極光激酶-A (Aurora-A)主要參與在細胞週期的進行，很多文獻報導指出Aurora-A在癌細胞中有異常大量表現，包括大腸直腸癌、乳癌、肝癌、及胃癌等，證明Aurora-A的異常表現與癌細胞生成有很大的關聯，因此，控制Aurora-A在細胞週期中的表現是很重要的，然而，Aurora-A在癌細胞大量表現的原因可能與mRNA表現量、轉錄能力及蛋白質穩定性增加有關。異源性核糖核蛋白Q1 (hnRNP Q1)是屬於RNA結合蛋白，並且參與mRNA代謝與轉譯的調控，但目前為止hnRNP Q1與癌症發生的相關性並不明確。根據RNA免疫沉澱及次世代定序結果，我們發現有一群與細胞週期相關的基因會受到hnRNP Q1調控，其中包含Aurora-A。在研究結果中，我們發現hnRNP Q1能增加Aurora-A蛋白質表現而非影響mRNA表現量，同時，也觀察到EGF增加hnRNP Q1與Aurora-A mRNA結合並增進Aurora-A mRNA的轉譯。 我們確認EGF是透過mTOR與ERK訊號傳遞路徑去調控hnRNP Q1對於Aurora-A mRNA相關的轉譯調控機制，同時，我們也發現hnRNP Q1可以促進一群紡錘絲監控蛋白(spindle assembly checkpoint)的轉譯。另一方面，在大腸直腸癌臨床檢體分析上，我們發現hnRNP Q1的表現與Aurora-A及紡錘絲監控蛋白表現呈現正相關。因此，我們認為hnRNP Q1是一個新的重要的細胞週期相關基因的調控因子，其在大腸直腸癌中與細胞週期相關基因過度表現而造成癌細胞生成或腫瘤發生有相關性。

Aurora-A, which is a serine/threonine kinase involved in regulating cell cycle progression, is frequently amplified and overexpressed in variety of cancers. Deregulation of Aurora-A has major roles in tumorigenesis. Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, an RNA binding protein, has been implicated in many post-transcriptional regulatory processes including mRNA splicing, RNA metabolism and translation. Using an RNA-immunoprecipitation (RIP)-seq analysis, a group of cell cycle-related genes targeted by hnRNP Q1 were identified, including Aurora-A kinase. Altering the hnRNP Q1 level influences the expression of the Aurora-A protein, but not its mRNA. Stimulation with epidermal growth factor (EGF) is found to enhance both binding between hnRNP Q1 and the Aurora-A mRNA as well as the efficacy of the hnRNP Q1-induced translation of the Aurora-A mRNA. The EGF/hnRNP Q1-induced translation of Aurora-A mRNA is mediated by the mTOR and ERK pathways. We also show that hnRNP Q1 up-regulates the translation of a group of spindle assembly checkpoint (SAC) genes. hnRNP Q1 overexpression is positively correlated with the levels of Aurora-A and these SAC genes in human colorectal cancer tissues. Taken together, our data indicate that hnRNP Q1 plays an important role in regulating a group of cell cycle-related genes expression. hnRNP Q1 may therefore contribute to tumorigenesis by up-regulating the translation of these genes in colorectal cancer.

1. Inamura K. Colorectal Cancers: An Update on Their Molecular Pathology. Cancers 10, 2018.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 68, 7-30, 2018.
3. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology 138, 2059-2072, 2010.
4. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330-337, 2012.
5. Coschi CH, Dick FA. Chromosome instability and deregulated proliferation: an unavoidable duo. Cellular and molecular life sciences : CMLS 69, 2009-2024, 2012.
6. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. The New England journal of medicine 361, 2449-2460, 2009.
7. Marisa L, de Reynies A, Duval A, Selves J, Gaub MP, Vescovo L, Etienne-Grimaldi MC, Schiappa R, Guenot D, Ayadi M, Kirzin S, Chazal M, Flejou JF, Benchimol D, Berger A, Lagarde A, Pencreach E, Piard F, Elias D, Parc Y, Olschwang S, Milano G, Laurent-Puig P, Boige V. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS medicine 10, e1001453, 2013.
8. Yan M, Wang C, He B, Yang M, Tong M, Long Z, Liu B, Peng F, Xu L, Zhang Y, Liang D, Lei H, Subrata S, Kelley KW, Lam EW, Jin B, Liu Q. Aurora-A Kinase: A Potent Oncogene and Target for Cancer Therapy. Medicinal research reviews 36, 1036-1079, 2016.
9. Marumoto T, Zhang D, Saya H. Aurora-A - a guardian of poles. Nature reviews Cancer 5, 42-50, 2005.
10. Fu J, Bian M, Jiang Q, Zhang C. Roles of Aurora kinases in mitosis and tumorigenesis. Molecular cancer research : MCR 5, 1-10, 2007.
11. Koh HM, Jang BG, Hyun CL, Kim YS, Hyun JW, Chang WY, Maeng YH. Aurora Kinase A Is a Prognostic Marker in Colorectal Adenocarcinoma. Journal of pathology and translational medicine 51, 32-39, 2017.
12. Warner SL, Bearss DJ, Han H, Von Hoff DD. Targeting Aurora-2 kinase in cancer. Molecular cancer therapeutics 2, 589-595, 2003.
13. Briassouli P, Chan F, Savage K, Reis-Filho JS, Linardopoulos S. Aurora-A regulation of nuclear factor-kappaB signaling by phosphorylation of IkappaBalpha. Cancer research 67, 1689-1695, 2007.
14. Hsueh KW, Fu SL, Chang CB, Chang YL, Lin CH. A novel Aurora-A-mediated phosphorylation of p53 inhibits its interaction with MDM2. Biochimica et biophysica acta 1834, 508-515, 2013.
15. Landen CN, Jr., Lin YG, Immaneni A, Deavers MT, Merritt WM, Spannuth WA, Bodurka DC, Gershenson DM, Brinkley WR, Sood AK. Overexpression of the centrosomal protein Aurora-A kinase is associated with poor prognosis in epithelial ovarian cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research 13, 4098-4104, 2007.
16. Yang SB, Zhou XB, Zhu HX, Quan LP, Bai JF, He J, Gao YN, Cheng SJ, Xu NZ. Amplification and overexpression of Aurora-A in esophageal squamous cell carcinoma. Oncology reports 17, 1083-1088, 2007.
17. Nishida N, Nagasaka T, Kashiwagi K, Boland CR, Goel A. High copy amplification of the Aurora-A gene is associated with chromosomal instability phenotype in human colorectal cancers. Cancer biology & therapy 6, 525-533, 2007.
18. Jiang S, Katayama H, Wang J, Li SA, Hong Y, Radvanyi L, Li JJ, Sen S. Estrogen-induced aurora kinase-A (AURKA) gene expression is activated by GATA-3 in estrogen receptor-positive breast cancer cells. Hormones & cancer 1, 11-20, 2010.
19. Wu CC, Yang TY, Yu CT, Phan L, Ivan C, Sood AK, Hsu SL, Lee MH. p53 negatively regulates Aurora A via both transcriptional and posttranslational regulation. Cell cycle 11, 3433-3442, 2012.
20. Yin N, Shi J, Wang D, Tong T, Wang M, Fan F, Zhan Q. IQGAP1 interacts with Aurora-A and enhances its stability and its role in cancer. Biochemical and biophysical research communications 421, 64-69, 2012.
21. Giovinazzi S, Morozov VM, Summers MK, Reinhold WC, Ishov AM. USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase. Cell death and differentiation 20, 721-731, 2013.
22. Lai CH, Huang YC, Lee JC, Tseng JT, Chang KC, Chen YJ, Ding NJ, Huang PH, Chang WC, Lin BW, Chen RY, Wang YC, Lai YC, Hung LY. Translational upregulation of Aurora-A by hnRNP Q1 contributes to cell proliferation and tumorigenesis in colorectal cancer. Cell death & disease 8, e2555, 2017.
23. Lai CH, Tseng JT, Lee YC, Chen YJ, Lee JC, Lin BW, Huang TC, Liu YW, Leu TH, Liu YW, Chen YP, Chang WC, Hung LY. Translational up-regulation of Aurora-A in EGFR-overexpressed cancer. Journal of cellular and molecular medicine 14, 1520-1531, 2010.
24. Krecic AM, Swanson MS. hnRNP complexes: composition, structure, and function. Current opinion in cell biology 11, 363-371, 1999.
25. Han SP, Tang YH, Smith R. Functional diversity of the hnRNPs: past, present and perspectives. The Biochemical journal 430, 379-392, 2010.
26. Chaudhury A, Chander P, Howe PH. Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: Focus on hnRNP E1's multifunctional regulatory roles. Rna 16, 1449-1462, 2010.
27. Geuens T, Bouhy D, Timmerman V. The hnRNP family: insights into their role in health and disease. Human genetics 135, 851-867, 2016.
28. Campos-Melo D, Droppelmann CA, Volkening K, Strong MJ. RNA-binding proteins as molecular links between cancer and neurodegeneration. Biogerontology 15, 587-610, 2014.
29. Mizutani A, Fukuda M, Ibata K, Shiraishi Y, Mikoshiba K. SYNCRIP, a cytoplasmic counterpart of heterogeneous nuclear ribonucleoprotein R, interacts with ubiquitous synaptotagmin isoforms. The Journal of biological chemistry 275, 9823-9831, 2000.
30. Mourelatos Z, Abel L, Yong J, Kataoka N, Dreyfuss G. SMN interacts with a novel family of hnRNP and spliceosomal proteins. The EMBO journal 20, 5443-5452, 2001.
31. Wigington CP, Williams KR, Meers MP, Bassell GJ, Corbett AH. Poly(A) RNA-binding proteins and polyadenosine RNA: new members and novel functions. Wiley interdisciplinary reviews RNA 5, 601-622, 2014.
32. Chen HH, Chang JG, Lu RM, Peng TY, Tarn WY. The RNA binding protein hnRNP Q modulates the utilization of exon 7 in the survival motor neuron 2 (SMN2) gene. Molecular and cellular biology 28, 6929-6938, 2008.
33. Bannai H, Fukatsu K, Mizutani A, Natsume T, Iemura S, Ikegami T, Inoue T, Mikoshiba K. An RNA-interacting protein, SYNCRIP (heterogeneous nuclear ribonuclear protein Q1/NSAP1) is a component of mRNA granule transported with inositol 1,4,5-trisphosphate receptor type 1 mRNA in neuronal dendrites. The Journal of biological chemistry 279, 53427-53434, 2004.
34. Williams KR, McAninch DS, Stefanovic S, Xing L, Allen M, Li W, Feng Y, Mihailescu MR, Bassell GJ. hnRNP-Q1 represses nascent axon growth in cortical neurons by inhibiting Gap-43 mRNA translation. Molecular biology of the cell 27, 518-534, 2016.
35. Kim DY, Kim W, Lee KH, Kim SH, Lee HR, Kim HJ, Jung Y, Choi JH, Kim KT. hnRNP Q regulates translation of p53 in normal and stress conditions. Cell death and differentiation 20, 226-234, 2013.
36. Chen HH, Yu HI, Chiang WC, Lin YD, Shia BC, Tarn WY. hnRNP Q regulates Cdc42-mediated neuronal morphogenesis. Molecular and cellular biology 32, 2224-2238, 2012.
37. Xing L, Yao X, Williams KR, Bassell GJ. Negative regulation of RhoA translation and signaling by hnRNP-Q1 affects cellular morphogenesis. Molecular biology of the cell 23, 1500-1509, 2012.
38. Shimizu Y, Nishitsuji H, Marusawa H, Ujino S, Takaku H, Shimotohno K. The RNA-editing enzyme APOBEC1 requires heterogeneous nuclear ribonucleoprotein Q isoform 6 for efficient interaction with interleukin-8 mRNA. The Journal of biological chemistry 289, 26226-26238, 2014.
39. Vu LP, Prieto C, Amin EM, Chhangawala S, Krivtsov A, Calvo-Vidal MN, Chou T, Chow A, Minuesa G, Park SM, Barlowe TS, Taggart J, Tivnan P, Deering RP, Chu LP, Kwon JA, Meydan C, Perales-Paton J, Arshi A, Gonen M, Famulare C, Patel M, Paietta E, Tallman MS, Lu Y, Glass J, Garret-Bakelman FE, Melnick A, Levine R, Al-Shahrour F, Jaras M, Hacohen N, Hwang A, Garippa R, Lengner CJ, Armstrong SA, Cerchietti L, Cowley GS, Root D, Doench J, Leslie C, Ebert BL, Kharas MG. Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells. Nature genetics 49, 866-875, 2017.
40. Quaresma AJ, Bressan GC, Gava LM, Lanza DC, Ramos CH, Kobarg J. Human hnRNP Q re-localizes to cytoplasmic granules upon PMA, thapsigargin, arsenite and heat-shock treatments. Experimental cell research 315, 968-980, 2009.
41. Passos DO, Quaresma AJ, Kobarg J. The methylation of the C-terminal region of hnRNPQ (NSAP1) is important for its nuclear localization. Biochemical and biophysical research communications 346, 517-525, 2006.
42. Yoo BC, Hong SH, Ku JL, Kim YH, Shin YK, Jang SG, Kim IJ, Jeong SY, Park JG. Galectin-3 stabilizes heterogeneous nuclear ribonucleoprotein Q to maintain proliferation of human colon cancer cells. Cellular and molecular life sciences : CMLS 66, 350-364, 2009.
43. Kim TD, Woo KC, Cho S, Ha DC, Jang SK, Kim KT. Rhythmic control of AANAT translation by hnRNP Q in circadian melatonin production. Genes & development 21, 797-810, 2007.
44. Kim JH, Paek KY, Ha SH, Cho S, Choi K, Kim CS, Ryu SH, Jang SK. A cellular RNA-binding protein enhances internal ribosomal entry site-dependent translation through an interaction downstream of the hepatitis C virus polyprotein initiation codon. Molecular and cellular biology 24, 7878-7890, 2004.
45. Kim DY, Woo KC, Lee KH, Kim TD, Kim KT. hnRNP Q and PTB modulate the circadian oscillation of mouse Rev-erb alpha via IRES-mediated translation. Nucleic acids research 38, 7068-7078, 2010.
46. Svitkin YV, Yanagiya A, Karetnikov AE, Alain T, Fabian MR, Khoutorsky A, Perreault S, Topisirovic I, Sonenberg N. Control of translation and miRNA-dependent repression by a novel poly(A) binding protein, hnRNP-Q. PLoS biology 11, e1001564, 2013.
47. Lyabin DN, Nigmatullina LF, Doronin AN, Eliseeva IA, Ovchinnikov LP. Identification of proteins specifically interacting with YB-1 mRNA 3' UTR and the effect of hnRNP Q on YB-1 mRNA translation. Biochemistry Biokhimiia 78, 651-659, 2013.
48. Kedzierska H, Piekielko-Witkowska A. Splicing factors of SR and hnRNP families as regulators of apoptosis in cancer. Cancer letters 396, 53-65, 2017.
49. Albrethsen J, Knol JC, Piersma SR, Pham TV, de Wit M, Mongera S, Carvalho B, Verheul HM, Fijneman RJ, Meijer GA, Jimenez CR. Subnuclear proteomics in colorectal cancer: identification of proteins enriched in the nuclear matrix fraction and regulation in adenoma to carcinoma progression. Molecular & cellular proteomics : MCP 9, 988-1005, 2010.
50. 丁乃筑. 探討hnRNP Q1及hnRNP A2/B1對於Aurora-A 轉譯調控之機制. 台南市: 國立成功大學; 2012.
51. Ingolia NT, Brar GA, Rouskin S, McGeachy AM, Weissman JS. The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments. Nature protocols 7, 1534-1550, 2012.
52. 陳盈如. Aurora-A基因5端非轉譯區的選擇性裁接之分析. 台南市: 國立成功大學; 2009.
53. Tang A, Gao K, Chu L, Zhang R, Yang J, Zheng J. Aurora kinases: novel therapy targets in cancers. Oncotarget 8, 23937-23954, 2017.
54. Wang F, Fu X, Chen P, Wu P, Fan X, Li N, Zhu H, Jia TT, Ji H, Wang Z, Wong CC, Hu R, Hui J. SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling. Cell research 27, 540-558, 2017.
55. Zhou Z, Qiu J, Liu W, Zhou Y, Plocinik RM, Li H, Hu Q, Ghosh G, Adams JA, Rosenfeld MG, Fu XD. The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. Molecular cell 47, 422-433, 2012.
56. Morton S, Yang HT, Moleleki N, Campbell DG, Cohen P, Rousseau S. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ. The Biochemical journal 399, 265-273, 2006.
57. Roda D, Castillo J, Telechea-Fernandez M, Gil A, Lopez-Rodas G, Franco L, Gonzalez-Rodriguez P, Rosello S, Perez-Fidalgo JA, Garcia-Trevijano ER, Cervantes A, Zaragoza R. EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells. PloS one 10, e0130543, 2015.
58. Parsa AT, Holland EC. Cooperative translational control of gene expression by Ras and Akt in cancer. Trends in molecular medicine 10, 607-613, 2004.
59. Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N. mTOR, translation initiation and cancer. Oncogene 25, 6416-6422, 2006.
60. Golob-Schwarzl N, Krassnig S, Toeglhofer AM, Park YN, Gogg-Kamerer M, Vierlinger K, Schroder F, Rhee H, Schicho R, Fickert P, Haybaeck J. New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors. European journal of cancer 83, 56-70, 2017.
61. Kumar JP. My what big eyes you have: how the Drosophila retina grows. Developmental neurobiology 71, 1133-1152, 2011.
62. Mardin BR, Isokane M, Cosenza MR, Kramer A, Ellenberg J, Fry AM, Schiebel E. EGF-induced centrosome separation promotes mitotic progression and cell survival. Developmental cell 25, 229-240, 2013.
63. Rea K, Sensi M, Anichini A, Canevari S, Tomassetti A. EGFR/MEK/ERK/CDK5-dependent integrin-independent FAK phosphorylated on serine 732 contributes to microtubule depolymerization and mitosis in tumor cells. Cell death & disease 4, e815, 2013.
64. Diogo V, Teixeira J, Silva PM, Bousbaa H. Spindle Assembly Checkpoint as a Potential Target in Colorectal Cancer: Current Status and Future Perspectives. Clinical colorectal cancer 16, 1-8, 2017.
65. Schvartzman JM, Sotillo R, Benezra R. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nature reviews Cancer 10, 102-115, 2010.
66. Bhonde MR, Hanski ML, Budczies J, Cao M, Gillissen B, Moorthy D, Simonetta F, Scherubl H, Truss M, Hagemeier C, Mewes HW, Daniel PT, Zeitz M, Hanski C. DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1: the lack of this suppression in p53MUT cells contributes to apoptosis. The Journal of biological chemistry 281, 8675-8685, 2006.
67. Simonetti G, Bruno S, Padella A, Tenti E, Martinelli G. Aneuploidy: Cancer strength or vulnerability? International journal of cancer, 2018.
68. Yamamoto S, Midorikawa Y, Morikawa T, Nishimura Y, Sakamoto H, Ishikawa S, Akagi K, Aburatani H. Identification of chromosomal aberrations of metastatic potential in colorectal carcinoma. Genes, chromosomes & cancer 49, 487-496, 2010.
69. Hresko RC, Mueckler M. Identification of pp68 as the Tyrosine-phosphorylated Form of SYNCRIP/NSAP1. A cytoplasmic RNA-binding protein. The Journal of biological chemistry 277, 25233-25238, 2002.