3.1.1 miRNAs and drug resistance of OSCC

A variety of anticancer drugs have been prescribed to treat OSCC. Platinum drugs are widely used in clinic because of their unique anticancer mechanisms and broad spectrums of anticancer activity. By using miRNA microarrays, Yu et al. [52] showed that expression levels of miR-214 and miR-23a were upregulated and accompanied by CDDP resistance, while the expression level of miR-21 was decreased with CDDP sensitivity in TSCC CDDP-resistant subline (Tca/CDDP) cells compared to CDDP-sensitive TSCC cells. miR-372 overexpression was detected in OSCC. Further, miR-372 was found to inhibit zinc finger and BTB domain-containing 7A protein (ZBTB7A), while ZBTB7A silencing increased the oncogenic potential and drug resistance of OSCC cells. Therefore, the sensitivity of OSCC to CDDP could be improved by miR-372 silencing [53]. Besides the aforementioned signaling pathways, exosomes exert synergistic roles in miRNA-mediated drug resistance of OSCC. For example, exosomes released from CDDP-resistant OSCC cells delivered miR-21 and ultimately enhanced CDDP resistance of OSCC cells [54].

For the other two chemotherapeutic agents (5-FU and Dox), miRNAs are also found to modulate the drug resistance of OSCC. Huang et al. [55] indicated that miR-365-3p enhanced OSCC chemosensitivity to 5-FU. The expression level of miR-221 was upregulated in Dox-treated OSCC cells compared to untreated OSCC cells. However, knockdown of miR-221 enhanced the sensitivity of OSCC cells to Dox [56]. Collectively, it can be concluded that miRNAs are involved in MDR regulation. Therefore, it is reasonable to target and regulate the expression levels of miRNAs to alleviate the drug-resistant process of OSCC.

3.1.2 lncRNAs and drug resistance of OSCC

A number of lncRNAs have been identified to be abnormally expressed in OSCC cells and involved in chemoresistance via regulating different target genes and biologic processes. For example, the interactions of lncRNAs mediating drug resistance of OSCC were based on the ceRNA theory that lncRNAs could act as miRNA sponges to weaken regulations of miRNAs on mRNAs [60]. Specifically, lncRNA HOXA11-AS overexpression was detected in OSCC tissues and cells compared to adjacent normal tissues and human oral keratinocytes. Mechanistically, lncRNA HOXA11-AS sponged miR-98–5p, which in turn suppress OSCC proliferation [61]. Meanwhile, lncRNA HOXA11-AS could also inhibit the expression level of miR-214-3p, and promote drug resistance of OSCC [62]. Notably, lncRNAs could also regulate exosomal miRNAs. For example, the downregulation of lncRNA X inactive specific transcript (XIST) enhanced exosomal miRNA-503 secretion and promoted cancer metastasis [63]. However, this regulatory mechanism has not been identified in OSCC and could be further explored in the future. Several oncogenic lncRNAs, such as lncRNA UCA1, lncRNA ANRIL, as well as lncRNA HOX transcript antisense RNA (HOTAIR), have been shown to participate in the drug resistance of OSCC.

LncRNA UCA1 was demonstrated to be upregulated in CDDP-resistant OSCC cells compared to CDDP-sensitive cells. Mechanistically, the expression level of miR-184 was inhibited by lncRNA UCA1. Moreover, in CDDP-resistant OSCC cells, miR-184 overexpression facilitated tumor suppression and chemosensitivity [64]. In addition to mediating the involvement of miRNAs in drug resistance of OSCC, lncRNAs may also recognize drug transporter proteins. For example, compared to normal and tumor adjacent tissues, lncRNA ANRIL was overexpressed in OSCC tissues. Meanwhile, lncRNA ANRIL silencing inhibited tumor cell proliferation, induced apoptosis, and increased CDDP cytotoxicity by impairing drug transporters MRP1 and ABCC2 [65]. Autophagy has also been shown to be involved in lncRNA-mediated CDDP resistance. For example, lncRNA HOTAIR was reported as an oncogene, which was overexpressed in OSCC cells compared to corresponding normal oral mucosa tissues and human oral keratinocytes [66]. Notably, lncRNA HOTAIR silencing inhibited cellular autophagy by downregulating expression levels of autophagy-related genes (ATG3 and ATG7), ultimately enhancing sensitivity to CDDP [67]. All of the above evidence suggest that targeted inhibition of several lncRNAs may be a potential therapeutic strategy to improve CDDP resistance in OSCC patients.

3.1.3 circRNAs and drug resistance of OSCC

It has been suggested that circRNAs are also involved in regulating the progression of drug resistance in cancers. Upregulated circITCH enhanced the toxicity of chemotherapeutic agents against drug-resistant multiple myeloma cells [68]. Similarly, the expression level of circITCH was reduced in OSCC tissues and cell lines compared to adjacent normal tissues and human oral keratinocytes, and circITCH overexpression significantly inhibited OSCC cell proliferation and induced apoptosis [69]. Therefore, it can be speculated that circRNA can also mediate the toxicity of chemotherapeutic drugs on OSCC cells. However, the mechanisms of circRNA-meditated drug resistance of OSCC need to be further explored.

Drug resistance of OSCC cells can be seen to involve a wide range of biological signaling pathways. Fortunately, mitigation of OSCC resistance by modulating ncRNAs is a reliable option. Presumably, signaling pathways identified do not yet address all barriers for drug resistance of OSCC. Therefore, more extensive and comprehensive mechanisms of ncRNAs mediating drug resistance of OSCC are expected to be elucidated.

3.2.1 Transmembrane transport proteins

One of the root causes of drug resistance can be attributed to reduced drug concentrations, which are often caused by enhanced expression of drug efflux pump genes. It subsequently generates decreased drug influx, increased efflux, and drug sequestration in intracellular vesicles and compartments [73]. Furthermore, ncRNAs are also involved in the drug efflux process (Table 2). These changes mainly involve adenosine triphosphate (ATP) binding cassette (ABC) family proteins, which has been divided into seven subfamilies (ABCA-ABCG) [74]. It has been well documented that members of the ABC transporter protein family were associated with the MDR of OSCC include p-glycoprotein (P-gp/MDR1/ABCB1), the MDR-associated protein family (MRP1/ABCC1), and breast cancer resistance proteins (BCRP/ABCG2) [75]. These ABC family proteins have similar transmembrane domains (TMD) that can pump drugs out of cancer cells to reduce the concentration of drugs in cancer cells (Figure 1).

The expression level of MDR1 has been found to be upregulated in cells treated with chemotherapeutic agents. Mechanistically, anticancer drugs are capable of triggering epigenetic alterations in the promoter region of the MDR1 gene, thereby resulting in a high expression level of P-gp in tumor cells [76]. Notably, ncRNAs are responsible for the MDR1-mediated drug efflux process. For example, miR-491-3p downregulated the expression level of MDR1 by directly binding to the 3’-UTR of ABCB1, thereby enhancing the sensitivity of hepatoma carcinoma cells to drugs, like Dox or vinblastine [77]. In 1997, Jain et al. [78] first estimated immunoreactivity of P-gp in oral tissues at different stages of tumorigenesis by flow cytometry and found that its expression was significantly elevated in recurrent OSCC tissues compared to normal tissues. Meanwhile, the expression level of P-gp was higher in T4-stage compared to the T3-stage in recurrent tumors. Another result also confirmed that a high expression level of ABCB1 was correlated with high tumor grades and poor differentiation [79]. It was known that miR-188-3p, an upstream regulator of ABCB1, could be sponged by circ_0109291. Recently, Gao et al. [80] found that circ_0109291 was highly expressed in CDDP-resistant OSCC tissues and cells compared to CDDP-sensitive OSCC tissues and cells. At the same time, miR-188-3p overexpression inhibited CDDP-resistant OSCC cells. Furthermore, miR-188-3p inhibitors and ABCB1 overexpression reversed the inhibitory effect of circ_0109291 silencing on CDDP-resistant OSCC cells. Thus, circ_0109291 can increase the expression level of ABCB1 by sponging miR-188-3p and promote CDDP resistance of OSCC cells. In addition, lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) that showed high expression level in CDDP-resistant OSCC cells also promoted CDDP resistance by regulating the expression level of P-gp [81].

Since P-gp cannot explain all drug-resistant processes of cancer cells, MRP1, or ABCC1, was firstly identified in small cell lung cancer [82]. Functionally, MDR1 is mainly confined to the extrusion of xenobiotics. MRP1, on the other hand, outputs both endobiotics and xenobiotics, thereby affecting physiological processes beyond drug distribution [83, 84]. The expression level of MRP1 is known to be significantly upregulated in several drug-resistant diseases, including non-small cell lung cancer [85] and epilepsy [86]. In CDDP-resistant A549 cells, expression levels of lncRNA MALAT1 and MRP1 were upregulated compared to A549 cells. It was further found that the upregulated MRP1 was triggered by lncRNA MALAT1, thereby diminishing the sensitivity of cells to CDDP [87]. All of the above evidence points to ncRNA as a potential window in the process of alleviating drug resistance. In OSCC, the expression level of MRP1 was found to be higher in cancerous tissues than in adjacent non-neoplastic tissues. Elevated expression level of MRP1 was detected in CDDP-resistant cells compared with clinical samples, suggesting intrinsic drug resistance in OSCC. Furthermore, a high expression level of MRP1 was significantly associated with OSCC clinical stage, lymph node metastasis, and histological grade [88]. Nakamura et al. [89] also revealed that an elevated expression level of MRP1 was detected in OSCC cell lines treated with CDDP compared to untreated OSCC cells. Similar results were also observed in OSCC cells treated with vincristine [90]. LncRNA MALAT1 was also known to upregulate the expression level of MRP1, which contributed to CDDP resistance in lung cancer [87]. LncRNA MALAT1 overexpression was also detected in CDDP-resistant OSCC cells compared to CDDP-sensitive OSCC cells [81]. Therefore, it can be hypothesized that lncRNA MALAT1 can upregulate the expression level of MRP1 and diminish the drug sensitivity of OSCC cells. However, the detailed regulatory mechanisms need to be further explored.

A third drug transporter, distantly related to P-gp and MRPs, is BCRP encoded by ABCG2, which was originally isolated from drug-resistant breast cancer cell lines [92, 93]. Meanwhile, growing evidence indicates that ncRNAs can engage in BCRP-mediated drug resistance. Inhibition of BCRP expression enhanced chemosensitivity through miR-302 targeting the 3'-UTR of BCRP mRNA [95]. Yanamoto et al. [96] found that locally recurrent OSCC patients treated with neoadjuvant chemotherapy had elevated expression levels of ABCG2. Furthermore, Lu et al. [97] demonstrated that the expression level of ABCG2 was upregulated in OSCC cells with resistance to 5-FU and CDDP compared to OSCC cells. It could be concluded that the expression level of BCRP correlated with drug resistance in OSCC cells. Cells that are free of Hoechst 33342 dye are described as side population (SP) cells. This type of cells harbored cancer stem cell properties with the capacity for tumor initiation and resistance to chemotherapeutic drugs [98]. In OSCC, Zhang et al. [99] revealed the expression level of ABCG2 was higher in SP cells compared to non-SP cells. Meanwhile, it has been confirmed that a high expression level of ABCG2 in SP cells facilitated the progression of drug resistance, cancer cell proliferation, and tumor invasion in OSCC [100]. Unfortunately, intensive studies on the mechanism of ncRNA-mediated ABCG2 regulation of drug resistance of OSCC are still lacking.

3.2.2 Epithelial-mesenchymal transition

Epithelial-mesenchymal transition (EMT) is a reversible cellular program characterized by the loss of polarity of epithelial cells and their transformation into mesenchymal cells with the ability to move freely [101]. The EMT process is initiated by EMT-activating transcription factors (EMT-TFs), including three protein families: Snail (Snail/SNAI1 and Slug/Snai2), basic helix-loop-helix (TWIST1, TWIST2, and TCF3), and zinc-finger E-box-binding homeobox (ZEB1 and ZEB2) (Figure 2) [102, 103]. First, epithelial genes such as E-cadherin, Claudin, cytokeratin, and zona occludens 1 are suppressed whilst mesenchymal phenotype genes including Vimentin, fibronectin, N-cadherin, and matrix metalloproteinases (MMPs) are activated [104]. Then, epithelial cells lose their typical polygonal, pebbled appearance and acquire a spindle-shaped mesenchymal morphology. Subsequently, the epithelial actin architecture restructures and cells acquire motility and invasiveness by forming lamellipodia, filopodia, and invadopodia, as well as by producing MMPs to degrade extracellular matrix (ECM) proteins [105]. Further, the mesenchymal cells produced are also able to reversibly return to back to their epithelial state in a process known as mesenchymal-epithelial transformation (MET) [106]. It has been established that the EMT process plays influential roles in specific processes such as embryonic development, tissue formation, and wound healing [107]. Furthermore, activation of inappropriate EMT process contributes to malignant progression of several cancers, such as cervical cancer, OSCC, and more [108, 109].

EMT is known to encompass multiple molecules and signaling pathways, and more recently ncRNAs have been shown to serve as crucial regulators of expressions and functions of EMT-TFs in OSCC pathologic processes (Table 3). For example, the expression level of circIGHG was found to be significantly upregulated in OSCC tissues compared to adjacent non-tumor tissues and was positively associated with EMT phenotype. It was further found that circIGHG induced EMT program via targeting miR-142-5p and thus, promoted OSCC progression [111]. Emerging evidence also suggested that EMT, particularly EMT-TFs, could affect the development of tumor drug resistance. EMT-TFs can bind to promoters of certain ABC transporter genes, thereby, activating the EMT program and enhancing drug resistance [112]. It can be seen that there were broad and profound mechanisms by which ncRNAs can mediate the EMT process and promote tumor drug resistance. LncRNA TINCR, a spliced lncRNA, is essential for normal epidermal differentiation. Compared with sensitive cells, the expression level of lncRNA TINCR was significantly increased in drug-resistant cells. Mechanistically, lncRNA TINCR, sponging miR-125b, stimulated human epidermal growth factor receptor 2 (HER-2) release and induced drug resistance. Furthermore, Snail-1 was a target gene of miR-125b. LncRNA TINCR silencing reversed drug resistance and EMT process by the regulation of miR-125b targeting HER-2 and Snail-1, respectively [113]. Therefore, the EMT program and tumor drug-resistant processes regulated by ncRNAs involve a variety of complex molecules and signaling pathways, with ncRNAs often acting as upstream regulators. It can be postulated that the expression levels of ncRNAs can be determinants of the EMT program and cell drug-resistance progression, and ncRNAs can serve as a potential target regulatory window in the inhibition of EMT program and tumor drug resistance.

Currently, accumulating evidence suggests complex associations between the EMT program and drug resistance of OSCC. It has been found that MDR tumor cells induced by various chemotherapeutic agents such as CDDP and epidermal growth factor receptor (EGFR) inhibitors frequently possess EMT phenotype. For example, EMT phenotype was observed in cetuximab-resistant OSCC cells with a concomitant loss of EGFR expression [116]. CDDP-resistant OSCC cell lines manifested an EMT phenotype, with decreased expression levels of E-cadherin and increased expression levels of TWIST and N-cadherin [117]. Sun et al. [118] constructed stabilized CDDP-resistant TSCC cell models and corroborated that CDDP-resistant cells exhibited mesenchymal phenotype compared to parental cells. Further results revealed that decreased expression levels of miR-200b and miR-15b contributed to chemotherapy-induced TSCC EMT phenotype. These results indicated that drug-resistant OSCC cells induced by chemotherapeutic agents tended to exhibit EMT phenotype, which predisposed residual cancer cells for being more aggressive. Notably, the EMT program also increased MDR emergence in OSCC. Snail overexpression inhibited expression levels of E-cadherin and β-catenin in OSCC cells and promoted the EMT process, as well as enhanced cellular resistance to erlotinib [119]. Lin et al. [120] found that OSCC cells with EMT phenotype induced by PAK1 (p21 (RAC1) activated kinase 1) exhibited a CDDP resistance. PAK1 took part in the invasion, migration, and cytoskeletal remodeling of OSCC cells [121]. In addition, miR-485-5p overexpression suppressed PAK1, to further reversing the EMT process. Thus, the EMT process and chemoresistance in OSCC can often coexist and mutually reinforce each other, which may involve common molecules and signaling pathways in both. Chemotherapy can induce the EMT process to promote tumor invasion and metastasis, which in turn can lead to MDR. These feedback loops collectively contribute to the malignant development of OSCC. Moreover, the paramount regulatory roles of ncRNAs in the EMT program and drug resistance of OSCC should also be considered. A better understanding of how ncRNAs regulate the EMT process and MDR can shed light on more effective ways to improve OSCC prognosis.

3.2.3 DNA damage repair

Small molecules binding to specific DNA sites are considered as potential chemotherapeutic agents. Currently, the mechanisms of many chemotherapeutic agents are to block tumor cell division by damaging DNA, such as CDDP, carboplatin, and 5-FU [122]. However, cancer cells have developed enhanced DNA repair capacity to diminish the sensitivity of cancer cells to therapy [123]. Under normal physiological conditions, multiple DNA damage responses exist for repairing damaged DNA to maintain genomic stability in cells, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end joining (NHEJ) [124, 125]. In addition, cells can mobilize low-fidelity trans-lesion synthesis (TLS) DNA polymerase to bypass damaged DNA lesions and prevent cell death through the TLS system [126]. These repair mechanisms are of great value in maintaining normal cell survivals. Nevertheless, in cancer cells, these mechanisms apparently are hindrances to the efficacy of chemotherapeutic agents. Growing studies suggest that following the use of chemotherapeutic agents, enhanced DNA repair mechanisms are identified as a primary mechanism of drug resistance [127-129].

Intriguingly, alteration of molecules in signaling pathways that regulate DNA repair capacity contributes to the sensitivity and resistance of chemotherapeutic agents (Figure 3). RAD51, an important HR repair protein, can repair DNA damage caused by chemotherapeutic agents, thereby reducing the efficacy of drugs and thus, trigger MDR [130, 131]. Enhanced DNA repair capacity was observed in drug-resistant gastric cancer cells [132]. Further results showed that interferon regulatory factor-1, a tumor suppressor, could directly suppress the expression level of RAD51 via binding the RAD51 promoter, thereby impairing DNA damage repair and ultimately reversing chemoresistance [132]. The tumor suppressor complex breast cancer susceptibility gene 1; BRCA1-associated RING domain protein 1 (BRCA1-BARD1) repairs DSBs by HR signaling pathway [133]. Zhao et al. [134] indicated that the BRCA1-BARD1 complex promoted the assembly of synaptic complexes, which are key intermediates in RAD51-mediated DNA repair. It is therefore clear that BRCA1 and BARD1 are key regulators of the functions of RAD51. These results suggest that targeting molecules that regulate DNA repair signaling pathways could be an effective approach to reversing MDR in OSCC.

It is becoming clear that ncRNAs affect protein stability and induce drug resistance in tumor cells by regulating DNA damage-responsive genes (Table 4). As a central role in NHEJ, X-Ray Cross Complementing 4 (XRCC4) was abundant on DNA ligase 4 and bound with XRCC4-like factor to form complexes that formed alternate helical filament DNA to help cells survive [135]. Reduced expression level of miR-151a was found in temozolomide (TMZ)-resistant cells. Mechanistically, miR-151a overexpression can sensitize TMZ-resistant cells by repressing XRCC4-mediated DNA repair [137]. More recently, mounting evidence revealed that altered expression levels of lncRNAs were present in tumor cells and that lncRNA expression profiling could correlate with the evolution of tumor drug resistance [138, 139]. By using a microarray screening, Sharma et al. [140] identified a new lncRNA caused by DNA damage, termed DNA damage-sensitive RNA1 (DDSR1). LncRNA DDSR1 was further found to be involved in HR signaling pathway to enhance DNA repair. Lnc-RI silencing interfered with HR signaling pathway, increased DSBs level, and decreased the expression level of RAD51. It was further found that miR-193a-3p could bind to lnc-RI and RAD51 mRNA and block their expression. Thus, lnc-RI competitively recognized miR-193a-3p to increase the expression level of RAD51 and stabilized HR signaling pathway [141]. The expression levels of circRNAs, a type of young ncRNAs, were detected as disordered in a variety of cancers and were considered as key regulators of cancer development, invasion, and metastasis [143, 144]. In recent years, circRNAs have also been found to participate in the progression of tumor drug resistance. In prostate cancer, circ_0062020 overexpression promoted the expression level of thyroid hormone receptor-interacting protein 13 (TRIP13) via sponging miR-615-5p [146]. NHEJ signaling pathway was thus actuated, leading to enhanced DNA repair and decreased drug sensitivity of tumor cells [147]. Although the biological function of circRNAs is not fully understood, explorations of a few circRNAs have provided navigation to mechanisms of tumor drug resistance. Research on multimolecular interactions (i.e. miRNAs-lncRNAs-circRNAs) could help to fully elucidate the drug resistance mechanisms of OSCC.

3.2.4 Autophagy

Autophagy is a highly conserved cellular process of intracellular lysosomal degradation and organelle recycling controlled by more than 40 autophagy-related genes [148, 149]. Autophagy can be categorized as at least three distinct forms: macroautophagy [150], microautophagy (wrapping and degrading cytoplasmic components by bending and folding inwards of lysosomal membranes) [151], and chaperone-mediated autophagy (direct transport of misfolded proteins recognized by translocons into lysosomes) [152]. The most typical type of autophagy is macroautophagy, so the term “autophagy” is often used to refer to macroautophagy. Autophagy plays roles in health and disease states, such as embryonic development [153] and neurodegenerative diseases [154]. Notably, autophagy is involved in cancer progression. Intriguingly, autophagy can exert both pro- and anticancer effects. Taking cancer promotion as an example, when cells are starved, autophagy is enhanced to meet the energy and material needs of cancer cells. The neighbor of BRCA1 gene 1 (NBR1), an autophagy-related receptor, could steer MHC I from the surface of cancer cells into the cytoplasm. As a result, autophagy can reduce the expression level of MHC I on the surface of cancer cells, thereby impeding antigen presentation [155]. In mouse models, blocking the autophagy process restored the expression level of MHC I on the surface of cancer cells, which in turn enhanced antigen presentation and thus, weaken the immune escape of cancer cells [156].

As a “junk cleaner”, the autophagy process is also detected in OSCC. Elevated expression level of LC3II (an autophagy-related gene) was observed in OSCC, whereas migration and invasion of OSCC cells were silenced by autophagy gene blockers [157]. It is well known that ncRNAs have been shown to function as cancer suppressors or oncogenes in OSCC progression. Then, whether autophagy and ncRNAs have synergistic or antagonistic effects in OSCC has attracted the attention of scholars. Gao et al. [158] found that hypoxia enhanced both the expression level of circCDR1as and the autophagy process in OSCC cells. Mechanistically, circCDR1as facilitated the autophagy process via targeting multiple key regulators. Meanwhile, circCDR1as enhanced the autophagy process in OSCC cells by sponging miR-671-5p, inhibiting mTOR, and upregulating AKT and ERK signaling pathways. Thus, ncRNAs serve as upstream messengers along signaling pathways responsible for the regulation of OSCC by autophagy, indicating that targeting ncRNAs could alleviate the autophagy-related OSCC process (Figure 4). However, it remains largely unknown as to how autophagy is regulated by other ncRNAs in OSCC.

Autophagy and ncRNAs are not only involved in cancer progression, but in recent years the two have been found to jointly regulate the development of cancer drug resistance (Table 5). For example, miR-519a enhanced TMZ-induced autophagy and apoptosis processes, while inhibition of miR-519a decreased cellular autophagy and promoted TMZ resistance. In vivo, miR-519a sensitized cells to TMZ and enhanced apoptosis by boosting the cellular autophagy process [159]. In OSCC, autophagic flux was higher in drug-resistant cells compared to parental cells, and inhibition of autophagy led to decreased stemness, suggesting that autophagy enhanced CDDP-induced stemness and chemoresistance in OSCC cells [79]. Interestingly, ncRNAs are also implicated in the autophagy-mediated drug-resistant process in OSCC cells. The expression levels of ATG3 and ATG7 were reduced after lncRNA HOTAIR blocking, which inhibited autophagy. In parallel, the rate of apoptosis increased and the sensitivity of OSCC cells to CDDP was enhanced [67]. Ectopic expression of lncRNA highly upregulated in liver cancer (HULC) induced autophagy process in cancer cells, while lncRNA HULC silencing sensitized cancer cells to anti-tumor drugs by inhibiting the autophagy process. Importantly, lncRNA HULC was aberrantly upregulated in OSCC cell lines compared to normal cells and inhibition of lncRNA HULC expression suppressed cancer cell proliferation and drug resistance [160, 161]. Thus, inhibition of lncRNA HULC to alleviate OSCC resistance may be partially mediated by the autophagic signaling pathways. Collectively, inhibition of the autophagy process modulated by expression levels of ncRNAs can impair resistance of OSCC cells to chemotherapeutic drugs, thereby, promoting apoptosis and alleviating OSCC progression. Autophagy inhibitors may be promising adjuvant approaches in the fight against the drug resistance of OSCC. Therefore, there is an urgent need to develop new autophagy modulators with higher efficacy and lower toxicity for the treatment of drug resistance of OSCC.

In general, with the progression of chemotherapeutic drug action on cancer cells and conditions of cancer cells, drug resistance mechanisms can be mainly attributed to drug efflux mediated by transmembrane transporter proteins, elevated apoptosis threshold induced by EMT, enhanced DNA repair capacity, and drug degradation due to autophagy process. Certainly, ncRNAs can also regulate the OSCC resistance process in other ways besides the aforementioned drug-resistant mechanisms. The glycolytic pathways can also be mediated by ncRNAs to trigger drug resistance of OSCC. Wang et al. [164] found that lnc-p23154 promoted Glut1 expression, triggered glycolytic dysregulation, and induced drug resistance of OSCC by directly targeting the 3'UTR of miR-378a-3p. Importantly, the mechanisms of different drug resistance of OSCC appear to be independent, but in fact the mechanisms interact with each other. For example, EMT-TFs could recognize ABC transporter genes to regulate drug efflux, and the BRCA1 gene is involved in both DNA damage repair and the autophagy process. At the same time, ncRNAs play connecting roles like bridges. Consequently, a better understanding of the mechanisms of ncRNA-mediated drug resistance of OSCC can improve the basis for developing approaches to target ncRNAs to alleviate OSCC resistance.