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Page 2 of 13 Zeng et al. Cancer Drug Resist 2024;7:31 https://dx.doi.org/10.20517/cdr.2024.57

INTRODUCTION
Head and neck squamous cell carcinoma (HNSCC) originates from the epithelial cells in the head and neck
region, encompassing various subtypes, such as oral squamous cell carcinoma (OSCC), laryngeal squamous
cell carcinoma (LSCC), nasopharyngeal carcinoma (NPC), and others. HNSCC is the sixth most common
cancer worldwide, with more than 890,000 new cases diagnosed each year. Despite advances in treatment,
[1]
the five-year survival rate has stagnated at around 65% for decades . Early detection of HNSCC is
challenging due to its deep anatomic location and complex structure, leading to a frequent diagnosis in the
middle and late stages of the disease. Consequently, postoperative adjuvant chemotherapy and radiotherapy
are often necessary . However, drug resistance and radioresistance significantly impact the prognosis of
[2]
patients with advanced HNSCC.

circRNAs are a unique group of non-coding RNAs that form closed loops due to covalent bonds, therefore
lacking 5’ and 3’ ends . This unique structure makes circRNAs insensitive to ribonucleases such as
[3]
exonucleases, ensuring their stability within cells . Recent advances in high-throughput sequencing and
[4]
computational analysis have unveiled the regulatory roles of circRNAs in gene expression in cancer at both
[5]
pre- and post-transcriptional levels . A better understanding of the association between circRNAs and
HNSCC will help us to more effectively study and explore new early diagnostic indicators and therapeutic
targets for HNSCC. This review aims to clarify the role of circRNAs in drug resistance in HNSCC and its
potential as a diagnostic and therapeutic target.

THE CLINICAL DIAGNOSTIC VALUE OF CIRCRNAS IN HNSCC
circRNAs are abundantly present in cells and play diverse roles in biological processes. Compared to other
non-coding RNAs (ncRNAs), such as micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs),
circRNAs are more stable in cells due to their closed circular RNA molecular structure. They can function
as miRNA sponges, interact with RNA-binding proteins, or be translated into peptides to affect downstream
gene expression. Notably, circRNAs often act as “miRNA sponges” or competitive endogenous RNAs
(ceRNAs) by containing miRNA binding sites, thereby regulating the function of miRNAs. Additionally,
circRNAs can interact with proteins, DNA, RNA, or transcription factors to regulate protein function or
gene transcription . circRNAs can also encode small peptides and participate in cellular biological
[6]
[7]
[8]
processes . Furthermore, circRNAs can interact with molecules associated with epigenetic modifications ,
affecting the regulation of various biological processes including tumor cell proliferation, apoptosis, cell
differentiation, development and the immune response.

circRNAs possess characteristics such as abundance, ubiquity, conservation, and stable expression in saliva,
blood, and exosomes [9-11] . Their expression in tissues and organs is stage-specific, making circRNAs highly
promising biomarkers. It has been widely proposed that circRNAs could serve as biomarkers for early
diagnosis and prognosis of tumors. The development of high-throughput sequencing technologies has
facilitated the identification of a growing number of dysregulated circRNAs and their expression patterns
are closely associated with patient prognosis. For example, circMAN1A2 exhibits high levels of expression
in NPC cell lines and is also significantly increased in the serum of individuals with NPC, indicating its
potential as a promising biomarker for the early detection of NPC . Similarly, circMYC expression in
[12]
[13]
exosomes can be used to differentiate radiation sensitivity in NPC patients , whereas the upregulation of
circSERPINA3 is correlated with NPC progression, including lymph node metastasis and unfavorable
[15]
[16]
[14]
overall survival outcomes . Additionally, high expression of circCRIM1 and circ-001387 are strongly
associated with unfavorable prognosis in patients with NPC. These findings support the potential
application of circRNAs in early diagnosis and prognostic evaluation of NPC.