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Page 6 of 13 Zeng et al. Cancer Drug Resist 2024;7:31 https://dx.doi.org/10.20517/cdr.2024.57

circBFAR Upregulation Proliferation; invasion miRNA-31-5p [67]
cireMTCL1 Upregulation Proliferation; metastasis; invasion CIQBP [69]
circRNAs: Circular RNAs; HNSCC: head and neck squamous cell carcinoma; EMT: Epithelial-Mesenchymal Transition; NPC: nasopharyngeal
carcinoma; OSCC: oral squamous cell carcinoma; LSCC: laryngeal squamous cell carcinoma.

circRNAs are associated with drug resistance in HNSCC
Chemotherapy is one of the most effective treatments for advanced HNSCC. Currently, the commonly used
first-line chemotherapy drugs include platinum drugs, 5-fluorouracil, imidazoles and taxanes. Platinum
drugs such as cisplatin and carboplatin inhibit the growth and division of cancer cells by interfering with
DNA replication and repair processes. The drug 5-fluorouracil (5-FU) is an antimetabolite drug that blocks
[81]
the growth and division of cancer cells by inhibiting DNA and RNA synthesis . Imidazoles, such as
methotrexate, also inhibit the growth and division of cancer cells by blocking DNA and RNA synthesis .
[82]
Taxanes, such as paclitaxel and docetaxel, block the division and spread of cancer cells by interfering with
microtubule polymerization . Overall, research on chemotherapy for HNSCC is progressing with the hope
[83]
of finding more effective treatments to improve the patients’ survival rate and quality of life. However, a
significant number of HNSCC patients exhibit chemotherapy resistance, posing a major challenge to
effective treatment.

The emergence of multidrug resistance in tumor cells is the main reason for chemotherapy failure [84,85] . With
the extensive investigation of circRNA biological function, increasing evidence suggests that certain
circRNAs are significantly upregulated in drug-resistant HNSCC tissues. Furthermore, circRNAs are closely
associated with some signaling pathways that are involved in drug resistance of HNSCC, such as PI3K/AKT,
MAPK, NF-κB, and Wnt/β-catenin signaling pathways . These circRNAs can act as "sponges" for miRNAs
[86]
by containing multiple miRNA binding sites, thereby adsorbing and inhibiting miRNA activity and
subsequently regulating downstream pathways that affect tumor sensitivity to drugs. Additionally, circRNAs
can influence tumor drug resistance, either by directly binding to proteins or through the regulation of
[75]
cellular autophagy [Figure 1].
circRNAs and chemoresistance in nasopharyngeal carcinoma
Specific circRNAs have been reported to play a role in metastasis and resistance to chemotherapy in NPC.
For instance, circCRIM1 is abundantly expressed in NPC tissues with high metastasis and can enhance
forkhead box Q1 (FOXQ1) expression by targeting miR-422a. This, in turn, promotes NPC metastasis and
confers resistance to docetaxel chemotherapy . circ-0008450 is upregulated in NPC tissues and promotes
[87]
resistance to cisplatin by targeting the miR-338-3p/Smad5 axis . circIPO7 is upregulated in NPC tissues
[88]
and binds to Y-box binding protein1 (YBX1) in the cytoplasm, promoting its phosphorylation at serine102
(p-YBX1S102) by the kinase AKT. This leads to the nuclear translocation of YBX1 and activation of genes
such as fibroblast growth factor receptor 1 (FGFR1), tenascin-C (TNC) and neurotrophic tyrosine kinase
receptor 1 (NTRK1), thereby promoting resistance to cisplatin in NPC . Another example is circ-0067717,
[89]
which is upregulated in paclitaxel-resistant NPC. This circRNA serves as a scaffold of tripartite motif
containing 41 (TRIM41) protein, which is a ubiquitin E3 ligase. TRIM41 induces p53 ubiquitination and
degradation, which results in reduced levels of p53 protein, ultimately promoting resistance to paclitaxel in
[90]
NPC . circPARD3 promotes cisplatin resistance of NPC side population cells. This effect is mediated
through the miR-579-3p/SIRT1/SSRP1 axis . circ-0028007 derived from the NUAK1 gene is upregulated in
[91]
poorly differentiated NPC cell lines and its silencing enhances the responsiveness of NPC to
[92]
paclitaxel/cisplatin . circNRIP1 is upregulated in the serum of chemotherapy-resistant NPC cells, and