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Page 328 Jiang et al. J Transl Genet Genom 2021;5:323-40 https://dx.doi.org/10.20517/jtgg.2021.21

According to the above studies, the dysregulation of JAK/STAT pathway is highly prevalent in NKTCL and
may play an important role in the pathogenesis of the disease through diverse mechanisms. JAK3 and
STAT3 are two latent therapeutic targets, and their inhibitors might have promising results in the treatment
of NKTCL patients. In the future, the feasibility and safety of the treatment strategy targeting the
deregulated JAK/STAT pathway should be further studied.

NF- B signaling pathway
NF-κB has critical biological implications in the growth, proliferation, differentiation, and regulation of
[53]
lymphocytes that are regarded as vital pathogenetic factors in lymphomas . Expression of RelA and cRel,
two canonical molecules of the NF-κB pathway in NKTCL, suggested abnormal activation of canonical
[13]
NF-κB pathway . In another study, RelB, a molecule of the alternative NF-κB pathway, was positive in
NKTCL tumor tissue. The differential expression of molecules might imply constitutive activation of NF-κB
pathway in NKTCL and that it might be involved in the development of the disease through various
[29]
mechanisms . Interestingly, EBV-encoded latent membrane protein 1 (LMP1) induced aberrant
expression of eukaryotic translation initiation factor 4E , survivin , and PD-L1 to participate in
[55]
[56]
[54]
NKTCL progression via NK-κB pathway, which further implied that targeting this carcinogenic pathway
might have potent clinical value for NKTCL patients.
PDGF signaling pathway
Platelet-derived growth factor alpha (PDGFRα) is overexpressed in NKTCL, and imatinib mesylate, a
PDGFR inhibitor, has a limited effect on the growth of the PDGFRα + NKTCL cell line, which indicates that
the PDGF pathway was involved in the pathogenic process of NKTCL. However, there was still no evidence
explaining the dysregulation of PDGFRα completely . Piccaluga et al. revealed that activated PDGFRα
[57]
[13]
fostered the proliferation of peripheral T-cell lymphomas, not otherwise specified (PTCL or NOS), cells
through autocrine loop.

Other oncogenic signaling pathways
Gene sets analysis also discerned other biological pathways in NKTCL including the MAPK, WNT, AKT,
and vascular endothelial growth factor (VEGF) signaling pathways . The NOTCH and aurora kinase A
[13]
(AURKA) pathways were upregulated in NKTCL. Notch inhibitors, which potently inhibited γ-secretase
and Notch processing, and an AURKA inhibitor (MK-8745) both may inhibit the proliferation and cell
[58]
cycle regulation of NK-lymphoma cell lines . The Akt/mammalian/mechanistic target of rapamycin
(mTOR) pathway is abnormally activated in EBV-associated T- and NK-cell lymphoma, and their inhibitors
[59]
restricted effectually proliferation of cell lines . The excessive expression of phosphatidylinositol 3-kinase
PIK3 isoforms, containing PIK3α, PIK3β, PIK3γ, and PIK3δ, indicated the abnormally dysregulated
[60]
activation of PIK3 pathway in NKTCL . VEGF was overexpressed in cutaneous NKTCL and related to
poor prognosis. It also provided a potential basis for disorder of the VEGF pathway in NKTCL . The
[61]
[18]
MYC/MAP3K6 pathway is considered to be a characteristic manifestation of MB subtype NKTCL .
Integrating the alterations of human genetics in NKTCL, we simply depict an oncogenic molecular network
linking dysregulated genes and signaling pathways in Figure 1. We also summarize the relevant content
about oncogenic signaling pathways in Table 2.

Epigenetic variations
PTPRK
PTPRK directly and selectively dephosphorylates the substrate, and loss of phosphatase activity will cause
the disruption of cell junctions and enhance invasive characteristics . Because of promoter
[62]