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Zhang et al. Cancer Drug Resist 2024;7:34 https://dx.doi.org/10.20517/cdr.2024.59 Page 5 of 20

[73]
inhibiting EMT . In a study by Chen et al., miR-132 was shown to inhibit proliferation and invasion while
[74]
enhancing CDDP chemosensitivity in OSCC cells via the TGF-β1/Smad2/3 signaling pathway .
Furthermore, miRNA-296-5p was found to increase the sensitivity of NPC cells to CDDP by targeting and
[75]
suppressing the STAT3/KLF4 signaling axis . These results highlight specific miRNAs play a key role in
the acquired chemoresistance of HNC by fine-tuning multiple signaling pathways.

miRNAs regulate chemoresistance in HNC by competitively binding to upstream lncRNAs
miRNAs also regulate chemoresistance in HNC by competitively binding to upstream lncRNAs. FOXD1
promotes OSCC chemoresistance by upregulating LPP expression via sponging miR-1252-5p and miR-3148
through CYTOR . PVT1 promotes cetuximab resistance in head and neck squamous carcinoma by
[76]
[77]
inhibiting miR-124-3p . KCNQ1OT1 promotes CDDP resistance in NPC through the miR-454/USP47
axis . NEAT1 promotes CDDP resistance in thyroid cancer(TC) through the miR-9-5p/SPAG9 axis .
[78]
[79]
CircRNAs also regulate chemoresistance in HNC by sponging miRNAs, such as circCRIM1 promoting
[80]
docetaxel resistance in NPC through the miR-422a/FOXQ1 axis .
Furthermore, miRNAs can also be involved in the chemoresistance of HNC by affecting drug resistance-
related enzymes, membrane transporters, angiogenesis, and other factors. Yuan et al. found that LINC-
PINT could reverse laryngeal cancer stemness and chemotherapy resistance through the miR-425-5p/
[82]
[81]
PTCH1/SHH axis . MiR-340 reverses multidrug resistance in NPC by inhibiting P-gp and BCRP .
Docetaxel can induce IL-8 secretion in OSCC cells, thereby promoting angiogenesis.

In recent years, strategies targeting miRNAs to reverse chemoresistance have received widespread attention.
Li et al. found that miR-101-3p mimics could inhibit the proliferation and CDDP resistance of NPC cells
through ZIC5 . Song et al. discovered that miR-619-5p inhibitors could enhance the CDDP sensitivity of
[47]
[83]
OSCC cells by activating ATXN3 [Table 2 and Figure 1]. Although miRNAs have shown good antitumor
and chemoresistance reversal effects at the animal level, their clinical application still faces many challenges,
such as the construction of miRNA delivery systems, in vivo stability, and off-target effects [84-87] . In addition,
the role of circRNAs and lncRNAs as endogenous miRNA sponges in reversing chemoresistance requires
further in-depth research.

LONG NON-CODING RNAs IN HNC CELL DRUG RESISTANCE
LncRNAs are extensively expressed and have specific interactions with DNA, RNA, and proteins, allowing
them to regulate chromatin function, modulate the assembly and function of membraneless nucleosomes,
influence the stability and translation of cytoplasmic mRNA, and participate in the regulation of signaling
pathways [88,89] . Moreover, lncRNAs play a crucial role in regulating processes such as apoptosis, drug efflux,
drug metabolism, DNA repair, EMT, autophagy, and ferroptosis. Consequently, they emerge as pivotal
mediators of tumor drug resistance [90-93] . In recent years, there has been a notable increase in the number of
lncRNAs associated with cancer development and progression. These lncRNAs can be explored and
[94]
[95]
investigated in meticulously curated databases like Lnc2Cancer3.0 or Cancer LncRNA Census .
CDDP resistance
[96]
CDDP stands as a highly extensively employed drug in the treatment of diverse solid tumors . Its principal
mode of action involves disrupting DNA repair mechanisms, leading to DNA damage and consequently
triggering apoptosis in cancer cells [97,98] . Nonetheless, drug resistance poses an inherent challenge in the
clinical utilization of CDDP, primarily stemming from three molecular mechanisms: heightened DNA
repair, modified cellular accumulation, and augmented drug inactivation .In 2014, Galluzzi et al.
[99]
Systematically categorized CDDP resistance into four distinct stages: Pre-Target, On-Target, Post-Target,