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Page 4 of 20 Zhang et al. Cancer Drug Resist 2024;7:34 https://dx.doi.org/10.20517/cdr.2024.59

[50]
consequently enhancing chemosensitivity . CircAP1M2 promotes CDDP resistance and autophagy in
[51]
OSCC by inhibiting miR-1249-3p to upregulate ATG9A expression . MiR-1278 inhibits autophagy and
[52]
CDDP resistance in NPC cells by targeting ATG2B . Therefore, targeting autophagy pathways through the
regulation of miRNAs may enhance the therapeutic sensitivity of HNC.

miRNAs affect chemoresistance by regulating the cell cycle and metabolism
miRNAs can also modulate the sensitivity of tumor cells to treatment by regulating energy metabolism and
cell cycle. Fan et al. discovered that downregulation of mitochondrial miR-2392 expression could lead to
impaired mitochondrial oxidative phosphorylation by inhibiting MT-CO3 translation, resulting in a shift of
glucose metabolism from oxidative phosphorylation to anaerobic glycolysis, ultimately causing CDDP
[53]
resistance in tongue squamous cell carcinoma (TSCC) . Chen et al. discovered that miR-5787 contributes
to CDDP resistance in TSCC by reprogramming glucose metabolism via inhibiting the translation of
[54]
MT-CO3 . In another study, Mortezagholi et al. demonstrated that miR-34 could reverse paclitaxel
resistance in OECM-1 oral cancer cells by inducing DNA damage and apoptosis in a p53-dependent
[55]
manner . HOXA11-AS enhances the proliferation, invasion, survival, and drug resistance of OSCC by
sponging miR-494 to promote NQO1 expression and recruiting EZH2 to the NQO2 promoter to suppress
NQO2 expression . Kang et al. demonstrated that cancer-associated fibroblast (CAF)-derived extracellular
[56]
vesicles carrying miR-876-3p can modulate CDDP resistance in OSCC by targeting insulin-like growth
factor binding protein 3 (IGFBP3) . Li et al. identified miR-194 as a tumor suppressor in LSCC that
[57]
[58]
inhibits cell proliferation and enhances chemosensitivity by targeting Wee1 .
miRNAs affect chemoresistance via exosome-mediated mechanisms
Exosomes, as an important mediator of intercellular communication, can carry functional molecules such as
miRNAs to mediate information exchange between tumor cells and the microenvironment, playing a key
role in tumor progression and chemoresistance [59-61] . Qin et al. found that CAF-derived exosomal miR-196a
could confer CDDP resistance to head and neck squamous carcinoma cells by targeting CDKN1B and
[62]
ING5 . Li et al. discovered that exosomal miR-106a-5p derived from CDDP-resistant cells could promote
NPC cell proliferation and suppress apoptosis by targeting ARNT2 and activating AKT phosphorylation,
thereby regulating tumorigenesis . This study revealed that tumor cells could remodel the tumor
[63]
microenvironment through exosomal miRNAs to acquire a chemoresistant phenotype.

miRNAs affect chemoresistance by regulating cancer stem cells
Cancer stem cells play a key role in tumor development, metastasis, and chemoresistance [64-66] . MiRNAs are
involved in the chemoresistance process of HNC by regulating cancer stemness. Recent studies have shown
that miRNA-485-5p can regulate the stemness and chemotherapy resistance of OSCC by targeting keratin
17 (KRT17) . MiR-21-3p overexpression maintained the stemness of this subpopulation. Lin et al.
[67]
discovered that activation of the miR-371/372/373 cluster could enhance the tumorigenicity and drug
[68]
tolerance of OSCC cells . Cai et al. found that EBV-encoded miR-BART7-3p enhanced the stemness and
[69]
chemotherapy resistance of NPC by inhibiting SMAD7 to activate the TGF-β pathway .
miRNAs affect chemoresistance by regulating other signaling pathways
In addition, miRNAs are also involved in chemoresistance of HNC by regulating multiple signaling
pathways. Zhang et al. found that miR-205-5p could induce EMT and CDDP resistance in NPC by targeting
PTEN to activate the PI3K/Akt pathway . Gu et al. discovered that miR-552 could promote the
[70]
[71]
proliferation and metastasis of laryngeal cancer cells by targeting p53 . Sheng et al. discovered that miR-21
enhances proliferation, apoptosis inhibition, and CDDP resistance in head and neck squamous cell
carcinoma (HNSCC) through the PTEN/PI3K/AKT pathway . Wu et al. found that the miR-577/EIF5A2
[72]
axis suppresses the proliferation of CDDP-resistant NPC by blocking the TGF-β signaling pathway and