Epstein-Barr Virus Infection in Lung Cancer: Insights and Perspectives

Abstract

Lung cancer (LC) is the leading cause of cancer death worldwide. Tobacco smoke is the most frequent risk factor etiologically associated with LC, although exposures to other environmental factors such as arsenic, radon or asbestos are also involved. Additionally, the involvement of some viral infections such as high-risk human papillomaviruses (HR-HPVs), Merkel cell polyomavirus (MCPyV), Jaagsiekte Sheep Retrovirus (JSRV), John Cunningham Virus (JCV), and Epstein-Barr virus (EBV) has been suggested in LC, though an etiological relationship has not yet been established. EBV is a ubiquitous gamma herpesvirus causing persistent infections and some lymphoid and epithelial tumors. Since EBV is heterogeneously detected in LCs from different parts of the world, in this review we address the epidemiological and experimental evidence of a potential role of EBV. Considering this evidence, we propose mechanisms potentially involved in EBV-associated lung carcinogenesis. Additional studies are warranted to dissect the role of EBV in this very frequent malignancy.

Keywords: Epstein–Barr virus; cancer; lung.

Figure 1

Epstein–Barr virus genome organization. (A) EBV lineal genome. (B) EBV circular genome representation.

Figure 2

EBV proteins in epithelial tumors and their functions in cancer progression. This model suggests initial damage that can be caused by environmental pollutants (xenobiotics). Next, the epithelial injury allows the EBV latency establishment with the subsequent EBV protein expression. Finally, the EBV protein expression allows the activation of different cell signaling pathways such as Wnt/β-catenin, NF-κB, JNK, JAK/STAT, EGFR/MAPK, and PI3K/AKT.

Figure 3

CD21 (CR2) transcript expression in LC (TCGA, n = 1325) according to sample type and histological classification of tumors (***: p < 0.001 for both; Welch’s t-test). The expression of CD21 was increased 1.8-fold in malignant tumors (1323 primary tumors and two recurrences) and increased 1.3-fold in lung AdC compared to normal tissue and lung SQC. Raw data were extracted from University of California, Santa Cruz (ena.ucsc.edu). UCSC Xena functional genomics explorer (https://xenabrowser.net) [200].

Figure 4

Hypothetical mechanism of interaction between cigarette smoke components or environmental contaminants with EBV in lung epithelial cells. This interaction involves local immunosuppression facilitating EBV infection, latency establishment, and latent/lytic switch activation.