2. Academic Validation
  3. Anoikis resistance and immune escape mediated by Epstein-Barr virus-encoded latent membrane protein 1-induced stabilization of PGC-1α promotes invasion and metastasis of nasopharyngeal carcinoma

Anoikis resistance and immune escape mediated by Epstein-Barr virus-encoded latent membrane protein 1-induced stabilization of PGC-1α promotes invasion and metastasis of nasopharyngeal carcinoma

  • J Exp Clin Cancer Res. 2023 Oct 7;42(1):261. doi: 10.1186/s13046-023-02835-6.
Chaoliang Liao # 1 2 3,  Min Li # 4,  Xue Chen # 5,  Chenpeng Tang 1 2,  Jing Quan 1 2,  Ann M Bode 6,  Ya Cao 2,  Xiangjian Luo 7 8 9
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, PR China.
  • 2 Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China.
  • 3 Department of Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545007, PR China.
  • 4 Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, PR China.
  • 5 Early Clinical Trial Center, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, PR China.
  • 6 The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
  • 7 NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, PR China. luocsu@csu.edu.cn.
  • 8 Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China. luocsu@csu.edu.cn.
  • 9 National Health Commission (NHC) Key Laboratory of Nanobiological Technology, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, PR China. luocsu@csu.edu.cn.
  • # Contributed equally.
PMID: 37803433 DOI: 10.1186/s13046-023-02835-6
Abstract

Background: Epstein-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.

Methods: Trypan 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.

Results: Our 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.

Conclusion: Our 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.

Keywords

Anoikis resistance; Immune escape; LMP1; Nasopharyngeal carcinoma; PGC-1α.

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