Abstract
microRNAs (miRNAs) are responsible for fine tuning the normal expression of RNA networks in human cells. Accumulating studies have demonstrated that abnormally expressed miRNAs have pivotal roles in the development of head and neck squamous cell carcinoma (HNSCC). Specifically, expression signatures of miRNAs in HNSCC have revealed dysregulated production of miRNAs and the resultant abnormal production of mRNAs and proteins. In this review, we discuss current findings regarding aberrantly expressed miRNAs and their contribution to HNSCC molecular pathogenesis.
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Head and neck squamous cell carcinoma
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. It arises in the oral cavity, nasopharynx, oropharynx, hypopharynx and larynx.1, 2 HNSCC is associated with smoking tobacco, consumption of strong alcoholic beverages and infection by human papillomavirus.2, 3 Even with current advances in multimodality therapy, the overall survival rate for HNSCC patients is poor and the mortality rates for this disease have not improved in the past 40 years.4, 5 Local recurrence and distant metastasis after advanced treatment appear to be major contributing factors in the poor survival rate of HNSCC patients.6
HNSCC is a heterogeneous disease with accumulated genetic alterations, such as chromosomal abnormalities, inactivation of tumor suppressors and activation of oncogenes.7 For example, there is frequent silencing of tumor suppressor genes (for example, p16ink4a, p14ARF and TP53) and activation of oncogenic genes (for example, CCND1, RB1, PI3K and EGFR).8 Dysregulated gene expression networks might contribute to malignant transformation and the invasive malignancy of HNSCC.
Recent advances in whole-exome sequencing have provided new insights into the molecular pathogenesis of HNSCC. These data have shown that multiple antitumor pathways (TP53, RB1/INK4/ARF and NOTCH) participate in tumor initiation and aggressiveness.9 The Cancer Genome Atlas (TCGA) study showed the presence of chromosomal amplifications in 3q26-3q28, a region involving HNSCC-promoting genes TP53 and SOX2 and the oncogene PIK3CA.10, 11 Moreover, in smoking-related HNSCCs, studies have demonstrated loss-of-function of both TP53 and CDKN2A as well as frequent copy-number amplification of 3q26-3q28 and 11q13-11q22.12 Whole-exome sequencing has demonstrated that mutations in the PI3K pathway were frequently involved in HNSCC.13
Identification of aberrantly expressed microRNAs based on expression signatures of HNSCC
In normal cells, miRNAs tightly regulate both protein-coding and protein-non-coding genes.14 A single miRNA can control thousands of targeted RNAs, and >60% of protein-coding genes may be influenced by miRNAs.15 Dysregulated miRNA expression disrupts the normal RNA networks present in healthy cells, leading to oncogenic development.15, 16 Aberrantly expressed miRNAs can be divided into two classes depending on their expression status.17 Overexpressed miRNAs can act as oncogenes if they repress tumor suppressor genes. In contrast, miRNAs with antitumor properties can enhance the development of cancer cells when they are downregulated (Figure 1). Strategies to identify abnormal expression of miRNAs and miRNA-mediated cancer pathways offer new directions in cancer research.
Oncogenic microRNA (miRNA) and tumor-suppressive miRNA in cancer cells. miRNAs can be separated into two main classes: those that are oncogenic and those that are tumor suppressive. Overexpressed miRNAs can act as oncogenes by repressing tumor suppressor genes, whereas underexpressed miRNA may normally function as antitumor miRNA by negatively regulating cancer-promoting genes.
Cytogenetic alterations constitute early events in the progression of cancer development. For example, changes in chromosomal structure can alter the expression of miRNAs. Chromosomal regions that are subject to amplification or loss may result in miRNAs with oncogenic behavior or loss of tumor-suppressive properties.18, 19 Recent evidence suggests that epigenetic alterations (heritable changes in gene expression without DNA sequence alteration) may lead to aberrant expression of miRNAs in HNSCC cells.20, 21, 22 It is well known that DNA hypermethylation of CpG islands leads to the inactivation of tumor-suppressive miRNA in cancer cells.19, 23 In oral cancer cells, miR-34b, miR-137, miR-193a and miR-203 function as tumor suppressors and these miRNAs are located on CpG islands and silenced through aberrant DNA methylation.24
Activation of DNA methyltransferases modulates the expression of both protein-coding and non-coding genes. Three DNA methyltransferases are particularly important: DNMT3A, DNMT3B and DNMT1.25 These methyltransferases are regulated by specific miRNAs, leading to demethylation of specific genomic sequences.26 Thus, downregulation of DNA methyltransferases permits expression of protein-coding and non-coding genes. Other important epigenetic gene controls are exerted by histone modification, such as histone acetylation (associated with active gene transcription) and methylation of histone H3 lysine 9 (inactivation of gene expression).21, 22 Evidence indicates that DNA methylation and histone modification cooperatively regulate transcription of the human genome21, 22, 26 and that epigenetic modifications affect cancer pathogenesis. Thus, it is important to elucidate the miRNA networks that control the expression of protein-coding and non-coding genes in cancer cells.
Advanced molecular technologies can identify abnormally expressed miRNAs in various types of cancer cells. To seek out differentially expressed miRNAs in HNSCC cells, we used HNSCC clinical specimens to establish microarray-based, PCR-based and deep sequencing-based miRNA expression signatures.27, 28, 29, 30 Moreover, we have demonstrated the roles of miRNAs in human SCC pathogenesis.31, 32 In this review, we highlight aberrantly expressed miRNAs in HNSCC based on 11 miRNA expression signatures from previously published studies.27, 28, 29, 30, 33, 34, 35, 36, 37, 38, 39 Differentially expressed miRNAs identified from signatures are summarized in Table 1. The signatures exhibit considerable variability in the differential expression of miRNAs. The variety of aberrantly expressed miRNAs may depend on technical aspects, patient populations and analysis platforms for miRNA signatures. However, there are certain miRNAs that frequently observed to be up- or downregulated among the 11 signatures. These data suggest that these miRNAs may contribute substantially to HNSCC pathogenesis (Tables 2 and 3).
Aberrantly expressed miRNAs in human chromosomes
High-resolution arrays for comparative genomic hybridization have used to document HNSCC features. Combined genome-wide gene expression studies have revealed candidate tumor suppressors or oncogenes that contribute to HNSCC initiation, progression and metastasis.40 It has hypothesized that novel cancer-related genes or miRNAs might be present in chromosomal regions that have deleted or amplified. To investigate the correlation between chromosomal alterations and miRNA expression in HNSCC cells, we have mapped dysregulated miRNAs in human chromosomes, merging the data from current array-based comparative genomic hybridization analysis (Figure 2).41, 42, 43, 44, 45
Chromosome mapping of aberrantly expressed microRNA (miRNA) in head and neck squamous cell carcinoma. Downregulated and upregulated miRNAs in chromosomes, merging the data from array for comparative genomic hybridization analysis (green bars are amplified regions whereas red bars show regions of loss). The blue arrows indicate downregulated miRNAs found in multiple profiling studies, and the brown arrows indicate upregulated miRNAs found in multiple signatures.
Six miRNAs (miR-127, miR-411, miR-376c, miR-376a, miR-410 and miR-487b) are located within chromosomal region 14q32 (Figure 2). In that region, large miRNA clusters are present and 42 intergenic miRNAs are located within 10 kb of one another.46 Past studies have indicated that this chromosomal region has pivotal roles in embryonic development.46, 47 Several reports showed that tumor-suppressive miRNAs were clustered there in several types of cancers. Among them, miR-410 inhibited cancer cell proliferation and invasion by targeting Wnt-7β, an activator of the Wnt-β-catenin pathway.48
Some miRNAs are grouped closely together within the human genome, that is, at distances <5 Kb pairs. These so-called ‘clustered miRNAs’ have studied to determine their functional role in human cancers.49 Several such clusters are downregulated in several signatures of HNSCC, including the miR-143/miR-145 cluster (5q32), the miR-30*/miR-30c-2 cluster (6q13), the miR-1-2/miR-133a-1 cluster (18q11.2), the miR-1-1/miR-133a-2 cluster (20q13.3) and the miR-99a/let-7c cluster (21q21) (Figure 2). The expression of clustered miRNAs has regulated by the same transcriptional mechanisms. In some miRNA clusters, all of the members of the clustered miRNAs control identical target genes.50
There is a consensus that certain clustered miRNAs (miR-145 and miR-143) are frequently reduced in a broad range of human cancers, and that these miRNAs possess tumor-suppressive activities.51, 52, 53, 54 Several reports showed that miR-145 and miR-143 targeted the same genes (GOLM1, HK2 and FSCN1).51, 52, 53 Tumor suppressor TP53 transcriptionally regulates the antitumor miR-145 by direct interacting with the miR-145 promoter region.55, 56, 57, 58 Interestingly, the MYC oncogene is directly repressed by miR-145.55, 59, 60 Research indicates that antitumor miR-145 participates in TP53 regulatory pathways, and contributes to the direct suppressor of MYC oncogenes.
Downregulated miRNAs act as tumor suppressors in HNSCC
We and other researchers have used gain-of-function studies to investigate the functional roles of miRNAs as tumor suppressors.29, 30, 31, 32 Tumor-suppressive miRNAs and their target genes are summarized in Table 4.
We have identified tumor-suppressive miRNAs in HNSCC based on expression signatures.27, 28, 29, 30 From those data, miR-375 was the most frequently downregulated miRNA in HNSCC cells. Restoration of miR-375 markedly suppressed cancer cell aggressiveness, suggesting this miRNA acts as a tumor suppressor.61, 62, 63 Our study showed that the metadherin (MTDH) and lactate dehydrogenase B genes were directly regulated by miR-375 in HNSCC cells.61 Similarly, another study showed the regulation of MTDH by miR-375. Moreover, silencing of MTDH in HNSCC cell lines resulted in significantly reduced tumor formation.64 Hypermethylation of the promoter regions of miR-375 silenced miR-375 expression in cancer cells.65, 66
The miR-99 family (miR-99a, miR-99b and miR-100) is evolutionarily ancient. The origin of the family precedes bilaterian ancestors.67 miRNAs in the same family have nearly identical sequences and target the same sets of genes.67 Among miR-99 family members, miR-99a and miR-100 are frequently downregulated in several HNSCC signatures (Table 2). The deregulation of miR-99 family members has been reported frequently in several types of cancers, and they have an important role in regulating cancer cell development and progression.68, 69 In a recent study, miR-99 family members were identified using a mouse dermal wound healing model. These miRNAs regulate cell proliferation and migration of skin and oral mucosa epithelial cells by regulating AKT/mTOR signaling.70 The same group showed that a miR-99 family member directly controlled HOXA1 in embryonic development.67
The miR-100 gene is mapped on human chromosome 11q24.1, which is frequently deleted in several types of cancer.71 Several reports showed that downregulation of miR-100 was involved in human cancers.72 miR-100 regulates the PI3K/AKT pathway, which is a key signaling system that promotes cancer cell proliferation and suppresses apoptosis in bladder cancer.73 On the other hand, miR-100 inhibits invasion through regulating HOXA1 in breast cancer.74 Because of the remarkable stability of miR-100 in blood, several reports revealed that the expression levels can be used as a biomarker for diagnosis and prognosis.72
The miR-125 family consists of several members, miR-125a (chromosome 11q24) and miR-125b (chromosome 24q21.1), with distinct seed sequences.75 A large number of studies have found that miR-125b is dysregulated in multiple types of cancers and has pivotal roles in cancer pathogenesis.76, 77, 78, 79 Overexpression of miR-125b-1 inhibited HNSCC cell aggressiveness via targeting of tumor-associated calcium signal transducer 2 (TACSTD2) as a glycoprotein.80
miR-125b regulates the ErbB genes, which are tyrosine kinase receptors.81 Surprisingly, miR-125b can also promote cell proliferation through its targeting of p53 expression.82 In fact, upregulated miR-125b promotes cancer cell aggressiveness in many cancers.75, 83, 84, 85, 86
miR-139 is located on chromosome 11q13.4. It acts as a tumor suppressor in colorectal cancer, hepatocellular cancer, breast cancer and non-small cell lung cancer,87, 88, 89, 90 and it may be a promising biomarker.91 Moreover, one report showed that miR-139 inhibited proliferation and metastasis via targeting of CXCR4 in laryngeal squamous cell carcinoma.92
The miR-204 gene is located in the cancer-associated genomic region (CAGR) 9q21.12. It exhibits a high frequency of loss of heterozygosity in various cancers including HNSCC.93 Furthermore, the expression levels of miR-204 in HNSCC were downregulated and it suppressed HNSCC cell migration, adhesion and invasion in HNSCC.93
We recently showed that six miRNAs (miR-26a, miR-26b, miR-29a, miR-29b, miR-29c and miR-218) markedly inhibited metastasis-related genes or pathways in HNSCC.30, 31, 32 For example, miR-26a/b, miR-29a/b/c and miR-218 commonly targeted lysyl oxidase-like 2 (LOXL2), which promotes metastasis in several types of cancers.94 Furthermore, the 11 signatures revealed that miR-26a-5p/miR-26b-5p, miR-29a-3p/miR-29c-3p and miR-218 were downregulated in HNSCC. Therefore, we will focus on these families below.
The three members of the miR-26-family are distributed as follows: miR-26a-1 (chromosome 3p22.2), miR-26a-2 (chromosome 12q14.1) and miR-26b (chromosome 2q35). The seed sequences of these miRNAs are identical, suggesting that all miR-26 family members regulate the same human genes. Interestingly, MYC protein directly binds to promoter regions of these miRNAs and MYC negatively suppresses the expression of these miRNAs.95 Expression of miR-26a and miR-26b was significantly downregulated in oral cancer tissues and restoration of both miR-26a and miR-26b significantly inhibited cancer cell migration and invasion.30, 87 miR-26a and miR-26b were reported to possess antitumor functions in several types of cancers.96, 97, 98, 99, 100
The four members of the miR-29 family consist of two miRNA clusters, one located at 7q32 (miR-29b-1 and miR-29a) and the other at 1q32 (miR-29b-2 and miR-29c).101 Downregulation of miR-29s was reported in esophageal cancer, hepatocellular cancer, gastric cancer and colon cancer.101 Furthermore, our past report revealed that expression of miR-29s significantly downregulated and inhibited cancer cell migration and invasion in HNSCC, prostate cancer, renal cell carcinoma and lung cancer.32, 102, 103, 104 On the other hand, miR-29 was upregulated in diffuse large B lymphoma.105
The miR-218 family is divided between two chromosomal regions: miR-218-1 at 4p15.31 and miR-218-2 at 5q34.106 Considerable evidence suggests that downregulation of miR-218 occurs in various cancers and that it normally acts as an antitumor miRNA, such as in colorectal cancer.107 Ectopic expression of miR-218 significantly suppressed HNSCC cell aggressiveness through targeting of genes involved in focal adhesion pathways, such as laminins and integrins.31
Upregulated miRNAs act as oncogenic genes in HNSCC
Upregulated microRNAs may possess oncogenic activities if they target tumor-suppressive genes. In the 11 microRNA profiles, miR-21 and miR-183 were the most frequently upregulated in HNSCC clinical specimens.
The miR-21 gene is located at 17q23.1. Several reports revealed that miR-21 was upregulated in various cancers including HNSCC, and this miRNA acts as a key promoter of oncogenic processes.108 Moreover, miR-21 was a prognostic marker and was associated with clinicopathological characteristics in HNSCC.109
miR-183, miR-96 and miR-182 are clustered microRNAs at 7q32.2.110 Although past reports showed that miR-183 acted as an oncogene in gastric cancer and colon cancer,111, 112 no report has shown that miR-183 is an oncogene in HNSCC.
The miR-223 gene is generated from a site located at Xq12. In the profiles, miR-223 was one of the most highly upregulated in HNSCC. Upregulated expression levels of miR-223 are reported in various types of cancer.113, 114 However, miR-223 suppresses proliferation and migration through targeting MAFB in nasopharyngeal carcinoma cells.115 Moreover, our past study revealed that miR-223 inhibited migration and invasion via its targeting of ITGB4 in prostate cancer.116
miR-31 is located at 9p21.3, and its expression status varies according to the cancer type. Upregulation of miR-31 was reported in EBV-associated nasopharyngeal carcinoma, lung cancer and ovarian cancer.117 Furthermore, expression of miR-31 was significantly upregulated in patients with early stage OSCC, suggesting that salivary miR-31 was a biomarker for this disease.118 On the other hand, our past report revealed that miR-31 was downregulated in prostate cancer tissues.119
miR-182 is transcribed from a locus at 7q32.2, and it is clustered with miR-183 and miR-96.110 miR-182 was overexpressed in papillary thyroid cancer, prostate cancer, breast cancer and lung cancer.110 Furthermore, the serum expression level of miR-182 is diagnostic with prognostic potential in ovarian cancer patients.120 In HNSCC, the expression level of miR-182 was upregulated in human papillomavirus-associated oropharyngeal carcinoma and related to cancer invasion and drug resistance.121
Conclusions
The discovery of miRNAs has opened new approaches in cancer research, providing insights into novel pathological processes underlying oncogenic transformation. Aberrantly expressed miRNAs disrupt tightly controlled RNA networks in normal cells and thereby promote pathologic events. The present review highlighted recent findings in HNSCC miRNA expression signatures. The identification of aberrant miRNA-regulated cancer networks is an exciting new development in cancer research and suggests new therapeutic approaches.
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This study was supported by the KAKENHI, grant numbers (C) 15K10800 and (C) 15K10801.
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Koshizuka, K., Hanazawa, T., Fukumoto, I. et al. The microRNA signatures: aberrantly expressed microRNAs in head and neck squamous cell carcinoma. J Hum Genet 62, 3–13 (2017). https://doi.org/10.1038/jhg.2016.105
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DOI: https://doi.org/10.1038/jhg.2016.105
