臺灣博碩士論文加值系統

背景：口腔癌是全球最常見的癌症之一，且在台灣男性癌症死亡原因排行第4名。干擾素(IFNs)包括第一型干擾素(IFN-α/β)和第Ⅱ型干擾素(IFNs-γ)是宿主防禦病毒和微生物致病菌感染眾所皆知強而有力的細胞激素。然而，最近它們已被證明參與癌症發展。鳥苷酸結合蛋白(GBPs)，GBP5和GBP6，屬於在癌細胞轉型上扮演重要角色的鳥苷三磷酸酶超家族。鳥苷三磷酸酶在細胞增殖、分化、訊息傳遞、細胞內蛋白運輸有發揮重要的作用。此外，GBPs的表現會被第Ⅱ型干擾素(IFN-γ)誘導。另外,(天門冬氨酸-谷氨酸-丙氨酸-天門冬氨酸)盒多肽六十(DDX60)，一種DEXD / H盒解旋酶，是病毒感染時產生RIG-I或MDA5依賴性的第I型干擾素所必需的。DDX60也屬於涉及癌症發展中大多數重要細胞過程的核糖核酸解旋酶。然而，到目前為止，GBP5、GBP6和DDX60在腫瘤中的作用尚未被確定，尤其是在口腔鱗狀上皮細胞癌。本研究旨在探討口腔鱗狀上皮細胞癌患者的GBP5、GBP6和DDX60表現含量與臨床病理參數和預後之間的相關性。
方法：我們從次世代定序分析的初步數據得知，在兩對口腔鱗狀上皮細胞癌組織與相應的癌旁正常組織的配對組織中，GBP5和DDX60在口腔鱗狀上皮細胞癌組織中的表現量顯著高於相應的癌旁正常組織，GBP6在口腔鱗狀上皮細胞癌組織中的表現量顯著低於相應的癌旁正常組織。我們使用定量即時聚合酶連鎖反應評估GBP5、GBP6和DDX60分別於23對口腔頰黏膜鱗狀上皮細胞癌患者及14對舌頭鱗狀上皮細胞癌患者其配對組織(腫瘤比正常)中訊息核糖核酸的表現量；再利用免疫組織化學染色法，分析494例口腔鱗狀上皮細胞癌患者包括180例口腔頰黏膜鱗狀上皮細胞癌、241例舌頭鱗狀上皮細胞癌和73例唇鱗狀細胞癌患者組織微陣列晶片上GBP5、GBP6和DDX60蛋白質的表現量。
結果：最後統計分析結果發現免疫組織化學染色法與次世代定序分析和定量即時聚合酶連鎖反應的結果是一致的。腫瘤組織與相應的癌旁正常組織相較之下，GBP5和DDX60的表達量顯著增加(p值均小於0.005)，而GBP6的表達量顯著減少(p值小於0.001)。在494例口腔鱗狀上皮細胞癌患者組織中，GBP5高表現量與年齡超過50歲（p值等於0.019）和腫瘤高分化程度（p值等於0.036）有關，而GBP6低表現量與腫瘤較差分化程度（p值小於0.001）有關。在180例頰黏膜鱗狀上皮細胞癌患者組織中，GBP5高表現量與年齡超過50歲（p值等於0.021）有關，而GBP6低表現量則與腫瘤較差分化程度（p值等於0.039）有關。在241例舌頭鱗狀上皮細胞癌患者組織中，GBP6低表現量與腫瘤較差分化程度（p值小於0.001）和淋巴結轉移(N1- N1，p值等於0.047)有關。此外，GBP6低表現量口腔鱗狀上皮細胞癌患者具有較差的疾病特異性存活率相關，尤其是對舌頭鱗狀上皮細胞癌患者。
在口腔鱗狀上皮細胞癌中，DDX60高表現量與男性（p值等於0.002）、腫瘤高分化程度相關(p值等於0.004)、病理分期晚期(Ⅲ-Ⅳ期，p值等於0.023)和較大的腫瘤 (T3-T4，p值等於0.001)有關。在頰黏膜鱗狀上皮細胞癌中，DDX60高表現量與病理分期晚期(Ⅲ-Ⅳ期，p值等於0.042)和較大的腫瘤（T3-T4，p值等於0.032）有關。在舌頭鱗狀上皮細胞癌中，DDX60高表現量與男性（p值等於0.023）、腫瘤高分化程度(p值小於0.001)和較大的腫瘤 (T3-T4，p值等於0.017)有關。此外，DDX60高表現量與唇鱗狀細胞癌患者較差的疾病特異性存活率及口腔鱗狀上皮細胞癌患者的復發率有關，尤其是舌頭鱗狀細胞癌患者。
結論：GBP5可能是腫瘤發展的生物標誌物，但不是口腔鱗狀上皮細胞癌的預測因子。GBP6可能是口腔鱗狀上皮細胞癌尤其是舌頭鱗狀細胞癌一個較好預後的預測因子。DDX60可能是口腔鱗狀上皮細胞癌腫瘤發展及預後的生物標誌物，特別是唇鱗狀細胞癌生存率和舌頭鱗狀細胞癌患者復發的預測因子。

Backgrounds: Oral cancer is one of the most common cancers worldwide and the fourth leading cause of cancer death among males in Taiwan. Interferons (IFNs) including Type I IFNs (IFN-α/β) and type II IFNs (IFN-γ) are well-known potent cytokine in host defenses against infection with viral and microbial pathogens. However, they have been proven in malignant transformation of tumor cells. Guanylate binding protein (GBP) 5 and GBP6 belong to the guanosine triphosphatase (GTPase) superfamily, which plays an important role in cell proliferation, differentiation, signal transduction, and intracellular protein transportation. In addition, GBP expression is mostly induced by IFN-γ. On the other hand, DDX60, a subtype of DEXD/H Box Helicase, is required for RIG-I- or MDA5-dependent type I interferon production. DDX60 belongs to a DEAD box RNA helicase involving in most cellular processes, such as essential for cancer development. However, roles of GBP5, GBP6 and DDX60 in cancer especially for oral squamous cell carcinoma (OSCC) were not identified so far. The purpose of this study was to investigate the association of the expression levels of GBP5, GBP6 and DDX60 with tumorigenesis, clinicopathologic outcomes, and survival of patients with OSCC and three primary subsites.
Methods: Our preliminary data from next generation sequencing (NGS) indicated that in two pairs of OSCC and corresponding tumor adjacent normal (CTAN) tissues, the gene expressions of GBP5 and DDX60 in OSCC tissue were significant higher than that in CTAN tissue but the GBP6 gene expression in OSCC tissue was significant decreased than that in CTAN tissue. Gene expressions of GBP5, GBP6 and DDX60 were further confirmed by real-time polymerase chain reaction (RT-PCR) using 23 pairs of mucosa squamous cell carcinoma (BMSCC) and CTAN tissues as well as 14 pairs of tongue squamous cell carcinoma (TSCC) and CTAN tissues. In the study, expression levels of GBP5, GBP6 and DDX60 were examined by immunohistochemistry with tissue microarray slides of 494 OSCC patients including 180 buccal mucosal SCC (BMSCC), 241 tongues SCC (TSCC), and 73 lip SCC (LSCC) patients.
Results: The expression results of GBP5, GBP6 and DDX60 assayed by NGS, RT-PCR and immunohistochemical staining were quite consistent. GBP5 and DDX60 expressions (all p <0.05) significantly increased, whereas GBP6 (p <0.001) expression decreased in tumor tissues compared to that in CTAN tissues, indicating that GBP5 and DDX60 might be oncoproteins, but GBP6 was a tumor suppressor. Among OSCC tissues of 494 patients, the higher GBP5 expression was associated with older age over 50 yrs. (>50 yrs.; p=0.019) and well differentiation (p=0.036), whereas decreased GBP6 expression was associated with poor differentiation (p<0.001). Among BMSCC tissues of 180 patients, the GBP5 expression was positively associated with older age (>50 yrs.; p=0.021), although GBP6 expression was negatively associated with poor differentiation (p=0.039). Among TSCC tissues of 241 patients, the loss of GBP6 expression was associated with poor differentiation (p<0.001) and lymph node metastasis (N1- N2, p=0.047). Moreover, the decreased GBP6 expression was correlated with the poor disease-specific survival (DSS) for only TSCC patients. Increased DDX60 expression was associated with males (p=0.002), well differentiation (p=0.004), advanced pathological stage (III-IV, p=0.023), and large tumor size (T3-T4, p=0.001) in OSCC. Higher DDX60 expression was associated with advanced pathological stage (III-IV, p=0.042) and larger tumor size (T3-T4, p=0.032) in BMSCC. Higher DDX60 expression was positively associated with males (p=0.023), well differentiation (p<0.001), and large tumor size (T3-T4, p=0.017) in TSCC. Moreover, the elevated DDX60 expression was correlated with the poor DSS in LSCC patients, and the poor disease-free survival (DFS) in OSCC, especially in TSCC patients.
Conclusion: GBP5 may be the biomarkers for tumor development but not for prognosis in OSCC. GBP6 may be a predictor of better prognosis in TSCC. DDX60 may be the biomarkers for tumor development and prognosis of OSCC, particularly for survival of LSCC and recurrence of TSCC.

Chinese Abstract------------------------------------------------------------------------------------------i
English Abstract-----------------------------------------------------------------------------------------iii
Contents----------------------------------------------------------------------------------------------------vi
Abbreviation------------------------------------------------------------------------------------------------x
Chapter I: Introduction --------------------------------------------------------------------------------1
1.1 Oral Cancer -----------------------------------------------------------------------------------------1
1.2 Tumor Microenvironment & Chronic Inflammation -----------------------------------2
1.3 Guanylate Binding Proteins (GBPs) -------------------------------------------------------3
1.4 DExD/H-box RNA Helicase Family --------------------------------------------------------4
Chapter II: Specific Aims ---------------------------------------------------------------------------6
Chapter III: Materials & Methods-----------------------------------------------------------------7
3.1 Patients and Tissue Specimens -----------------------------------------------------------7
3.2 Collection of Target Cells by Laser Capture Microdissection (LCM) from Frozen
Sections ---------------------------------------------------------------------------------------------8
3.3 Hematoxylin and Eosin Stain ---------------------------------------------------------------9
3.4 Extraction of RNA from LCM Captured Cells for Next Generation Sequencing (NGS)-------9
3.5 NGS --------------------------------------------------------------------------------------------------9
3.6 RNA Extraction----------------------------------------------------------------------------------10
3.7 Quantitative Real-Time PCR Analysis -------------------------------------------------10
3.8 Tissue Microarray (TMA) Construction ------------------------------------------------12
3.9 Immunohistochemistry (IHC) --------------------------------------------------------------12
3.10 IHC Analysis and Score -------------------------------------------------------------------13
3.11 Statistical Analysis --------------------------------------------------------------------------14
Chapter IV: Results----------------------------------------------------------------------------------16
4.1 Section 1. Screening of GBP5, GBP6 and DDX60 in OSCC ------------------16
4.1.1Transcriptome profiling of OSCC, including BMSCC ----------------------------16
4.1.2 Analyze of gene expression levels of GBP5, GBP6 and DDX60 in paired tissues
of OSCC -----------------------------------------------------------------------------------------16
4.2 Section 2. Investigating the correlation of expressions levels of GBP5 and GBP6
with OSCC -------------------------------------------------------------------------17
4.2.1 Expression levels of GBP5 and GBP6 in normal tissue, CTAN tissue and tumor
tissue ---------------------------------------------------------------------------------------------17
4.2.2 Relation of GBP5 and GBP6 expressions to the demographic and clinicopathologic
outcomes in patients with BMSCC ---------------------------------------------------19
4.2.3 Relation of GBP5 and GBP6 expressions to the demographic and clinicopathologic
outcomes in patients with TSCC -------------------------------------------------------20
4.2.4 Relation of GBP5 and GBP6 expressions to the demographic and clinicopathologic
outcomes in patients with LSCC --------------------------------------------------------21
4.2.5 Relation of GBP5 and GBP6 expressions to the demographic and clinicopathologic
outcomes in patients with OSCC -------------------------------------------------------21
4.2.6 The association of expression levels of GBP5 and GBP6 with the survival of
OSCC patients --------------------------------------------------------------------------------23
4.3 Section 3. Investigating the correlation of expression levels of DDX60 with OSCC
-------------------------------------------------------------------------------------------24
4.3.1 The expression level of DDX60 in normal tissue, CTAN tissue and tumor tissue
-------------------------------------------------------------------------------------------------------24
4.3.2 Relation of DDX60 expression to the demographic and clinicopathologic outcomes
in patients with BMSCC -------------------------------------------------------------------25
4.3.3 Relation of DDX60 expression to the demographic and clinicopathologic outcomes
in patients with TSCC ----------------------------------------------------------------------26
4.3.4 Relation of DDX60 expression to the demographic and clinicopathologic outcomes
in patients with LSCC ----------------------------------------------------------------------27
4.3.5 Relation of DDX60 expressions to the demographic and clinicopathologic outcomes
in patients with OSCC ---------------------------------------------------------------------28
4.3.6 The association of the expression levels of DDX60 with the survival of OSCC
patients ----------------------------------------------------------------------------------------29
Chapter V: Discussion &Conclusion---------------------------------------------------------31
References--------------------------------------------------------------------------------------------39
Tables--------------------------------------------------------------------------------------------------47
Figures-------------------------------------------------------------------------------------------------59
Indexes------------------------------------------------------------------------------------------------74

Balkwill, F., and Mantovani, A. (2001). Inflammation and cancer: back to Virchow? Lancet 357, 539-545.

Beatty, G.L., and Paterson, Y. (2000). IFN-gamma can promote tumor evasion of the immune system in vivo by down-regulating cellular levels of an endogenous tumor antigen. Journal of immunology 165, 5502-5508.

Berg, D.J., Davidson, N., Kuhn, R., Muller, W., Menon, S., Holland, G., Thompson-Snipes, L., Leach, M.W., and Rennick, D. (1996). Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. The Journal of clinical investigation 98, 1010-1020.

Boehm, U., Guethlein, L., Klamp, T., Ozbek, K., Schaub, A., Futterer, A., Pfeffer, K., and Howard, J.C. (1998). Two families of GTPases dominate the complex cellular response to IFN-gamma. Journal of immunology 161, 6715-6723.

Bourne, H.R., Sanders, D.A., and McCormick, F. (1991). The GTPase superfamily: conserved structure and molecular mechanism. Nature 349, 117-127.

Britzen-Laurent, N., Lipnik, K., Ocker, M., Naschberger, E., Schellerer, V.S., Croner, R.S., Vieth, M., Waldner, M., Steinberg, P., Hohenadl, C., et al. (2013). GBP-1 acts as a tumor suppressor in colorectal cancer cells. Carcinogenesis 34, 153-162.

Brodsky, I.E. (2013). RNA helicase DHX33 puts a new twist on NLRP3 inflammasome activation. Immunity 39, 94-96.

Budtz-Jorgensen, E. (1981). Oral mucosal lesions associated with the wearing of removable dentures. Journal of oral pathology 10, 65-80.

Camisasca, D.R., Silami, M.A., Honorato, J., Dias, F.L., de Faria, P.A., and Lourenco Sde, Q. (2011). Oral squamous cell carcinoma: clinicopathological features in patients with and without recurrence. ORL J Otorhinolaryngol Relat Spec 73, 170-176.

Chi, L.M., Lee, C.W., Chang, K.P., Hao, S.P., Lee, H.M., Liang, Y., Hsueh, C., Yu, C.J., Lee, I.N., Chang, Y.J., et al. (2009). Enhanced interferon signaling pathway in oral cancer revealed by quantitative proteome analysis of microdissected specimens using 16O/18O labeling and integrated two-dimensional LC-ESI-MALDI tandem MS. Molecular & cellular proteomics : MCP 8, 1453-1474.

Curado, M.P., and Hashibe, M. (2009). Recent changes in the epidemiology of head and neck cancer. Current opinion in oncology 21, 194-200.

Dayal, Reddy, R., and Anuradha Bhat, K. (2000). Malignant potential of oral submucous fibrosis due to intraoral trauma. Indian journal of medical sciences 54, 182-187.

Degrandi, D., Konermann, C., Beuter-Gunia, C., Kresse, A., Wurthner, J., Kurig, S., Beer, S., and Pfeffer, K. (2007). Extensive characterization of IFN-induced GTPases mGBP1 to mGBP10 involved in host defense. Journal of immunology 179, 7729-7740.

Ebrahimi A, C.J., Zhang WJ, et al. (2011). Lymph node ratio as an independent prognostic factor in oral squamous cell carcinoma. Head Neck 33:1245–1251.

Fairman, M.E., Maroney, P.A., Wang, W., Bowers, H.A., Gollnick, P., Nilsen, T.W., and Jankowsky, E. (2004). Protein displacement by DExH/D "RNA helicases" without duplex unwinding. Science 304, 730-734.

Farrar, M.A., and Schreiber, R.D. (1993). The molecular cell biology of interferon-gamma and its receptor. Annual review of immunology 11, 571-611.

Fellenberg, F., Hartmann, T.B., Dummer, R., Usener, D., Schadendorf, D., and Eichmuller, S. (2004). GBP-5 splicing variants: New guanylate-binding proteins with tumor-associated expression and antigenicity. The Journal of investigative dermatology 122, 1510-1517.

Feller, L., Altini, M., and Lemmer, J. (2013). Inflammation in the context of oral cancer. Oral oncology 49, 887-892.

Fu, T.Y., Hsieh, I.C., Cheng, J.T., Tsai, M.H., Hou, Y.Y., Lee, J.H., Liou, H.H., Huang, S.F., Chen, H.C., Yen, L.M., et al. (2015). Association of OCT4, SOX2, and NANOG expression with oral squamous cell carcinoma progression. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

Fuller-Pace, F.V. (2006). DExD/H box RNA helicases: multifunctional proteins with important roles in transcriptional regulation. Nucleic acids research 34, 4206-4215.

Fuller-Pace, F.V. (2013). DEAD box RNA helicase functions in cancer. RNA biology 10, 121-132.

Gao, S., Wang, L., Liu, W., Wu, Y., and Yuan, Z. (2014). The synergistic effect of homocysteine and lipopolysaccharide on the differentiation and conversion of raw264.7 macrophages. Journal of inflammation 11, 13.

Germain, D.R., Graham, K., Glubrecht, D.D., Hugh, J.C., Mackey, J.R., and Godbout, R. (2011). DEAD box 1: a novel and independent prognostic marker for early recurrence in breast cancer. Breast cancer research and treatment 127, 53-63.

Giampieri, S., Manning, C., Hooper, S., Jones, L., Hill, C.S., and Sahai, E. (2009). Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nature cell biology 11, 1287-1296.

Gorbacheva, V.Y., Lindner, D., Sen, G.C., and Vestal, D.J. (2002). The interferon (IFN)-induced GTPase, mGBP-2. Role in IFN-gamma-induced murine fibroblast proliferation. The Journal of biological chemistry 277, 6080-6087.

Goubau, D., Deddouche, S., and Reis e Sousa, C. (2013). Cytosolic sensing of viruses. Immunity 38, 855-869.

Grunvogel, O., Esser-Nobis, K., Reustle, A., Schult, P., Muller, B., Metz, P., Trippler, M., Windisch, M.P., Frese, M., Binder, M., et al. (2015). DDX60L Is an Interferon-Stimulated Gene Product Restricting Hepatitis C Virus Replication in Cell Culture. Journal of virology 89, 10548-10568.

Guimaraes, D.P., Oliveira, I.M., de Moraes, E., Paiva, G.R., Souza, D.M., Barnas, C., Olmedo, D.B., Pinto, C.E., Faria, P.A., De Moura Gallo, C.V., et al. (2009). Interferon-inducible guanylate binding protein (GBP)-2: a novel p53-regulated tumor marker in esophageal squamous cell carcinomas. International journal of cancer Journal international du cancer 124, 272-279.

Hueng, D.Y., Tsai, W.C., Chiou, H.Y., Feng, S.W., Lin, C., Li, Y.F., Huang, L.C., and Lin, M.H. (2015). DDX3X Biomarker Correlates with Poor Survival in Human Gliomas. International journal of molecular sciences 16, 15578-15591.

Jankowsky, E., Gross, C.H., Shuman, S., and Pyle, A.M. (2001). Active disruption of an RNA-protein interaction by a DExH/D RNA helicase. Science 291, 121-125.

Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T., and Thun, M.J. (2008). Cancer statistics, 2008. CA: a cancer journal for clinicians 58, 71-96.

Kim, B.H., Shenoy, A.R., Kumar, P., Das, R., Tiwari, S., and MacMicking, J.D. (2011). A family of IFN-gamma-inducible 65-kD GTPases protects against bacterial infection. Science 332, 717-721.

Kolb, R., Liu, G.H., Janowski, A.M., Sutterwala, F.S., and Zhang, W. (2014). Inflammasomes in cancer: a double-edged sword. Protein & cell 5, 12-20.

Kreshover, S.J., and Salley, J.J. (1957). Predisposing factors in oral cancer. Journal of the American Dental Association 54, 509-514.

Landskron, G., De la Fuente, M., Thuwajit, P., Thuwajit, C., and Hermoso, M.A. (2014). Chronic inflammation and cytokines in the tumor microenvironment. Journal of immunology research 2014, 149185.

Lee, L.A., Huang, C.G., Liao, C.T., Lee, L.Y., Hsueh, C., Chen, T.C., Lin, C.Y., Fan, K.H., Wang, H.M., Huang, S.F., et al. (2012). Human papillomavirus-16 infection in advanced oral cavity cancer patients is related to an increased risk of distant metastases and poor survival. PloS one 7, e40767.

Li, M., Mukasa, A., Inda, M.M., Zhang, J., Chin, L., Cavenee, W., and Furnari, F. (2011). Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma. The Journal of experimental medicine 208, 2657-2673.

Lin, W.W., and Karin, M. (2007). A cytokine-mediated link between innate immunity, inflammation, and cancer. The Journal of clinical investigation 117, 1175-1183.

Linder, P. (2006a). Dead-box proteins: a family affair--active and passive players in RNP-remodeling. Nucleic acids research 34, 4168-4180.

Linder, P. (2006b). Helicases and NTP-Driven Nucleic Acid Machines: Structure, Function and Roles in Human Disease. Nucleic acids research 34, 4081-4081.

Linder, P., Lasko, P.F., Ashburner, M., Leroy, P., Nielsen, P.J., Nishi, K., Schnier, J., and Slonimski, P.P. (1989). Birth of the D-E-A-D box. Nature 337, 121-122.

Liu, S.Y., Yen, C.Y., Yang, S.C., Chiang, W.F., and Chang, K.W. (2004). Overexpression of Rac-1 small GTPase binding protein in oral squamous cell carcinoma. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 62, 702-707.

Lorsch, J.R. (2002). RNA chaperones exist and DEAD box proteins get a life. Cell 109, 797-800.

Lu, R., Zhang, J., Sun, W., Du, G., and Zhou, G. (2015). Inflammation-related cytokines in oral lichen planus: an overview. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 44, 1-14.

Mathew, P., Austin, R.D., Varghese, S.S., and Manojkumar, A.D. (2015). Effect of copper-based fungicide (bordeaux mixture) spray on the total copper content of areca nut: Implications in increasing prevalence of oral submucous fibrosis. Journal of International Society of Preventive & Community Dentistry 5, 283-289.

Mitoma, H., Hanabuchi, S., Kim, T., Bao, M., Zhang, Z., Sugimoto, N., and Liu, Y.J. (2013). The DHX33 RNA helicase senses cytosolic RNA and activates the NLRP3 inflammasome. Immunity 39, 123-135.

Miyashita, M., Oshiumi, H., Matsumoto, M., and Seya, T. (2011). DDX60, a DEXD/H box helicase, is a novel antiviral factor promoting RIG-I-like receptor-mediated signaling. Molecular and cellular biology 31, 3802-3819.

Nagy, K.N., Sonkodi, I., Szoke, I., Nagy, E., and Newman, H.N. (1998). The microflora associated with human oral carcinomas. Oral oncology 34, 304-308.

Nantais DE, S.M., Stickney JT, Vestal DJ, Buss JE (1996). Prenylation of an interferon-gamma-induced GTP-binding protein : The human guanylate binding protein, huGBP1. . J Leukoc Biol 60, 423–431.

Orgaz, J.L., Herraiz, C., and Sanz-Moreno, V. (2014). Rho GTPases modulate malignant transformation of tumor cells. Small GTPases 5, e29019.

Oshiumi, H., Miyashita, M., Okamoto, M., Morioka, Y., Okabe, M., Matsumoto, M., and Seya, T. (2015). DDX60 Is Involved in RIG-I-Dependent and Independent Antiviral Responses, and Its Function Is Attenuated by Virus-Induced EGFR Activation. Cell reports 11, 1193-1207.

Parkin, D.M., Bray, F., Ferlay, J., and Pisani, P. (2005). Global cancer statistics, 2002. CA: a cancer journal for clinicians 55, 74-108.

Patrone, L., Damore, M.A., Lee, M.B., Malone, C.S., and Wall, R. (2002). Genes expressed during the IFN gamma-induced maturation of pre-B cells. Molecular immunology 38, 597-606.

Popa, C., Netea, M.G., van Riel, P.L., van der Meer, J.W., and Stalenhoef, A.F. (2007). The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. Journal of lipid research 48, 751-762.

Przewoznik, M., Homberg, N., Naujoks, M., Potzl, J., Munchmeier, N., Brenner, C.D., Anz, D., Bourquin, C., Nelson, P.J., Rocken, M., et al. (2012). Recruitment of natural killer cells in advanced stages of endogenously arising B-cell lymphoma: implications for therapeutic cell transfer. Journal of immunotherapy 35, 217-222.

Rupper, A.C., and Cardelli, J.A. (2008). Induction of guanylate binding protein 5 by gamma interferon increases susceptibility to Salmonella enterica serovar Typhimurium-induced pyroptosis in RAW 264.7 cells. Infection and immunity 76, 2304-2315.

Schwer, B. (2001). A new twist on RNA helicases: DExH/D box proteins as RNPases. Nature structural biology 8, 113-116.

Shenoy, A.R., Wellington, D.A., Kumar, P., Kassa, H., Booth, C.J., Cresswell, P., and MacMicking, J.D. (2012). GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Science 336, 481-485.

Tanner, N.K., and Linder, P. (2001). DExD/H box RNA helicases: from generic motors to specific dissociation functions. Molecular cell 8, 251-262.
Vabret, N., and Blander, J.M. (2013). Sensing microbial RNA in the cytosol. Frontiers in immunology 4, 468.

van Monsjou, H.S., Wreesmann, V.B., van den Brekel, M.W., and Balm, A.J. (2013). Head and neck squamous cell carcinoma in young patients. Oral oncology 49, 1097-1102.

Vestal, D.J., and Jeyaratnam, J.A. (2011). The guanylate-binding proteins: emerging insights into the biochemical properties and functions of this family of large interferon-induced guanosine triphosphatase. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 31, 89-97.

Vincent, S., Marty, L., and Fort, P. (1993). S26 ribosomal protein RNA: an invariant control for gene regulation experiments in eucaryotic cells and tissues. Nucleic acids research 21, 1498.

Wang, R., Jiao, Z., Li, R., Yue, H., and Chen, L. (2012). p68 RNA helicase promotes glioma cell proliferation in vitro and in vivo via direct regulation of NF-kappaB transcription factor p50. Neuro-oncology 14, 1116-1124.

Wang, Z., Luo, Z., Zhou, L., Li, X., Jiang, T., and Fu, E. (2015). DDX5 promotes proliferation and tumorigenesis of non-small-cell lung cancer cells by activating beta-catenin signaling pathway. Cancer science 106, 1303-1312.

Warnakulasuriya, S. (2009). Global epidemiology of oral and oropharyngeal cancer. Oral oncology 45, 309-316.

Whitmore, S.E., and Lamont, R.J. (2014). Oral bacteria and cancer. PLoS pathogens 10, e1003933.

Yang, L., Lin, C., and Liu, Z.R. (2005). Phosphorylations of DEAD box p68 RNA helicase are associated with cancer development and cell proliferation. Molecular cancer research : MCR 3, 355-363.

Yin, J., Park, G., Lee, J.E., Choi, E.Y., Park, J.Y., Kim, T.H., Park, N., Jin, X., Jung, J.E., Shin, D., et al. (2015). DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Brain : a journal of neurology 138, 2553-2570.
Yu, C.J., Chang, K.P., Chang, Y.J., Hsu, C.W., Liang, Y., Yu, J.S., Chi, L.M., Chang, Y.S., and Wu, C.C. (2011). Identification of guanylate-binding protein 1 as a potential oral cancer marker involved in cell invasion using omics-based analysis. Journal of proteome research 10, 3778-3788.

Zaidi, M.R., and Merlino, G. (2011). The two faces of interferon-gamma in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 17, 6118-6124.

Zamarron, B.F., and Chen, W. (2011). Dual Roles of Immune Cells and Their Factors in Cancer Development and Progression. International journal of biological sciences.

Zhang, Y., You, J., Wang, X., and Weber, J. (2015). The DHX33 RNA Helicase Promotes mRNA Translation Initiation. Molecular and cellular biology 35, 2918-2931.