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Page 2 of 20 Zhang et al. Cancer Drug Resist 2024;7:34 https://dx.doi.org/10.20517/cdr.2024.59

INTRODUCTION
Head and neck cancer (HNC) ranks as the sixth most prevalent malignant neoplasm, presenting significant
[1]
challenges in terms of treatment . It affects various anatomical sites including the lips, oral cavity, pharynx,
larynx, nose, salivary glands, and thyroid. Squamous cell carcinoma (SCC) and its variants constitute more
[2]
than 90% of the histopathological types . Major risk factors associated with HNC include tobacco and
[3]
alcohol use, as well as infections with human papillomavirus (HPV) and Epstein-Barr virus (EBV) .
Globally, the incidence of HNC has been gradually declining, primarily attributed to the reduction in
[4,5]
tobacco use and lifestyle modifications .

Treatment decisions are guided by the precise location, stage, and pathologic characteristics of the disease.
For around 30%-40% of patients diagnosed with early-stage disease (Stage I or II), the typical
recommendation involves a single treatment modality such as surgery or radiotherapy. Conversely, roughly
60% of patients presenting with locally or regionally advanced disease upon diagnosis typically receive a
multidisciplinary approach encompassing a combination of treatments. These may involve surgery,
radiotherapy, chemotherapy, and immunotherapy, as well as additional measures such as nutritional
support, psychological counseling, supportive care, and rehabilitation . Various studies have indicated that
[2]
the overall 5-year survival rate for individuals with HNC falls below 50%, underscoring the persisting
[2,6]
challenges in current treatment outcomes . The inadequate response of patients to antitumor therapy, and
in some cases, the development of drug resistance, contribute to unsatisfactory clinical outcomes and stand
as significant factors leading to mortality .
[7]
Unfortunately, the key determinants underlying this resistance phenomenon remain largely elusive.
Advances in molecular biology and gene sequencing have unveiled that approximately 98% of human DNA
[8]
is designated non-protein coding . Non-coding RNAs constitute a diverse group of RNA transcripts that
lack protein-coding potential. Significant subtypes include microRNAs (miRNAs), circular RNAs
(circRNAs), and long non-coding RNAs (lncRNAs) . Emerging research has revealed the potential of non-
[9]
coding RNAs to modulate multiple facets of cellular functions, encompassing growth, proliferation,
differentiation, development, metabolism, infection, immunity, cell death, organelle biogenesis, messenger
signaling, DNA repair, and self-renewal [10-12] . Moreover, non-coding RNAs exhibit close associations with
various common diseases, particularly cancer [9,13-15] . Additionally, non-coding RNAs function as widespread
regulators of various cancer-related characteristics, including proliferation, apoptosis, invasion, metastasis,
and genomic instability, thus playing a crucial role in mediating resistance to different cancer therapies [16,17] .
Consequently, gaining a comprehensive understanding of the mechanisms underlying non-coding RNAs
and drug resistance holds significant importance in the context of HNC treatment. In addition, the research
on overcoming tumor drug resistance through the regulation of non-coding RNAs offers many
advantages [16,18-28] [Table 1].

This review aims to provide a comprehensive summary of the intricate relationship between non-coding
RNAs and drug resistance in HNC. It delves into the various types of non-coding RNAs and their potential
roles in mediating resistance to different therapeutic approaches utilized in HNC treatment. Through an
analysis of the current literature, this review seeks to enhance our understanding of the mechanisms
underlying drug resistance in HNC and identify potential avenues for improving treatment outcomes.

miRNAs IN HNC CELL DRUG RESISTANCE
miRNAs, approximately 22 nucleotides in length, constitute a class of endogenous non-coding RNAs. These
molecules regulate diverse biological processes, including cell proliferation, differentiation, and apoptosis,
through specific binding to the 3’-untranslated region (3’-UTR) of target gene mRNAs, thereby inducing