Amino acids are essential for the survival of all living organisms and living cells. Amino acid transporters mediate the transport and absorption of amino acids, and the dysfunction of these proteins can induce human diseases. Cationic amino acid transporters (CAT family, SLC7A1-4, and SLC7A14) are considered to be a group of transmembrane transporters, of which SLC7A1-3 are essential for arginine transport in mammals. Numerous studies have shown that CAT family-mediated arginine transport is involved in signal crosstalk between malignant tumor cells and immune cells, especially T cells. The modulation of extracellular arginine concentration has entered a number of clinical trials and achieved certain therapeutic effects. Here, we review the role of CAT family on tumor cells and immune infiltrating cells in malignant tumors and explore the therapeutic strategies to interfere with extracellular arginine concentration, to elaborate its application prospects. CAT family members may be used as biomarkers for certain cancer entities and might be included in new ideas for immunotherapy of malignant tumors.
