ReviewMicroRNAs in human tongue squamous cell carcinoma: From pathogenesis to therapeutic implications
Introduction
Tumors of the oral cavity, nasal cavity, pharynx and larynx, which are collectively defined as head and neck squamous cell carcinoma, are among the 10 most prevalent malignancies worldwide [1]. Of those, oral squamous cell carcinoma (OSCC) comprises almost one fourth of all head and neck cancer cases with a rapidly increasing incidence especially among young and middle aged individuals due to pervading smoking and alcohol abuse habits [2], [3], [4]. Being one of the most aggressive and devastating cancer types of oral cavity, tongue squamous cell carcinoma (TSCC) comprises 41% of the oral squamous cancer cases and displays a significant proclivity for local invasion and a high recurrence risk [5]. Although overall cancer incidence and cancer associated mortality decreased in the past 5 years, both TSCC incidence and TSCC associated mortality rates increased significantly during the same period [6]. Besides, despite advances in multimodal diagnosis and treatment techniques in the past few decades, the 5-year survival rate for TSCC remained almost unchanged, which makes TSCC one of the most lethal cancer types in the head and neck region [7], [8].
Improvement in patient survival necessitates comprehensive understanding of cancer pathogenesis process, therefore, considerable efforts have been devoted to elucidation of genomic and epigenomic mechanisms participating in multistep carcinogenesis and the progression of TSCC. However, researchers mostly focused on protein coding genes and underestimated the contribution of non-coding genome, especially those of microRNAs, to TSCC initiation, progression, metastasis, chemo-radioresistance and recurrence.
MicroRNAs are endogenously synthesized, 18–24 nucleotide-long, small, non-coding RNAs, which have recently become one of the most popular subjects in cancer research field. They post-transcriptionally regulate mRNA expression through incorporating into the RNA induced silencing complex (RISC), binding to the semi-complementary sequences on 3′ untranslated regions (3′UTR) of target mRNAs and then inducing either mRNA degradation or translational inhibition. They are predicted to modulate the expression of at least 60% of all human genes and participate in regulation of almost all biological processes through their spatial and temporal expression [9], [10]. Their deregulation is implicated in pathogenesis of various diseases, including human cancers, where they can act as potent oncogenes or tumor suppressors [9], [11].
In squamous cell carcinoma of tongue, there are several reports providing evidences for participation of microRNAs in TSCC pathogenesis. Here, we reviewed and summarized important findings including our own works on microRNAs as implicated in TSCC and the most current literature to shed light on the roles of microRNAs in squamous cell carcinoma of tongue. Besides, the possible functions of microRNAs in TSCC pathogenesis occurring during cancer initiation, progression, invasion or metastasis are summarized.
Section snippets
Tongue squamous cell carcinogenesis and microRNAs
Mature microRNAs are derived from primary-microRNAs through a sequential process carried out by Drosha/Dicer family proteins [12], [13], [14], [15]. In a recent study, Dicer expression was reported to be lower in TSCC cell line UM-1 compared to normal gingival epithelial cells, which point disturbed microRNA processing during TSCC carcinogenesis [16]. Besides, in a study where tongue carcinogenesis was modeled in mice using Nitroquinoline 1-Oxide (4NQO)-induction, several microRNAs including
Oncogenic microRNAs in TSCC
Of the deregulated microRNAs, the oncogenic miR-21 has been identified as one with the most profoundly altered expression in independent datasets. Its increased expression in TSCC relative to adjacent normal tissues has been confirmed in a study, where samples from 103 patients were evaluated using quantitative real time polymerase chain reaction (qRT-PCR). Its expression level significantly correlated with clinical staging, differentiation status, lymph node metastasis, and survival of the
Tumor suppressor microRNAs in TSCC
Tumor suppressor microRNAs have reduced expression in TSCC specimens compared to the normal epithelial tissue in tongue, where they induce elevated expression of their oncogenic targets in the cancer cells. The list of microRNAs that were commonly downregulated in TSCC profiling studies are represented in Table 2.
It has been previously shown that mir-375 is significantly downregulated in both TSCC tissues and cell lines with respect to the corresponding controls. Forced ectopic expression of
MicroRNAs as potential markers for diagnosis of TSCC
Deregulated microRNA expression is observed in various tumor types, which makes them putative diagnostic and prognostic markers as well as potential therapeutic targets. The list of microRNAs utilized as diagnostic biomarkers in TSCC is provided in Table 3.
In a recent study, miR-424, an oncogenic microRNA in TSCC, has been demonstrated to be overexpressed preferentially in TSCC tissues, but not in tumors originating from gingiva or floor of the mouth. MiR-424 expression has been also reported
MicroRNAs as potential markers for prognosis of TSCC
In addition to their potential as diagnostic markers, microRNAs are considered amongst the strongest candidates for estimation of prognosis in TSCC. Their deregulation has been associated with several clinical and pathological features of TSCC patients (Table 4).
A distinctive expression pattern of let-7 family microRNAs in aggressive TSCC has been detected in young patients. In the same study, in addition to let-7 family microRNAs, miR-130a-3p, miR-361-5p, miR-99a-5p, and miR-29c-3p has been
MicroRNAs in TSCC metastasis
Along with their oncogenic and tumor suppressor features, microRNAs are notably implicated in tumor metastasis. Although the underlying mechanisms are not fully understood, some microRNAs are identified as important effectors in metastatic pathways considering their impacts on the cellular features like migration and invasion.
Dicer, coding for a microRNA-processing enzyme, has been shown to be downregulated in squamous carcinoma of the tongue. Its downregulation enhanced relative migratory and
MicroRNAs in TSCC chemoresistance and therapy
Although microRNAs have a wide range of targets due to partial complementarity with their target sequences on the 3′UTR of target transcripts, scientists and clinicians aim to utilize them in therapeutic applications to cure cancer. Enlightening the mechanism of actions, finding their true targets in specific tissue types, and determining the precise expression pattern are necessary to develop efficient and practical therapies. Until now, there are several microRNAs that are suggested as
Concluding remarks and future potentials
In the past decade, it has been noticed that microRNAs are significant players in cancer pathogenesis either as genetic or epigenetic regulators. Until now more than 2500 human microRNAs have been identified [67] and they are estimated to target and regulate the expression of at least 60% of genes in the human genome. Their abnormal expression is participated in several diseases including TSCC. Extensive microRNA expression profiling in tumor samples and their further in vitro and in vivo
Conflict of interest statement
None declared.
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