The etiology and pathogenesis of SNIP are still unclear and may be related to HPV infection. p53, gelsolin and cathepsin S have been found to be abnormally expressed in SNIP tissue, some of which are possibly associated with the occurrence and development of SNIP [16–18]. However, there are few studies on how to regulate the expression levels of these genes at the posttranscriptional level. Our previous microarray study found that 58 miRNAs, as ncRNAs, were significantly differentially expressed in SNIP tissues, and the expression level of miRNA-214-3p was correlated with SNIP tumor stage and recurrence [19]. Kakizaki et al [20] also found that miR-296-3p might play a critical role in the malignant transformation of SNIP via the regulation of PTEN and the subsequent inhibition of the PI3K/Akt signaling pathway. To explore the expression levels and potential molecular mechanism of lncRNAs in SNIP, we detected the expression profile of lncRNAs in SNIP tissues by a microarray assay. Our data revealed that a total of 3,435 lncRNAs (1,668 upregulated and 1,767 downregulated) were significantly differentially expressed in the SNIP tissues compared with the corresponding nontumorous tissues. These epigenetic studies suggested that noncoding RNAs likely participate in the occurrence and development of SNIP by regulating the expression of tumor-related genes.
The biological functions of lncRNAs are very complex and have not yet been fully elucidated. It is generally accepted that lncRNAs can regulate the expression level of mRNAs through a variety of molecular mechanisms, such as interfering with the transcription of the promoter regions of protein-encoding genes, inhibiting RNA polymerase II or mediating chromatin remodeling and histone modification toregulate the expression of downstream genes, blocking mRNA cleavage by complementary double chain structure, and combining with miRNA response elements (MREs) to interfere with the expression of miRNA target genes [21–23]. Thus, lncRNAs can directly bind to transcription factors or change chromatin structure at the transcriptional level. They can also be involved in regulating mRNA processing and translation at the posttranscriptional level. Our study showed that there was a complex coexpression network between the lncRNAs and mRNAs in SNIP. Furthermore, the mRNAs coexpressed with lncRNA AKTIP were enriched in tumor-related biological processes and signaling pathways, such as chemical carcinogenesis, the p53 signaling pathway, and viral protein interactions with cytokines and cytokine receptors. These results revealed that lnc-AKTIP on chromosome 16q12.2 might regulate the pathogenesis of SNIP through mRNAs coexpressed with lncRNAs and a variety of potential molecular mechanisms.
In addition, our bioinformatics analysis indicated that lnc-AKTIP potentially interacted with lnc-AKTIP and PCBP2 protein. PCBP2 is one of the major cellular poly(rC)-binding proteins. Together with PCBP1, this protein also functions as a translational coactivator of poliovirus RNA via a sequence-specific interaction with stem-loop IV of the internal ribosome entry site (IRES), promoting poliovirus RNA replication by binding to its 5'-terminal cloverleaf structure. It has also been implicated in translational control of 15-lipoxygenase mRNA, HPV mRNA, and hepatitis A virus RNA [24, 25]. Wen D et al [26] reported that LINC02535 functions with PCBP2 to facilitate the repair of DNA damage and then to promote cervical cancer progression by stabilizing RRM1 mRNA. Our study also found that lncRNA AKTIP might also bind to multiple tumor-related transcription factors, such as IRF-1, p53 and GATA-2.Thus, lncRNA AKTIP may also regulate the occurrence and development of SNIP via some potential interaction mechanisms between ncRNAs and proteins.
A growing number of studies have confirmed that lncRNAs can be used as molecular biomarkers for the diagnosis and prognosis evaluation of many diseases. For instance, serum lncRNA LOC284454 has been shown to be a good clinical diagnostic biomarker in nasopharyngeal carcinoma, oral cancer, and thyroid cancer [27]. Kopczynska M et al [28] reported that in head and neck squamous cell carcinoma (HNSCC) patients, HPV-positive patients with high lncRNA PRINS expression demonstrated significantly better overall survival and disease-free survival than those with low expression. A majority of HPV-positive patients with high PRINS expression demonstrated a high number of immune cells within tumors. It is likely that lncRNA PRINS could be used as a potential prognostic biomarker for HNSCC patients. Along with these clues, we investigated which of the differentially expressed lncRNAs in SNIP tissue could be used as diagnostic biomarkers. Our study demonstrated that lnc-AKTIP could yield a ROC curve area of 0.939 with 95.1% sensitivity and 81.6%specificity in discriminating SNIP patients from controls. Therefore, lnc-AKTIP probably provides great potential asa novel biomarker in the molecular pathological diagnosis of SNIP. However, its specificity needs to be analyzed in depth between SNIP and other sinonasal tumors. In addition, it remains to be further explored whether plasma/serumlnc-AKTIP can serve as a noninvasive diagnostic biomarker for the early detection of SNIP.
The expression levels of lncRNAs are closely related to the pathological characteristics of many tumors. Wang P et al [29] demonstrated that lncRNA NEAT1 might act as an oncogene. Its increased expression was correlated with T grade, neck nodal metastasis, clinical staging, drinking history, and smoking history in laryngeal squamous cell carcinoma patients. We also found that the expression of lnc-AKTIP was significantly associated with tumor staging of SNIP, which provided a new clue for us to clarify the epigenetic mechanism of SNIP.
In conclusion, our investigation, although preliminary, has revealed the expression profiles of lncRNAs and their potential biological functions in SNIP. We have further demonstrated the potential interaction between lnc-AKTIP and multiple tumor-related transcription factors and the significant correlation between the downregulation of lnc-AKTIP and SNIP tumor stage. Lnc-AKTIP might act as a putative biomarker in SNIP. Such information would be helpful in further investigating the pathogenesis of SNIP and identifying novel therapeutic targets for the treatment of SNIP patients.