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Jiang et al. J Transl Genet Genom 2021;5:323-40 https://dx.doi.org/10.20517/jtgg.2021.21 Page 331

[43]
may contribute to the development of NKTCL . Loss of function mutations of BCOR are considered
[41]
highly specific in NKTCL . Another study demonstrated that BCOR and MLL2 were mutated genes
[46]
followed only by STAT3 . The two aberrant mutated chromatin-modifying genes may also be significant
targets of NKTCL epigenetic therapy. All the content regarding epigenetic variations is summarized in
Table 3.

microRNAs and lncRNAs
microRNAs
microRNAs are small non-coding RNAs with a length of 19-24 bp nucleotides that negatively regulate target
genes and are associated with the regulation of crucial biological processes such as cell growth,
[68]
differentiation, and apoptosis . Many studies have revealed the functional significance of microRNAs
dysregulation in NKTCL.

Ng et al. discovered that miR-342-5p, miR-26b, miR-363, miR-150, miR28-5p, miR-26a, and miR-101
[69]
were downregulated in NKTCL tumor tissues and in vitro, as compared with normal NK cells. These
microRNAs inhibited the growth of NKTCL cell lines in vitro. Nevertheless, the expression of miR-155 and
[69]
miR-378 were upregulated . miR-150 may impact the sensitivity of NKTCL cells to radiotherapy by
inhibiting the PI3K/AKT/mTOR pathway and participate in the development of lymphoma .
[70]
miR-15a is downregulated in NKTCL cell lines and tumor tissues, which may predict poor prognosis and
response to treatment . Paik et al. proved that the overexpression of miR-146a in NKTCL cells may
[71]
[72]
[73]
inhibit NF-κB pathway and thus serve as a feasible tumor suppressor. In addition, Liang et al. found that
miR-223 targeted the 3’-untranslated region (UTR) of PRDM1 gene to downregulate its expression at the
post-transcriptional level. miR-21 is overexpressed in NKTCL, acting as an oncogenic RNA which mediates
apoptotic activity reduction through the abnormally dysregulated PTEN/AKT signaling pathway. Aberrant
overexpression of miR-155 may induce activation of SHIP1/AKT pathway and affect the occurrence of
[74]
NKTCL .
lncRNAs
In addition to microRNAs, some long non-coding RNAs (lncRNAs) have also been thought to be involved
in the oncogenesis of NKTCL. ZFAS1 suggested genes participate in critical pathways associated with cell
[76]
[75]
growth and tumor transformation, such as NF-κB and WNT signaling pathways . Recently, Wang et al.
discovered that brain cytoplasmic RNA 1 in NKTCL tissue was significantly higher in contrast to normal
NK cells, which may induce autophagy via inhibiting PI3K/AKT/mTOR and p53/mTOR signaling pathways
and enhance the resistance to L-asparaginase. lncRNA X-inactive-specific transcript (XIST) is overexpressed
in NKTCL, and its downstream target miR-497 could decrease the synthesis of the anti-apoptotic molecule
Bcl-w to further regulate XIST-mediated proliferation and migration of NKTCL cells . In addition to
[77]
these, small nucleolar RNA host gene 12 is upregulated in NKTCL, as a direct transcription target of c-myc,
[78]
which accelerates the proliferation of tumor cells and may suppress the response to cisplatin .

In summary, studies on the connection between non-coding RNAs and NKTCL not only present the
possible therapeutic value of non-coding RNA but also provide enlightenment for overcoming the
resistance of NKTCL patients. These potential targets and their significance are summarized in Table 4.

Immune-related changes
PD-1 and PD-L1
Programmed death-1 (PD-1) is an immune checkpoint receptor that binds to PD-L1 expressed by neoplasm