Dataset Information

Platelet-derived extracellular vesicles inhibit ferroptosis and promote distant metastasis of nasopharyngeal carcinoma by upregulating ITGB3.

ABSTRACT: Nasopharyngeal carcinoma (NPC) is a malignancy with high metastatic and invasive nature. Distant metastasis contributes substantially to treatment failure and mortality in NPC. Platelets are versatile blood cells and the number of platelets is positively associated with the distant metastasis of tumor cells. However, the role and underlying mechanism of platelets responsible for the metastasis of NPC cells remain unclear. Here we found that the distant metastasis of NPC patients was positively correlated with the expression levels of integrin β3 (ITGB3) in platelet-derived extracellular vesicles (EVs) from NPC patients (P-EVs). We further revealed that EVs transfer occurred from platelets to NPC cells, mediating cell-cell communication and inducing the metastasis of NPC cells by upregulating ITGB3 expression. Mechanistically, P-EVs-upregulated ITGB3 increased SLC7A11 expression by enhancing protein stability and activating the MAPK/ERK/ATF4/Nrf2 axis, which suppressed ferroptosis, thereby facilitating the metastasis of NPC cells. NPC xenografts in mouse models further confirmed that P-EVs inhibited the ferroptosis of circulating NPC cells and promoted the distant metastasis of NPC cells. Thus, these findings elucidate a novel role of platelet-derived EVs in NPC metastasis, which not only improves our understanding of platelet-mediated tumor distant metastasis, but also has important implications in diagnosis and treatment of NPC.

SUBMITTER: Li F

PROVIDER: S-EPMC9576525 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Platelet-derived extracellular vesicles inhibit ferroptosis and promote distant metastasis of nasopharyngeal carcinoma by upregulating ITGB3.

Li Fei F Xu Ting T Chen Peiling P Sun Rui R Li Chaoyi C Zhao Xin X Ou Jinxin J Li Jingyao J Liu Taoshu T Zeng Maozhen M Zheng Weizhong W Lin Yunchen Y Yang Le L Li Zecang Z Chen Haisheng H Zhang Qing Q

International journal of biological sciences 20220924 15

Nasopharyngeal carcinoma (NPC) is a malignancy with high metastatic and invasive nature. Distant metastasis contributes substantially to treatment failure and mortality in NPC. Platelets are versatile blood cells and the number of platelets is positively associated with the distant metastasis of tumor cells. However, the role and underlying mechanism of platelets responsible for the metastasis of NPC cells remain unclear. Here we found that the distant metastasis of NPC patients was positively c ...[more]

PMID: 36263165

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Project description:BackgroundCircular RNAs (circRNAs), a new type of noncoding RNA (ncRNA), have been identified as significant gene expression regulators and are involved in cancer progression. However, the roles of circRNAs in nasopharyngeal carcinoma (NPC) remain largely unknown.MethodsHere, the expression profile of circRNAs in a pair of NPC cell lines with different metastatic abilities (S18 and S26 cells) was analyzed by RNA-sequencing. Quantitative reverse transcription PCR was used to detect the expression level of circCRIM1 in NPC cells and tissues. Then, function experiments in vitro and in vivo were performed to evaluate the effects of circCRIM1 on NPC metastasis and EMT. Mechanistically, RNA immunoprecipitation, luciferase reporter assay, pull-down assay with biotinylated miRNA, fluorescent in situ hybridization were performed to confirm the interaction between circCRIM1 and miR-422a in NPC. The clinical value of circCRIM1 was evaluated in NPC metastasis and chemosensitivity.ResultsWe identified that circCRIM1 was upregulated in highly metastatic NPC cells. CircCRIM1 was also overexpressed in NPC tissues with distant metastasis, and its overexpression promoted NPC cell metastasis and EMT. Mechanistically, circCRIM1 competitively bound to miR-422a and prevented the suppressive effects of miR-422a on its target gene FOXQ1, which finally led to NPC metastasis, EMT and docetaxel chemoresistance. Furthermore, high circCRIM1 expression was associated with unfavorable survival in NPC patients. We established a prognostic model based on circCRIM1 expression and N stage that effectively predicted the risk of distant metastasis and treatment response to docetaxel-containing induction chemotherapy in NPC patients.ConclusionsOur findings reveal the critical role of circCRIM1 specifically in promoting NPC metastasis and chemoresistance via a ceRNA mechanism and provide an exploitable biomarker and therapeutic target for prognosis and treatment resistance in NPC patients.

Project description:BackgroundGastric cancer (GC) is a malignant tumor of the digestive tract originating from the epithelial cells of the gastric mucosa, which is highly invasive and heterogeneous, posing a serious threat to human health. In recent years, ferroptosis, as a novel mode of programmed cell death, has shown potential anticancer effects in tumor therapy. Total Astragalus saponins (TAS), a natural product derived from Astragalus membranaceus, have been shown to possess various pharmacological activities, including anticancer effects. This study aimed to investigate the effects of TAS on GC cells, focusing on the mechanism of action of its regulation of the silent information regulator 3 (SIRT3) in inducing ferroptosis in GC cells.MethodsWe treated SGC-7901 cells with TAS at concentrations of 50, 100, and 200 µg/mL. After TAS treatment, the SGC-7901 cells were transfected with a vector designed to knock down SIRT3 expression. We assessed cell proliferation, viability, and apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay), colony formation assay, and flow cytometry. SIRT3 expression was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Fe2+, malondialdehyde (MDA), lactate dehydrogenase (LDH), and superoxide dismutase assay kits were used to detect the level of reactive oxygen species (ROS) by fluorescent probe assay. Western blot was used to detect apoptosis-related proteins and SIRT3 protein expression.ResultsTAS dose-dependently inhibited SGC-7901 cell proliferation and viability (P<0.05) and induced apoptosis (P<0.05). TAS promoted the expression of SIRT3 and ACSL4 proteins (P<0.05), inhibited the expression of SLC7A11 and GPX4 proteins (P<0.05), and induced ferroptosis of SGC-7901 cells (P<0.05). Knockdown of the SIRT3 gene attenuated the effect of TAS treatment on ferroptosis (P<0.05).ConclusionsTAS has therapeutic potential for GC and can effectively inhibit the proliferation and viability of SGC-7901 cells, and the mechanism may be that TAS upregulates SIRT3 to promote the ferroptosis of SGC-7901 cells.

Dataset Information

Platelet-derived extracellular vesicles inhibit ferroptosis and promote distant metastasis of nasopharyngeal carcinoma by upregulating ITGB3.

Publications

Platelet-derived extracellular vesicles inhibit ferroptosis and promote distant metastasis of nasopharyngeal carcinoma by upregulating ITGB3.

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