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LMP1 promotes nasopharyngeal carcinoma metastasis through NTRK2-mediated anoikis resistance.

ABSTRACT: Anoikis resistance is an important mechanism that mediates tumor metastasis. Studies have found that Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) promotes the occurrence, development, and metastasis of nasopharyngeal carcinoma (NPC). However, the related mechanism, especially whether LMP1 is involved in NPC metastasis through anoikis resistance, has not yet been elucidated. In present study, we showed that LMP1 enhanced the ability of NPC cells to resist anoikis by upregulating neurotrophic tyrosine kinase receptor type 2 (NTRK2 or TrkB) expression through NF-?B signaling and promoted the migration and invasion of NPC cells. After knockdown of NTRK2, the p-ERK and p-AKT in NPC cells were inhibited, and twist expression was further reduced, resulting in upregulation of E-cadherin expression and downregulation of vimentin expression. Subsequently, the results of a xenograft experiment showed that inhibiting NTRK2 could reduce LMP1-mediated NPC metastasis in vivo. In summary, these findings demonstrated that EBV-LMP1 upregulates twist expression to promote epithelial-mesenchymal transition (EMT) through the NTRK2-mediated AKT/ERK signaling pathway, thus mediating anoikis resistance and promoting NPC metastasis. These data will provide new molecular markers and potential targets for NPC metastasis.

SUBMITTER: Li Z

PROVIDER: S-EPMC7407352 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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LMP1 promotes nasopharyngeal carcinoma metastasis through NTRK2-mediated anoikis resistance.

Li Zhilan Z Zhou Zhuan Z Wu Xia X Zhou Qin Q Liao Chaoliang C Liu Ying Y Li Dan D Shen Liangfang L Feng Deyun D Yang Lifang L

American journal of cancer research 20200701 7

Anoikis resistance is an important mechanism that mediates tumor metastasis. Studies have found that Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) promotes the occurrence, development, and metastasis of nasopharyngeal carcinoma (NPC). However, the related mechanism, especially whether LMP1 is involved in NPC metastasis through anoikis resistance, has not yet been elucidated. In present study, we showed that LMP1 enhanced the ability of NPC cells to resist anoikis by upregulat ...[more]

PMID: 32775002

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Project description:BackgroundEpstein-Barr virus (EBV) is the first discovered human tumor virus that is associated with a variety of malignancies of both lymphoid and epithelial origin including nasopharyngeal carcinoma (NPC). The EBV-encoded latent membrane protein 1 (LMP1) has been well-defined as a potent oncogenic protein, which is intimately correlated with NPC pathogenesis. Anoikis is considered to be a physiological barrier to metastasis, and avoiding anoikis is a major hallmark of metastasis. However, the role of LMP1 in anoikis-resistance and metastasis of NPC has not been fully identified.MethodsTrypan blue staining, colony formation assay, flow cytometry, and TUNEL staining, as well as the detection of apoptosis and anoikis resistance-related markers was applied to evaluate the anoikis-resistant capability of NPC cells cultured in ultra-low adhesion condition. Co-immunoprecipitation (Co-IP) experiment was performed to determine the interaction among LMP1, PRMT1 and PGC-1α. Ex vivo ubiquitination assay was used to detect the ubiquitination level of PGC-1α. Anoikis- resistant LMP1-positive NPC cell lines were established and applied for the xenograft and metastatic animal experiments.ResultsOur current findings reveal the role of LMP1-stabilized peroxisome proliferator activated receptor coactivator-1a (PGC-1α) in anoikis resistance and immune escape to support the invasion and metastasis of NPC. Mechanistically, LMP1 enhances PGC-1α protein stability by promoting the interaction between arginine methyltransferase 1 (PRMT1) and PGC-1α to elevate the methylation modification of PGC-1α, thus endowing NPC cells with anoikis-resistance. Meanwhile, PGC-1α mediates the immune escape induced by LMP1 by coactivating with STAT3 to transcriptionally up-regulate PD-L1 expression.ConclusionOur work provides insights into how virus-encoded proteins recruit and interact with host regulatory elements to facilitate the malignant progression of NPC. Therefore, targeting PGC-1α or PRMT1-PGC-1α interaction might be exploited for therapeutic gain for EBV-associated malignancies.

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LMP1 promotes nasopharyngeal carcinoma metastasis through NTRK2-mediated anoikis resistance.

Publications

LMP1 promotes nasopharyngeal carcinoma metastasis through NTRK2-mediated anoikis resistance.

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