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Non-Coding RNAs in HNSCC: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Rodney Hull.

 Non-coding RNAs (ncRNAs) play an important role in the development and progression of head and neck squamous cell carcinoma (HNSCC). These RNAs regulate the expression of coding genes.

  • head and neck squamous cell carcinoma (HNSCC)
  • aberrant splicing events
  • human papillomavirus (HPV) infection
  • non-coding RNA (ncRNA)
  • methylation
  • mutational burden

1. Introduction

The term head and neck cancers are used to describe a variety of tumors that arise in the mouth, nose, throat, sinuses or salivary glands [1]. Head and neck cancers are the sixth most common form of malignancy, with a total of 600,000 reported cases around the globe each year [2]. Over 90% of these cases are squamous carcinoma of the head and neck, referred to as head and neck squamous cell carcinoma (HNSCC) [3]. More than two-thirds of HNSCC incidents are diagnosed in developing countries [4]. The estimated average age of patients is 60 years, and the incident rate is highest in males [5]. The first indications that a patient is suffering from these types of cancers include changes in the sound of the voice, a persistent sore throat that will not heal, difficulty in swallowing and most notably, the development of lumps or lesions in the throat [6]. Even with major advances in diagnosis, radiation therapy and immunotherapy, the 5-year survival rate for HNSCC patients has not improved in recent decades [7,8][7][8]. Additionally, due to the lack of appropriate biomarkers for the early diagnosis of HNSCC, in many patients, the cancer is only detected at the later stages of the disease, leading to a poor prognosis [4,9][4][9].

The primary risk factors for HNSCC involve smoking and heavy alcohol use [10]. Human papillomavirus (HPV) is classified as a distinct risk factor, giving rise to tumors that are distinct from those caused by other risk factors [11]. Genome-wide systematic sequencing of mRNAs, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs have led to the identification of probable methylation sites, single nucleotide polymorphisms (SNPs), mutations and variations in copy number in a variety of different genres. This has led to the identification of numerous potential biomarkers for HNSCC [12,13,14,15,16][12][13][14][15][16]. In addition to these genomic and epigenetic changes, alternative splicing events have also been implicated in the initiation and progression of head and neck cancer [17].

2. Non-Coding RNAs in HNSCC

Recent studies have indicated that non-coding RNAs (ncRNAs) play an important role in the development and progression of HNSCC. These RNAs regulate the expression of coding genes. MicroRNAs (miRNAs) can either promote or inhibit the expression of target genes by binding directly to their target mRNA. They then affect the stability of the mRNA [72][18]. This is why the aberrant regulation of miRNAs is an important contributing factor in the development of this disease [73][19]. LncRNAs may control gene expression by promoting transcription, silencing transcription or by promoting or inhibiting translation [74][20]. Not only do these ncRNAs regulate the expression of protein-coding genes, but they also regulate the expression of other ncRNAs, and since these molecules act by binding to target mRNA, they also compete for the target binding sites on these mRNA targets. Both these types of ncRNA can also be used to fulfil the role of biomarkers for cancer diagnosis and prognosis, as they are found in the body fluids [75][21].

2.1. MicroRNA Profile in HNSCC

A number of miRNAs have been identified as playing an important role in the development and progression or prevention of HNSCC by acting as either oncogenes or as tumor suppressors [72,76,77,78,79][18][22][23][24][25]. AS can generate mRNA with different MicroRNA response elements (MREs) that can alter the ability of miRNA to target them. Different miRNAs can easily be generated through the use of alternate promoters and alternate termination sequences to generate miRNAs with different 5’ and 3’ UTRs. The sequence of miRNAs can also be altered by alternate polyadenylation [80][26]. An early study that examined miRNA profile changes in HNSCC found that the expression of 20 miRNAs was different in HNSCC samples when compared to normal tissue [76][22], while a later study using more sensitive deep sequencing found 365 miRNAs with significantly different expression levels in HNSCC samples [81][27]. Further characterization of these miRNAs that are differentially expressed in HNSCC revealed that 49 of these miRNAs were associated in some way with p53. Sixteen of these miRNAs were also associated with lower survival rates in HNSCC patients [82][28].

MiRNAs whose expression changes in HNSCC cell lines and patients’ samples that play a tumor suppressor role include miR-200 [83][29], mi-R375 [84][30], miR-26a [85][31], miR-7 [86][32], miR-107 [87][33] miR-218 [88][34] and members of the let-7 micro-RNA family [89][35]. In addition to this, multiple miRNAs were reported to be downregulated in HNSCC. These include miR-206 [90][36], miR-10a-5p, miR-125a-5p, miR-144-3p, miR-195-5p and miR-203 [91][37]. MiR-200 knockdown results in the development of aggressive cancer, while increased levels of, Mi-RNA-200 inhibits cell growth [83][29]. Another miRNA that acts as a tumor suppressor in multiple cancers, including HNSCC, is mi-R375; however, it was found to act as an oncogene in cancers, such as lung cancer. It was also found that the expression ratio of miR21 to mi-R375 in tumors compared to normal tissue is a good indicator of patient survival. The lower this ratio is, the worse the survival outcome [84][30]. MiR-26a acts as a tumor suppressor by inhibiting cell migration and metastasis as well as lowering the expression of the enhancer of zeste homolog 2 (EZH2). This results in decreased cell growth [85][31]. Many of the other tumor suppressor miRNAs function by inhibiting the expression of genes that promote cell proliferation. MiR-7 inhibits EGFR expression [86][32], miR-107 inhibits Akt, Stat3 and Rho GTPases via Protein kinase Cε (PKCε) [87][33]. Other tumor suppressor miRNAs function by inhibiting cell migration, invasion, and metastasis by inhibiting signaling cascades. For example, miR-218 dysregulates the focal adhesion pathway, preventing cell migration [88][34].

The changes in miRNA expression in HPV positive HNSCC have also been studied. Specific effects of HPV infection in the development of HNSCC rely on the dysregulation of miRNA expression levels and changes in the location of cellular miRNA. MiR-363 is overexpressed in HPV positive HNSCC, where it functions in cell cycle regulation and reduces cell growth and invasion [92,93][38][39]. Analysis of the transcription levels of miR-106a and miR-92a did not reveal any variations in expression between HPV positive and HPV negative HNSCC cell lines [93][39], yet in the presence of HPV-16, MiR-155 has been shown to be downregulated [93][39]. Studies have shown that in HPV positive HNSCC cells, miR-181a and miR-29a were downregulated in comparison to HPV negative HNSCC cells [93][39]. MiR-29a interacts with and stabilizes p53 [94][40]. Since HPV-16 E6 increases the rate of p53 degradation [20][41], MiR-29a deregulation in conjunction with E6 expression could further decrease p53 levels following chronic HPV infection [93][39].

MiRNAs that were found to function as oncogenes include miR-21 [95][42], miR-375 [96][43] and miR-184 [97][44]. Some of the miRNAs that promote HNSCC development and progression that function by the inhibition of apoptosis include miR-21 [95][42]. Additionally, many of these miRNAs whose expression is increased in HNSCC are also associated with decreased HNSCC survival; an example of this is miR-21 [96][43]. MiRNAs, who were found to be expressed at higher levels in HNSCC, but whose effects are not known include miR-133b, miR-455-5p and miR-196 [98][45], miR-26a, miR-21 [95][42], miR-106b-3p, miR-2, miR-19a, miR-33a and miR-31 [97][44].

2.2. LncRNAs in HNSCC

Multiple studies have identified numerous lncRNAs whose expression is altered in many cancers [97][44]. As in many other cancers, the lncRNA HOX antisense intergenic RNA (HOTAIR) is deregulated in HNSCC. This lncRNA is overexpressed in poorly differentiated HNSCCs, and higher expression is associated with more advanced stages of the disease [99][46]. Those lncRNAs whose expression is increased in HNSCC include nuclear paraspeckle assembly transcript 1 (NEAT1) [100][47], HOXA transcript at the distal tip (HOTTIP), urothelial cancer associated 1 (UCA1) [101][48], lncRNA-regulator of reprogramming (ROR) [102][49] and H19 [103][50]. The expression of other lncRNAs is downregulated in HNSCC, and this lower expression is associated with a poorer prognosis. This is a possible indication that they play an antitumor function. These include AC026166.2-001, RP11-169D4.1-001, growth-arrest-specific 5 (GAS5) [100][47], LET [104][51], X-inactive specific transcript (XIST) [105][52], maternally-expressed 3 (MEG3) [106][53], and lnc-JPHl-7 [107][54].

(References would be added automatically after the entry is online)

References

  1. Johnson, N.W.; Amarasinghe, H.K. Epidemiology and Aetiology of Head and Neck Cancers. In Head and Neck Cancer: Multimodality Management; Bernier, J., Ed.; Springer International Publishing: Cham, Switzerland, 2016; pp. 1–57.
  2. Rettig, E.M.; D’Souza, G. Epidemiology of head and neck cancer. Surg. Oncol. Clin. N. Am. 2015, 24, 379–396.
  3. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30.
  4. Zhang, L.; Zhang, W.; Wang, Y.F.; Liu, B.; Zhang, W.F.; Zhao, Y.F.; Kulkarni, A.B.; Sun, Z.J. Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma. Cell Death Dis. 2015, 6, e1771.
  5. Polanska, H.; Raudenska, M.; Gumulec, J.; Sztalmachova, M.; Adam, V.; Kizek, R.; Masarik, M. Clinical significance of head and neck squamous cell cancer biomarkers. Oral Oncol. 2014, 50, 168–177.
  6. Economopoulou, P.; Kotsantis, I.; Psyrri, A. Special Issue about Head and Neck Cancers: HPV Positive Cancers. Int. J. Mol. Sci. 2020, 21, 3388.
  7. Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 2012, 62, 10–29.
  8. Cohen, E.E.; LaMonte, S.J.; Erb, N.L.; Beckman, K.L.; Sadeghi, N.; Hutcheson, K.A.; Stubblefield, M.D.; Abbott, D.M.; Fisher, P.S.; Stein, K.D.; et al. American Cancer Society Head and Neck Cancer Survivorship Care Guideline. CA Cancer J. Clin. 2016, 66, 203–239.
  9. Rothenberg, S.M.; Ellisen, L.W. The molecular pathogenesis of head and neck squamous cell carcinoma. J. Clin. Investig. 2012, 122, 1951–1957.
  10. La Vecchia, C.; Tavani, A.; Franceschi, S.; Levi, F.; Corrao, G.; Negri, E. Epidemiology and prevention of oral cancer. Oral Oncol. 1997, 33, 302–312.
  11. Gillison, M.L.; Koch, W.M.; Capone, R.B.; Spafford, M.; Westra, W.H.; Wu, L.; Zahurak, M.L.; Daniel, R.W.; Viglione, M.; Symer, D.E.; et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J. Natl. Cancer Inst. 2000, 92, 709–720.
  12. Liu, J.; Pan, S.; Hsieh, M.H.; Ng, N.; Sun, F.; Wang, T.; Kasibhatla, S.; Schuller, A.G.; Li, A.G.; Cheng, D.; et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl. Acad. Sci. USA 2013, 110, 20224–20229.
  13. Jamali, Z.; Asl Aminabadi, N.; Attaran, R.; Pournagiazar, F.; Oskouei, S.G.; Ahmadpour, F. MicroRNAs as prognostic molecular signatures in human head and neck squamous cell carcinoma: A systematic review and meta-analysis. Oral Oncol. 2015, 51, 321–331.
  14. Marur, S.; Forastiere, A.A. Head and neck squamous cell carcinoma: Update on epidemiology, diagnosis, and treatment. In Mayo Clinic Proceedings; Elsevier: Amsterdam, The Netherlands, 2016; pp. 386–396.
  15. Zhang, X.; Feng, H.; Li, D.; Liu, S.; Amizuka, N.; Li, M. Identification of Differentially Expressed Genes Induced by Aberrant Methylation in Oral Squamous Cell Carcinomas Using Integrated Bioinformatic Analysis. Int. J. Mol. Sci. 2018, 19, 1698.
  16. Zhao, X.; Sun, S.; Zeng, X.; Cui, L. Expression profiles analysis identifies a novel three-mRNA signature to predict overall survival in oral squamous cell carcinoma. Am. J. Cancer Res. 2018, 8, 450–461.
  17. Zhao, X.; Si, S.; Li, X.; Sun, W.; Cui, L. Identification and validation of an alternative splicing-based prognostic signature for head and neck squamous cell carcinoma. J. Cancer 2020, 11, 4571–4580.
  18. Wu, B.H.; Xiong, X.P.; Jia, J.; Zhang, W.F. MicroRNAs: New actors in the oral cancer scene. Oral Oncol. 2011, 47, 314–319.
  19. Sannigrahi, M.; Sharma, R.; Panda, N.; Khullar, M. Role of non-coding RNAs in head and neck squamous cell carcinoma: A narrative review. Oral Dis. 2018, 24, 1417–1427.
  20. Ransohoff, J.D.; Wei, Y.; Khavari, P.A. The functions and unique features of long intergenic non-coding RNA. Nat. Rev. Mol. Cell Biol. 2018, 19, 143–157.
  21. Denaro, N.; Merlano, M.C.; Russi, E.G.; Lo Nigro, C. Non coding RNAs in head and neck squamous cell carcinoma (HNSCC): A clinical perspective. Anticancer Res. 2014, 34, 6887–6896.
  22. Ramdas, L.; Giri, U.; Ashorn, C.L.; Coombes, K.R.; El-Naggar, A.; Ang, K.K.; Story, M.D. miRNA expression profiles in head and neck squamous cell carcinoma and adjacent normal tissue. Head Neck 2009, 31, 642–654.
  23. Wong, T.S.; Liu, X.B.; Wong, B.Y.; Ng, R.W.; Yuen, A.P.; Wei, W.I. Mature miR-184 as Potential Oncogenic microRNA of Squamous Cell Carcinoma of Tongue. Clin. Cancer Res. 2008, 14, 2588–2592.
  24. Childs, G.; Fazzari, M.; Kung, G.; Kawachi, N.; Brandwein-Gensler, M.; McLemore, M.; Chen, Q.; Burk, R.D.; Smith, R.V.; Prystowsky, M.B.; et al. Low-level expression of microRNAs let-7d and miR-205 are prognostic markers of head and neck squamous cell carcinoma. Am. J. Pathol. 2009, 174, 736–745.
  25. Hui, A.B.; Lenarduzzi, M.; Krushel, T.; Waldron, L.; Pintilie, M.; Shi, W.; Perez-Ordonez, B.; Jurisica, I.; O’Sullivan, B.; Waldron, J.; et al. Comprehensive MicroRNA profiling for head and neck squamous cell carcinomas. Clin. Cancer Res. 2010, 16, 1129–1139.
  26. Hata, A.; Lieberman, J. Dysregulation of microRNA biogenesis and gene silencing in cancer. Sci. Signal. 2015, 8, re3.
  27. Yoon, A.J.; Wang, S.; Kutler, D.I.; Carvajal, R.D.; Philipone, E.; Wang, T.; Peters, S.M.; LaRoche, D.; Hernandez, B.Y.; McDowell, B.D.; et al. MicroRNA-based risk scoring system to identify early-stage oral squamous cell carcinoma patients at high-risk for cancer-specific mortality. Head Neck 2020, 42, 1699–1712.
  28. Ganci, F.; Sacconi, A.; Ben-Moshe, N.B.; Manciocco, V.; Sperduti, I.; Strigari, L.; Covello, R.; Benevolo, M.; Pescarmona, E.; Domany, E.; et al. Expression of TP53 mutation-associated microRNAs predicts clinical outcome in head and neck squamous cell carcinoma patients. Ann. Oncol. 2013, 24, 3082–3088.
  29. Kita, Y.; Vincent, K.; Natsugoe, S.; Berindan-Neagoe, I.; Calin, G.A. Epigenetically regulated microRNAs and their prospect in cancer diagnosis. Expert Rev. Mol. Diagn. 2014, 14, 673–683.
  30. Harris, T.; Jimenez, L.; Kawachi, N.; Fan, J.B.; Chen, J.; Belbin, T.; Ramnauth, A.; Loudig, O.; Keller, C.E.; Smith, R.; et al. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Am. J. Pathol. 2012, 180, 917–928.
  31. Yu, L.; Lu, J.; Zhang, B.; Liu, X.; Wang, L.; Li, S.Y.; Peng, X.H.; Xu, X.; Tian, W.D.; Li, X.P. miR-26a inhibits invasion and metastasis of nasopharyngeal cancer by targeting EZH2. Oncol. Lett. 2013, 5, 1223–1228.
  32. Kalinowski, F.C.; Giles, K.M.; Candy, P.A.; Ali, A.; Ganda, C.; Epis, M.R.; Webster, R.J.; Leedman, P.J. Regulation of epidermal growth factor receptor signaling and erlotinib sensitivity in head and neck cancer cells by miR-7. PLoS ONE 2012, 7, e47067.
  33. Datta, J.; Smith, A.; Lang, J.C.; Islam, M.; Dutt, D.; Teknos, T.N.; Pan, Q. microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cɛ. Oncogene 2012, 31, 4045–4053.
  34. Kinoshita, T.; Nohata, N.; Hanazawa, T.; Kikkawa, N.; Yamamoto, N.; Yoshino, H.; Itesako, T.; Enokida, H.; Nakagawa, M.; Okamoto, Y.; et al. Tumour-suppressive microRNA-29s inhibit cancer cell migration and invasion by targeting laminin-integrin signalling in head and neck squamous cell carcinoma. Br. J. Cancer 2013, 109, 2636–2645.
  35. Alajez, N.M.; Shi, W.; Wong, D.; Lenarduzzi, M.; Waldron, J.; Weinreb, I.; Liu, F.F. Lin28b promotes head and neck cancer progression via modulation of the insulin-like growth factor survival pathway. Oncotarget 2012, 3, 1641–1652.
  36. Zhang, T.; Han, G.; Wang, Y.; Chen, K.; Sun, Y. MicroRNA expression profiles in supraglottic carcinoma. Oncol. Rep. 2014, 31, 2029–2034.
  37. Lu, Z.M.; Lin, Y.F.; Jiang, L.; Chen, L.S.; Luo, X.N.; Song, X.H.; Chen, S.H.; Zhang, S.Y. Micro-ribonucleic acid expression profiling and bioinformatic target gene analyses in laryngeal carcinoma. OncoTargets Ther. 2014, 7, 525–533.
  38. Chapman, B.V.; Wald, A.I.; Akhtar, P.; Munko, A.C.; Xu, J.; Gibson, S.P.; Grandis, J.R.; Ferris, R.L.; Khan, S.A. MicroRNA-363 targets myosin 1B to reduce cellular migration in head and neck cancer. BMC Cancer 2015, 15, 861.
  39. Wald, A.I.; Hoskins, E.E.; Wells, S.I.; Ferris, R.L.; Khan, S.A. Alteration of microRNA profiles in squamous cell carcinoma of the head and neck cell lines by human papillomavirus. Head Neck 2011, 33, 504–512.
  40. Park, S.Y.; Lee, J.H.; Ha, M.; Nam, J.W.; Kim, V.N. miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nat. Struct. Mol. Biol. 2009, 16, 23–29.
  41. Zur Hausen, H. Papillomaviruses and cancer: From basic studies to clinical application. Nat. Rev. Cancer 2002, 2, 342–350.
  42. Li, J.; Huang, H.; Sun, L.; Yang, M.; Pan, C.; Chen, W.; Wu, D.; Lin, Z.; Zeng, C.; Yao, Y.; et al. MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor. Clin. Cancer Res. 2009, 15, 3998–4008.
  43. Avissar, M.; Christensen, B.C.; Kelsey, K.T.; Marsit, C.J. MicroRNA expression ratio is predictive of head and neck squamous cell carcinoma. Clin. Cancer Res. 2009, 15, 2850–2855.
  44. Liu, C.J.; Lin, S.C.; Yang, C.C.; Cheng, H.W.; Chang, K.W. Exploiting salivary miR-31 as a clinical biomarker of oral squamous cell carcinoma. Head Neck 2012, 34, 219–224.
  45. Saito, K.; Inagaki, K.; Kamimoto, T.; Ito, Y.; Sugita, T.; Nakajo, S.; Hirasawa, A.; Iwamaru, A.; Ishikura, T.; Hanaoka, H.; et al. MicroRNA-196a is a putative diagnostic biomarker and therapeutic target for laryngeal cancer. PLoS ONE 2013, 8, e71480.
  46. Fu, W.M.; Lu, Y.F.; Hu, B.G.; Liang, W.C.; Zhu, X.; Yang, H.D.; Li, G.; Zhang, J.F. Long noncoding RNA Hotair mediated angiogenesis in nasopharyngeal carcinoma by direct and indirect signaling pathways. Oncotarget 2016, 7, 4712–4723.
  47. Zou, A.E.; Ku, J.; Honda, T.K.; Yu, V.; Kuo, S.Z.; Zheng, H.; Xuan, Y.; Saad, M.A.; Hinton, A.; Brumund, K.T.; et al. Transcriptome sequencing uncovers novel long noncoding and small nucleolar RNAs dysregulated in head and neck squamous cell carcinoma. RNA 2015, 21, 1122–1134.
  48. Tang, H.; Wu, Z.; Zhang, J.; Su, B. Salivary lncRNA as a potential marker for oral squamous cell carcinoma diagnosis. Mol. Med. Rep. 2013, 7, 761–766.
  49. Li, L.; Gu, M.; You, B.; Shi, S.; Shan, Y.; Bao, L.; You, Y. Long non-coding RNA ROR promotes proliferation, migration and chemoresistance of nasopharyngeal carcinoma. Cancer Sci. 2016, 107, 1215–1222.
  50. Wu, T.; Qu, L.; He, G.; Tian, L.; Li, L.; Zhou, H.; Jin, Q.; Ren, J.; Wang, Y.; Wang, J.; et al. Regulation of laryngeal squamous cell cancer progression by the lncRNA H19/miR-148a-3p/DNMT1 axis. Oncotarget 2016, 7, 11553–11566.
  51. Sun, Q.; Liu, H.; Li, L.; Zhang, S.; Liu, K.; Liu, Y.; Yang, C. Long noncoding RNA-LET, which is repressed by EZH2, inhibits cell proliferation and induces apoptosis of nasopharyngeal carcinoma cell. Med. Oncol. 2015, 32, 226.
  52. Song, P.; Ye, L.F.; Zhang, C.; Peng, T.; Zhou, X.H. Long non-coding RNA XIST exerts oncogenic functions in human nasopharyngeal carcinoma by targeting miR-34a-5p. Gene 2016, 592, 8–14.
  53. Jia, L.F.; Wei, S.B.; Gan, Y.H.; Guo, Y.; Gong, K.; Mitchelson, K.; Cheng, J.; Yu, G.Y. Expression, regulation and roles of miR-26a and MEG3 in tongue squamous cell carcinoma. Int. J. Cancer 2014, 135, 2282–2293.
  54. Zou, A.E.; Zheng, H.; Saad, M.A.; Rahimy, M.; Ku, J.; Kuo, S.Z.; Honda, T.K.; Wang-Rodriguez, J.; Xuan, Y.; Korrapati, A.; et al. The non-coding landscape of head and neck squamous cell carcinoma. Oncotarget 2016, 7, 51211–51222.
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