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Zeng et al. Cancer Drug Resist 2024;7:31 https://dx.doi.org/10.20517/cdr.2024.57 Page 3 of 13

As for OSCC, there remains a deficiency in readily available, precise, and non-invasive biomarkers for early
detection. Saliva samples are not only easy to obtain but also rich in circRNAs in OSCC. Certain circRNAs
[17]
have been observed to exhibit notable upregulation in OSCC cell lines, such as the case of circ-1001242
[18]
and circ-0086414 . Furthermore, circ-0001874 and circ-0001971 can be identified in saliva samples from
individuals with oral cancer and their expression is strongly linked to the malignancy of the tumors . The
[19]
expression levels of these circRNAs are correlated with tumor stage and size and may be used for the
diagnosis of OSCC.

Regarding LSCC, there have also been reports on circRNAs as clinical diagnostic markers. Kan et al.
examined the whole circRNA expression in LSCC tissues compared with adjacent non-tumor tissues using
[20]
microarray analysis. They identified 698 circRNAs with differential expressions in LSCC tissues .
Subsequent quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis showed the
highest upregulation of hsa-circRNA-1008555 and downregulation of hsa-circRNA-1044912 in LSCC. The
expression of hsa-circRNA-1008555 was also significantly elevated in LSCC patients who have neck lymph
node metastases or are at advanced clinical stages. Conversely, hsa-circRNA-1044912 is significantly
decreased in LSCC patients with T3-4 stages, neck lymph node metastases, other advanced clinical stages or
poor differentiation . These data suggest the correlation between circRNAs and the staging and prognosis
[20]
of LSCC. Taken together, the identification of circRNAs has great potential for disease diagnosis and
prediction of HNSCC.

THE VALUE OF CIRCRNAS IN THE PROGRESSION OF HNSCC
circRNAs play a significant role in regulating proliferation in HNSCC. Various circRNAs have been
identified to promote or inhibit proliferation by interacting with specific miRNAs and modulating
downstream target genes. For example, circ-0046263 promotes NPC proliferation by upregulating insulin-
[21]
like growth factor binding protein 3 (IGFBP3) expression through miR-133a-5p sponge activity .
circZNF609 [22-24] , circTMTC1 , circTRAF3 , and Epstein-Barr virus (EBV)-encoded circRNA
[26]
[25]
circRPMS1 also promote NPC proliferation through distinct mechanisms. Conversely, circKIAA0368 ,
[27]
[28]
[32]
[33]
circ-0004788 , circ-0081534 [30,31] , circITCH , circHIPK3 , and circSETD3 [34,35] have been found to inhibit
[29]
NPC proliferation. In OSCC, circHIPK3 , circDOCK1 , hsa-circ-0001971, hsa-circ-0001874 , and hsa-
[38]
[37]
[36]
[39]
[40]
circ-0011946 are overexpressed and stimulate proliferation, whereas hsa-circ-0004491 , hsa-circ-
0002203 , hsa-circ-0063772 , circ-0000140 , hsa-circ-0007059 , hsa-circ-0055538 , and hsa-circ-
[42]
[45]
[41]
[44]
[43]
[46]
0092125 are tumor suppressors that inhibit proliferation and promote apoptosis. circ-100290 functions as
a ceRNA by sequestering miR-29b and miR-378a, regulating cyclin-dependent kinase 6 (CDK6) and glucose
transporter 1 (GLUT1) expression in OSCC [47,48] . circPKD2 promotes apoptosis and inhibits proliferation
and invasion in OSCC [49,50] . In LSCC, circ-100290 is significantly elevated and enhances proliferation by
modulating miR-29a-3p expression . Further studies are needed to elucidate the specific regulatory
[51]
mechanisms of these circRNAs, which could provide potential new targets and therapeutic approaches for
HNSCC.
Furthermore, various circRNAs have been identified to promote or inhibit invasion and metastasis of
[52]
[53]
HNSCC by regulating different molecular pathways. For example, circCTDP1 , circARHGAP12 ,
[56]
[55]
[54]
circRNF13 , circ-0000215 , circSETD3 , and circCAMSAP1 enhance NPC invasion and metastasis,
[35]
[59]
whereas circCCNB , hsa-circ-0000345 and circTGFBR2 inhibit the migration and invasion of NPC.
[58]
[57]
The overexpression of circPVT1 in NPC significantly promotes NPC migration and invasion, showing a
positive correlation with the disease progression and TNM stages of NPC . circRILPL1 is highly expressed
[60]
in NPC and promotes NPC proliferation and metastasis through binding to Rho-associated coiled-coil
containing protein kinase 1 (ROCK1) and importin7 (IPO7) to activate the Hippo-YAP signaling