EBV latent membrane proteins promote hybrid epithelial-mesenchymal and extreme mesenchymal states of nasopharyngeal carcinoma cells for tumorigenicity

Zhu, Nannan; Xu, Xiaoting; Wang, Yan; Zeng, Mu‐Sheng; Yuan, Yan

doi:10.1371/journal.ppat.1009873

Cited by 18 publications

(20 citation statements)

References 46 publications

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“…These findings are comparable to earlier reports that have shown that EBV maintains a type II latency profile in EBV-associated epithelial cancers, such as EBV-associated gastric carcinoma (EBVaGC) and nasopharyngeal carcinoma 28 . Recent studies have reported that LMP2A and LMP1 play a role in epithelial-to-mesenchymal transition in nasopharyngeal carcinoma, thereby, playing a critical role in the onset of cancer 30 , and IHC expression of LMP1 of EBV has been recently reported in the prostate carcinoma samples 31 . Although BZLF1 is an intermediate early gene, few studies have reported its crucial role in establishing and regulating the EBV latency in the host cells 32 , 33 .…”

Section: Discussionmentioning

confidence: 99%

Detection and characterization of latency stage of EBV and histopathological analysis of prostatic adenocarcinoma tissues

Kettab

Sheikh

Fatima

et al. 2022

Sci Rep

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The pathophysiology of prostate cancer involves both genetic and acquired factors, including pathogens, such as viruses. A limited number of studies have shown the presence of Epstein-Barr virus (EBV) in prostate cancer tissues. However, there is a dearth of data exploring EBV latency profile in prostate cancer, and the relationship of EBV with histopathological features of prostate cancer. In this study, prostate cancer and benign prostatic hyperplasia (BPH) samples were screened for the presence of EBV, followed by the characterization of the EBV latency profile and analysis of histopathological parameters in EBV-positive and EBV-negative groups. A conventional PCR strategy was employed using virus-specific primers to screen EBV in 99 formalin-fixed paraffin-embedded (FFPE) prostate cancer and 33 BPH samples received for histopathological analysis during the years 2019–2020. Subsequently, cDNA samples were used in a qPCR array to analyze the expression of EBV latency-associated genes to map the latency profile EBV maintains in the samples. Finally, statistical analyses were performed to determine the correlation between EBV and several histopathological features of the samples. EBV was detected in 39% of prostate cancer and 24% of BPH samples. The histopathological analysis of prostate cancer samples identified all samples as prostatic adenocarcinoma of acinar type, while statistical analyses revealed EBV-positive samples to exhibit significantly higher (p < 0.05) Gleason major and total Gleason scores as compared to EBV-negative samples. In the EBV-positive samples, variable expression patterns of latency-associated genes were observed, where most of the samples exhibited EBV latency II/III-like profiles in prostate cancer, while latency-II-like profiles in BPH samples. This study suggests a high prevalence of EBV in prostate samples, where EBV exhibited latency II/III-like profiles. Furthermore, EBV-positive samples exhibited a higher Gleason score suggesting a possible link between EBV and the onset/progression of prostate cancers. However, future functional studies are required to understand the role of the EBV gene expression profile in the onset/progression of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Detection and characterization of latency stage of EBV and histopathological analysis of prostatic adenocarcinoma tissues

Kettab

Sheikh

Fatima

et al. 2022

Sci Rep

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“…VM, defined by PAS + /CD34 − staining, are tube-like structures that imitate the function of endothelial blood vessels. VM has been described in NPC ( 30 ) and associated with rapid disease progression and poor patient outcomes ( 10 ). Epstein–Barr virus (EBV), plays a crucial role in NPC malignant behaviors, which is also associated with VM formation.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Inhibits Migration and Vasculogenic Mimicry in Nasopharyngeal Carcinoma Via Exosomal MiR-125a

Wan

Zhang

et al. 2022

Front. Oncol.

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Vasculogenic mimicry (VM) is a kind of tumor vasculature providing blood supply for tumor growth, and the formation of VM is independent of vascular endothelial cells. Instead, VM structures are formed by differentiated tumor cells such as nasopharyngeal carcinoma cells. Recently, studies have shown that anti-angiogenic therapy failed to improve the overall survival for patients, namely, nasopharyngeal carcinoma patients. The existence of VM structure is probably one of the reasons for resistance for anti-angiogenic therapy. Therefore, it is important to study the mechanism for VM formation in nasopharyngeal carcinoma. In this study, the bioinformatic analysis revealed that microRNA-125a-3p (miR-125a) was highly expressed in normal nasopharyngeal epithelial tissue than in nasopharyngeal carcinoma. An in vitro study demonstrated that miR-125a plays an inhibitory role in nasopharyngeal carcinoma cell migration and VM formation, and further studies confirmed that TAZ is a direct downstream target for miR-125a. On this basis, we artificially engineered human mesenchymal stem cells (MSCs) to generate exosomes with high miR-125a expression. Treatment with these miR-125a-over-expressing exosomes attenuated the migration and VM formation in nasopharyngeal carcinoma cells. In addition, the inhibitory role of these exosomes on VM formation and migration in nasopharyngeal carcinoma was also confirmed in vivo. Overall, the current study shows that MSCs can be utilized to generate exosomes with high miR-125a level, which could be therapeutic nanoparticles targeting VM formation in nasopharyngeal carcinoma and used as a complement to anti-angiogenic therapy in the future.

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“…Interestingly, as epithelial or carcinoma cells progress toward high-grade malignancy, they often activate epithelial-to-mesenchymal transition (EMT). It has been reported recently that in breast cancer and nasopharyngeal carcinoma, the cells residing in intermediate hybrid E/M (baring both epithelial and mesenchymal cell markers) state along the epithelial-to-mesenchymal spectrum exhibit the highest tumorigenicity [ 20 , 21 ]. Therefore, it is likely that acquisition of a hybrid E/M state, regardless of MEndT or EMT process, is essential for tumorigenicity of both carcinomas and sarcomas.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, MEndT, like its reverse process EndMT, is not a binary switch but a dynamic transition, which generates many intermediate phenotypic states arrayed along the mesenchymal (M)-to-endothelial (E) spectrum including mesenchymal-like (M), endothelial-like (E), and hybrid M/E states. Studies suggested that tumor cells staying in different stages have different roles in tumor progression [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus vFLIP promotes MEndT to generate hybrid M/E state for tumorigenesis

et al. 2021

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Kaposi sarcoma (KS) is an angioproliferative and invasive tumor caused by Kaposi sarcoma-associated herpesvirus (KSHV). The cellular origin of KS tumor cells remains contentious. Recently, evidence has accrued indicating that KS may arise from KSHV-infected mesenchymal stem cells (MSCs) through mesenchymal-to-endothelial transition (MEndT), but the transformation process has been largely unknown. In this study, we investigated the KSHV-mediated MEndT process and found that KSHV infection rendered MSCs incomplete endothelial lineage differentiation and formed hybrid mesenchymal/endothelial (M/E) state cells characterized by simultaneous expression of mesenchymal markers Nestin/PDGFRA/α-SAM and endothelial markers CD31/PDPN/VEGFR2. The hybrid M/E cells have acquired tumorigenic phenotypes in vitro and the potential to form KS-like lesions after being transplanted in mice under renal capsules. These results suggest a homology of KSHV-infected MSCs with Kaposi sarcoma where proliferating KS spindle-shaped cells and the cells that line KS-specific aberrant vessels were also found to exhibit the hybrid M/E state. Furthermore, the genetic analysis identified KSHV-encoded FLICE inhibitory protein (vFLIP) as a crucial regulator controlling KSHV-induced MEndT and generating hybrid M/E state cells for tumorigenesis. Overall, KSHV-mediated MEndT that transforms MSCs to tumorigenic hybrid M/E state cells driven by vFLIP is an essential event in Kaposi sarcomagenesis.

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EBV latent membrane proteins promote hybrid epithelial-mesenchymal and extreme mesenchymal states of nasopharyngeal carcinoma cells for tumorigenicity

Cited by 18 publications

References 46 publications

Detection and characterization of latency stage of EBV and histopathological analysis of prostatic adenocarcinoma tissues

Detection and characterization of latency stage of EBV and histopathological analysis of prostatic adenocarcinoma tissues

Mesenchymal Stem Cells Inhibits Migration and Vasculogenic Mimicry in Nasopharyngeal Carcinoma Via Exosomal MiR-125a

Kaposi’s sarcoma-associated herpesvirus vFLIP promotes MEndT to generate hybrid M/E state for tumorigenesis

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