Page 80 - Read Online

Page 4 of 13 Zeng et al. Cancer Drug Resist 2024;7:31 https://dx.doi.org/10.20517/cdr.2024.57

[61]
[43]
[47]
pathway . In OSCC, circ-0000140 and circ-100290 promote migration and invasion, whereas circ-
[65]
[64]
0001971 [19,62,63] regulates various biological processes. In LSCC, circSHKBP1 , circ-103862 , circ-
0036722 , and circBFAR promote proliferation and invasion, whereas circPARD3 and circeMTCL1
[67]
[66]
[69]
[68]
play a role in invasion and migration. Furthermore, several other circRNAs, including circ-0005033 , circ-
[70]
0044520 , and circ-0023028 , have also been implicated in the regulation of LSCC proliferation, invasion,
[72]
[71]
and migration. These circRNAs interact with specific miRNAs and downstream target genes to modulate
the metastatic potential of HNSCC. Further studies are necessary to deepen our understanding of the
regulatory mechanisms of these circRNAs and identify potential therapeutic targets for interventions in
HNSCC metastasis [Table 1].
ROLE OF CIRCRNAS IN RADIOTHERAPY, CHEMOTHERAPY, AND IMMUNOTHERAPY OF
HNSCC
circRNAs are associated with radioresistance in HNSCC
Radiotherapy resistance is a significant challenge in the treatment of HNSCC and is closely related to
patient prognosis. circRNAs are involved in this process. For example, overexpression of circ-000543 in
radioinsensitive NPC contributes to the development of radioresistance. This circRNA functions by binding
to miR-9, thereby upregulating platelet-derived growth factor receptor B (PDGFRB) expression .
[73]

In addition, circRNAs can also modulate genes involved in the DNA damage response and repair. For
example, the expression of circATRNL1 significantly decreased after radiation exposure, which may lead to
radiation resistance in tumor cells by inhibiting apoptosis and cell cycle arrest in OSCC. Therefore,
increasing the expression of circATRNL1 may help improve the sensitivity of OSCC to radiotherapy,
[74]
thereby enhancing its effectiveness . In general, circRNAs affect the responsiveness of tumors to
radiotherapy by regulating apoptosis pathways and DNA damage response and repair pathways post-
radiation. Thus, identifying targets for radiosensitization and reversing radioresistance of HNSCC is of great
interest.

circRNAs are associated with immune evasion in HNSCC
circRNAs can regulate the malignant progression of head and neck cancer through mechanisms such as
[75]
immune evasion . This mechanism refers to the escape of tumor cells from the immune system attack
through different mechanisms, thus promoting tumor proliferation and invasion. Immune evasion
mechanisms include inhibiting the activity of immune cells, changing tumor cell surface molecules to avoid
being recognized by the immune system, and producing immunosuppressive factors, among others. By
studying the mechanism of immune evasion, researchers found that the process can be regulated to achieve
therapeutic effects such as inhibiting tumor proliferation and invasion. Immunotherapy has been widely
used in HNSCC. Immune checkpoint inhibitors, in particular, are a common form of immunotherapy .
[76]
These drugs enhance the ability of immune cells to attack tumors by blocking the inhibitory signals between
tumor cells and immune cells. In addition, personalized immunotherapy is also used in HNSCC. This
therapy analyzes the patient’s tumor tissue or blood samples, identifies the tumor-specific antigens, and uses
those antigens to activate the patient’s own immune system to attack and kill the tumor cells .
[77]

An example of a circRNA associated with immune evasion in HNSCC is circBART2.2, encoded by EBV,
which can promote programmed death-ligand 1 (PD-L1) expression by activating the innate immune
signaling pathway, leading to immune escape in NPC . In addition, circCDR1as can regulate the immune
[78]
escape process of OSCC by regulating the expression of miR-7 . Similarly, has-circ-0069313 participates in
[79]
the immune escape of OSCC by modulating the expression of miR-325-3p and subsequently affecting
forkhead box P3 (FOXP3) . These circRNAs may influence the immune escape ability of LSCC by
[80]
modulating immune-related genes.