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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 1-5

Mechanisms correlated with chemotherapy resistance in tongue cancers


1 Department of Oral Geriatrics, School and Hospital of Stomatology, Jilin University, Changchun 130021, China
2 Department of Otolaryngology Head and Neck Surgery, The Second Hospital, Jilin University, Changchun, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Dan Yu
Department of Otolaryngology Head and Neck Surgery, The Second Hospital, Jilin University, Changchun 130041
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_763_17

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 > Abstract 

Tongue cancer is one of the most common and deadly types of head and neck cancer. The incidence of tongue cancer has been particularly high and remained been increasing in some countries. A main reason for poor prognosis and clinical outcome for tongue cancer was its resistance to chemotherapies, behind which the mechanisms have been not clear. In this review, we summarized literatures published in recent years and listed the proteins, biomacromolecules, and signaling pathways related to this drug resistance. We hoped that this summary could provide reference for researchers to develop new treatment strategies for tongue cancer.

Keywords: Resistance, tongue cancer, treatment


How to cite this article:
Han G, Xu C, Yu D. Mechanisms correlated with chemotherapy resistance in tongue cancers. J Can Res Ther 2018;14:1-5

How to cite this URL:
Han G, Xu C, Yu D. Mechanisms correlated with chemotherapy resistance in tongue cancers. J Can Res Ther [serial online] 2018 [cited 2019 Nov 20];14:1-5. Available from: http://www.cancerjournal.net/text.asp?2018/14/1/1/226761


 > Introduction Top


Head and neck cancers included tumors originated from any part on head and neck except for eyes, brain, ears, thyroid, and esophagus. Laryngocarcinoma, paranasal sinuses carcinoma, and oral cancers have been frequently considered as head and neck cancers. The pathologic condition was often very complicated for head and neck tumors, and it has proved that most of the tumors were squamous cell carcinomas.[1],[2],[3]

Tongue cancer was one common type of oral cancers, which has been a serious health issue in many countries with significant mortality. According to statistical data, the incidence of this disease has been rising among younger people. The pathogenesis of tongue cancer has not yet been clear. Some common carcinogenic factors were all thought to be related with tongue cancer, including heat, chronic injuries, and ultraviolet. This tumor was characterized by high lymphatic metastasis, together with recurrence and drug resistance, which constituted the three main causes of death in patients with tongue cancer. In general, the choice of primary treatment of tongue cancer was based on the stage of the tumor while surgical treatment remained to be the best option. For advanced stage tumors in which surgery was not feasible or postoperative therapy, radiotherapy or chemotherapy or their combination was recommended.[3],[4],[5],[6],[7],[8]

Chemotherapy resistance has been a major challenge in the success treatment of cancers. As the cancer cells quickly gained tolerance to first-line chemotherapies such as 5-fluorouracil (5-FU), cisplatin and docetaxel, and target drugs in the majority of patients, the clinical outcomes remained unsatisfactory, while the reason remained unknown. Although researchers have been continuously exploring alternative treatments, it was not enough to improve the current status of tongue cancer. Therefore, it was significant to reveal the mechanisms behind this drug resistance, and the obstacle may be overcome, thus developing effective therapies.[3],[9],[10],[11],[12]


 > Mechanisms Top


Epidermal growth factor receptor

Epidermal growth factor (EGF) receptor mutations were frequently found in various cancers, and EGF was important in the proliferation of tumor cells. Researchers proved that as recombinant human EGF was added, the resistance against chemotherapy was enhanced in tongue cancer cell lines, which could be attenuated by the silence of EGF.[13] In squamous cell tongue carcinoma cell lines, one of the EGFs, amphiregulin, was found to be overexpressed. Erk2 was proved to be essential to transduce the signal transducer between Met activation and amphiregulin, where Met often predicted poor clinical outcome.[14]

Metabolism

The glutathione S-transferase (GST) expression was one indicator of multidrug resistance. The drug resistance could be reversed by decreased GST activity in tongue cancer cells.[15] On cisplatin treatment, expression of one subunit of the glutamate/cystine transporter system xc-, xCT, was significantly increased, and levels of glutathione were also elevated, which together participated in cisplatin resistance in tongue squamous cell carcinoma (TSCC) cells. Inhibition of xCT could attenuate this resistant reaction.[16] Another protein related with glycometabolism and participated in chemotherapy resistance was RAGE, which indicated receptor for advanced glycation end-products. Blockade of RAGE could enhance the antitumor effects of cisplatin through suppressing canonical pathway proteins and autophagy-related proteins while increasing noncanonical proteins and proapoptotic proteins.[17]

Tongue cancer chemotherapy resistance-associated protein

Increased expression of tongue cancer chemotherapy resistance-associated protein1 (TCRP1) was observed in cisplatin-resistant tumor cell lines, which was mainly expressed in cytoplasmic. Efficiency of cisplatin was predicted to be the worst in TCRP1-positive patients.[18] Studies showed that c-Myc upregulated TCRP1 through directly binding to its promoter. c-Myc upregulation was determined in cisplatin-resistant cell lines. Along with TCRP1, c-Myc indicated worse prognosis in patients with tongue cancers.[19] In another study, cell transformation and tumorigenesis could be enhanced by the upregulation of TCRP1, involving the phosphorylation of the oncogenic kinase 3-phosphoinositide-dependent protein kinase-1 through direct interaction.[20]

Zinc finger E-box-binding homeobox 1

In tongue cancer cell lines, CA9 overexpression induced chemotherapy resistance, which could be reversed by the knockdown of CA9. Zinc finger E-box-binding homeobox 1 (ZEB1) was a transcriptional regulator that could bind to the promoter of CA9. Overexpression of ZEB1 leads to stable pHi and decreased cell apoptosis. Clinically, expression of ZEB1 and CA9 was associated with a poor prognosis.[21] 14-3-3σ, which belonged to a highly conserved soluble acid family, its expression can be induced by chemotherapy and the knockdown of 14-3-3σ enhanced chemotherapy resistance in tongue cancer cells. 14-3-3σ inhibited β-catenin signaling through binding to GSK3β. 14-3-3σ can also upregulate GSK3-β protein level which leads to sensitization of tongue cancer cells to chemotherapy. Moreover, the 14-3-3σ/GSK3-β/β-catenin axis was associated with ZEB1, which was a negative effector in this feedback loop.[22]

miRNAs

Decreased levels of miR-491-3p were observed in tongue cancer cells that were resistant to multiple drugs. Functional inhibition of this miRNA could enhance resistance of tongue cells to chemotherapy. mTORC2 activity was increased in resistant tongue cancer cells, and mTORC2 component, Rictor, was directly targeted by miR-491-3p. This inhibition of mTORC2 activity resulted in the sensitization of tongue cancer cells to chemotherapy. Taken together, high expression of Rictor and low levels of miR-491-3p were positively correlated with poor prognosis in patients with tongue cancer.[23]

MiR-21 was an oncogenic molecule correlated to the resistance of several kinds of human cancer cells. Levels of miR-21 were increased in drug-resistant tongue cancer cell lines. Overexpression of miR-21 was regulated by MYCN. CADM1 expression was directly targeted by miR-21 and downregulated in these cell lines. Researchers demonstrated that CADM1 inhibited nuclear translocation of BMI1. High levels of miR-21 and MYCN and low level of CADM1 predicted a poor prognosis in TC patients, suggesting that the MYCN/miR-21/CADM1 axis was one of the major mechanisms on chemotherapy resistance of tongue cancer.[24] The upregulation of miR-21 and downregulation of PDCD4 were also related. Inhibition of miR-21 was associated with increased PDCD4 protein level while silence of PDCD4 leads to resistant to cisplatin therapy and weakened growth-inhibitory effects.[25]

MiR-24 was significantly upregulated in tongue carcinoma cells and tissues. This dysregulation was found to be related to higher grade and later stage of carcinoma. It considered that this effect of miR-24 was through targeting PTEN, which lead to increased activation of Akt pro-survival pathway.[26]

MiR-222 expression was related with cisplatin resistance and migratory/invasive potential in tongue cancer. Knockdown of ATP-binding cassette subfamily G member 2 (ABCG2) enhanced response to cisplatin and inhibited migratory/invasive activity of TSCC cell line. The reduced expression of the ABCG2 could be induced by miR-222. Together, the miR-222-ABCG2 pathway played an important role in cisplatin resistance in TSCC.[27]

The overexpression of miR-23a significantly promoted twist expression by a c-Jun N-terminal kinase-dependent mechanism, which could be reversed by miR-23a knockdown. Increased expression of twist and miR-23a was critical in promoting chemotherapy resistance in tongue cancer cells as well as the poor prognosis of tongue cancer patients.[28]

MiR-203 expression was significantly decreased in tongue cancer samples and was even lower after cisplatin treatment in tongue cancer cell line. While PIK3CA upregulation resulted in cisplatin resistance, miR-203 expression can reduce PIK3CA expression and Akt activation and suppress cell proliferation. Studies have demonstrated that the effect of miR-203 was especially dependent on PIK3CA.[29]

Tripartite motif-containing 14

Tripartite motif-containing 14 (TRIM14) was located on mitochondrion and participates in immunoreactions. It was proved to be upregulated in cell lines and samples of tongue cancer. Clinical analysis showed that TRIM14 expression was related with the tumor, node, and metastasis classification and was a prognostic indicator in patients with TSCC. Overexpression of TRIM14 promoted cisplatin resistance in TSCC cells in vitro. Evidences showed that nuclear factor-kappa B (NF-κB) signaling pathway was involved in TRIM14-induced proliferation, angiogenesis, and tumorigenicity.[30] There were also evidences that TRIM14 was related with epithelial-mesenchymal transition (EMT) and was able to induce generation of stem-like cells. miR-15b seemed to target cancer-initiating cells and sensitized TSCC cells to chemotherapies.[31]

B-cell lymphoma-2

B-cell lymphoma-2 (Bcl-2) was the most underemphasized oncogene in the investigation of tumor cell apoptosis. Elevated levels of Bcl-2 were observed in tongue carcinoma cell lines, which induced a resistance to cisplatin. Inhibition of Bcl-2 suppressed proliferation and increased apoptosis in oral TSCC (OTSCC) cells and made the cells sensitize to cisplatin.[32] It demonstrated that there was a positive correlation between activator protein 1 (AP-1) and NF-κB expression, and level of Bcl-2 protein and mRNA were correlated with and AP-1 expression, which together regulate progression and chemotherapy resistance of tongue cancer.[33]

Other molecules

Upregulated expression of metastasis associated in colon cancer-1 (MACC1) was related with poor overall survival in tongue squamous cell carcinoma (TSCC) patients. After the knockdown of MACC1, cisplatin resistance of TSCCA cells would be significantly inhibited as well as their migration and invasion activities. Levels of MACC1 and extracellular matrix metalloproteinase (MMP) inducer were relative in TSCC tissues.[34]

Erythrocyte membrane protein band 4.1 like 5 (EPB41L5) was a protein participating in EMT, which could induce drug resistance. High levels of EPB41L5 were correlated with poor clinical outcomes in patients with tongue cancer. Expression of EPB41L5 was demonstrated to be related with ADP-ribosylation factor 6, KLF8, and FOXO3 levels.[35]

Podocalyxin (PODXL) was important in malignant progression of many types of cancers, which was associated with cisplatin response in tongue cancer cells. Level of PODXL was positively related with expression of BMI1 and focal adhesion kinase (FAK) activity. Depending on FAK, the stability of BMI1 mRNA would be increased with the overexpression of PODXL, thus leading to enhancement of chemotherapy resistance in OTSCC cells.[36]

Treatment of a demethylating agent was able to restore sensitivity to cisplatin resistance in a cisplatin-resistant TSCC cell line as well as in a xenograft model with that cell line. These results suggested that methylation of some key genes took part in the mechanism of cisplatin resistance.[37]

Sam68 was a member of RNA APs. Detection of Sam68 was meaningful in predicting prognosis of patients with OTSCC. Sam68 was involved in cell apoptosis-signaling pathways. Upregulation of Sam68 contributed to cisplatin resistance through the induction of caspase-9 and caspase-3 and PARP while the silence of Sam68 could restore the sensitivity to chemotherapy.[38]

The αvβ3, an important type of integrins, took parts in adhesion, migration, and invasion in tumor cells. A tongue squamous carcinoma cell line overexpressing αvβ3 was resistant to many antitumor drugs. The cell line turned out to be more adhesive and invasive. Experiment results showed that this process involved integrin-linked kinase and was depend on the loss of phosphotyrosine kinase pSrc (Y418) as treatment with pSrc (Y418) inhibitors could also lead to multidrug resistance.[39]

NNK has been proved to be a carcinogenic metabolite in tobacco smoke. NNK exposure could induce upregulation of many cancer-related proteins including Snail and aldehyde dehydrogenase 1 and increase migration and invasion in tongue cancer cell line. Snail-Raf kinase inhibitor protein signaling pathway seemed to be crucial in drug resistance caused by NNK.[40]

The p21 activated kinase 1 (PAK1), as well as ERCC1 (a DNA excision repair protein) and YAP (an essential effector in Hippo signaling pathway), was overexpressed and related with cisplatin resistance in tongue cancer cells. While EMT and chemotherapy resistance could be reversed by high levels of miR-485-5p through inhibiting expression of PAK1.[41]

NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome was highly expressed and activated in tissues of tongue cancer patients who went through chemotherapies based on 5-FU, which was also found in experiments in vitro or in xenograft models. This high level of NLRP3 inflammasome was related with 5-FU resistance and poor prognosis and was characterized by ROS inducement and interleukin 1 beta secretion. Apoptosis induced by 5-FU could be promoted by the silence of NLRP3 in tongue cancer cells.[42]


 > Conclusion Top


Tongue cancer was one of the most fatal subtypes of head and neck cancer. The incidence of tongue cancer kept increasing, especially in young population. Surgery was recommended for treating tongue cancer at earlier stage while radio- and chemo-therapies were also frequently adopted for late-stage disease and postoperative procedures. The resistance of first-line drugs was the main barrier for obtaining satisfying clinical efficacy. It was very meaningful to understand the mechanisms related with this chemotherapy resistance in tongue cancer. Some proteins or biomacromolecules have been proved to participate in the process, including SET/I2PP2A, MMP-9 and-2, multidrug resistance protein 1 and topoisomerase IIβ, and cancer stem cells also seemed to be involved.[43],[44],[45] However, the mechanisms of chemotherapy resistance was complicated and almost involved in every process in cells. Hence, a lot of hard work should be required to fully understand this drug resistance and contribute to development of effective therapies.[1],[3]

Financial support and sponsorship

This work is supported by grants from Science and Technology Department of Jilin Province Youth Foundation (20150520042JH, 20160520150JH); the National Natural Science Foundation of China (81502348, 81572653).

Conflicts of interest

There are no conflicts of interest.

 
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