臺灣博碩士論文加值系統

癌症治療上，抗藥性以及遠端轉移的發生為低存活率的主要原因。口腔癌細胞的分子異常往往導致EGFR/PI3K/Akt的訊息傳遞路徑過度活化，而此訊息傳遞路徑與癌細胞抗藥性及轉移能力有著顯著的相關性，即使已有許多EGFR標靶藥物被廣泛使用，但是抗藥現象依然存在。為了提升治療效率，透析口腔癌細胞轉移機制以及發掘關鍵標靶治療的分子標的，儼然刻不容緩。因此，此篇論文的研究主旨，在於探究轉錄因子 HBP1(HMG box-containing protein 1) 在口腔癌惡化過程的角色，提供證據支持HBP1是口腔癌發展的重要抑癌基因。
首先，在Chapter 1我們回顧HBP1的生理功能，尤其是在細胞週期、細胞凋亡、細胞分化、以及細胞老化等生理現象的調節角色，進而了解HBP1與腫瘤之間的相關性。值得一提的是，已有研究發現EGCG、NAC、Emodin以及放射線治療會透過提升HBP1的表現而抑制腫瘤生長，當降解腫瘤細胞內HBP1的表現後，上述處理的抑癌效果明顯減弱，足見HBP1是重要的抑癌因子，但是， HBP1調節口腔癌細胞生長與侵襲轉移之角色尚不明確。
Chapter 2主要提供證據支持HBP1是口腔癌細胞中EGFR/PI3K/Akt訊息傳遞路徑下游關鍵調節因子的假說。當我們使用EGFR與PI3K的化學活性抑制劑，或是利用siRNA減低EGFR或Akt表現，皆導致HBP1 mRNA與蛋白質表現上升，尤其，降解HBP1表現顯著減弱EGFR標靶藥物erlotinib的抑癌效果。臨床口腔腫瘤檢體分析顯示，高EGFR/低HBP1表現與口腔癌轉移息息相關。可見，HBP1是口腔癌細胞中EGFR/PI3K/Akt訊息傳遞路徑的關鍵負調控者，提升HBP1表現將有助於彌補或改善癌細胞對 EGFR標靶藥物的阻抗。
接著，在Chapter 3我們試圖了解EGFR/PI3K/Akt訊息傳遞路徑如何調節HBP1表現。當我們利用MAPPER搜尋引擎尋找可能調解HBP1啟動子的轉錄因子時發現，HBP1啟動子上-132 bp至-125 bp及-343 bp至-336 bp具有轉錄因子FOXO1的高親和位點，而FOXO1為EGFR/PI3K/Akt路徑的Akt直接調控下游標的。為了闡明FOXO1是HBP1表現的轉錄因子，我們利用一系列的Reporter gene配合CHIP assay，證實FOXO1的確可以透過上述位點調控HBP1轉錄。生理上，FOXO1抑制口腔癌細胞群落生長及侵襲轉移能力則因HBP1表現降解而顯著受到影響。這個章節提供HBP1是FOXO1的直接轉錄標的之證據，而且，EGFR/PI3K/Akt 至少可以透過FOXO1調節HBP1表現。
文獻指出HBP1具有調節乳癌與前列腺癌細胞侵襲轉移的能力，但其標的基因以及HBP1在口腔癌侵襲的角色尚不清楚。因此，我們於Chapter 4探究HBP1在口腔癌細胞侵襲轉移的分子機制。原位腫瘤惡化成具有侵襲轉移能力的過程中，調節腫瘤微環境的MMP (matrix metalloproteinase) 家族成員扮演關鍵角色。當我們剔除口腔癌細胞HBP1後，口腔癌細胞的爬行侵襲能力因而增強，而且，剔除HBP1 mRNA的Microarray分析結果指出，整體 MMP 家族成員的mRNA 表現呈現不等程度的上升，推測MMP是HBP1調節癌細胞侵襲的標的基因，尤其是與口腔癌惡化極具相關的MMP-2、9以及13。如預期地，MMP-2、9、13的蛋白質表現量以及其酵素活性皆與HBP1表現呈現負相關，尤其與MMP-13的關係更為顯著。尤其，MMP-13的近端啟動子有一類似N-Myc啟動子上的HBP1連結序列，因此，我們建立一系列帶有突變位點的報導基因，配合HBP1突變型，證明HBP1直接抑制MMP13基因的轉錄，藉此，HBP1進而抑制口腔癌細胞的轉移能力。
綜合以上結果，此篇論文證明HBP1為口腔癌細胞EGFR/PI3K/Akt/FOXO1訊息傳遞路徑的一個新的下游標的，除此，HBP1透過負調節其標的基因MMP13的轉錄，達到抑制口腔癌細胞的侵襲轉移能力。這些證據提供HBP1做為未來口腔癌藥物開發及其治療策略應用的潛在標的。

Cancer treatment often becomes complicated when distal metastasis and/or drug resistance occur(s). Indeed, distal metastasis is heavily implicated with high mortality rates and low survival rates in cancer patients. In terms of oral cancer, the cancer cells often display dysregulated EGFR, as well as sustained activation of the PI3K/Akt signaling transduction pathway that governs tumorigenesis. Accordingly, several EGFR-targeting drugs have been developed to treat oral cancer. However, drug resistance does occur. Therefore, discovering new potential cellular molecules to be therapeutic targets may improve this unfavorable circumstance.
This study is aimed at investigating the tumor suppressing potential of the transcription factor HMG box-containing protein 1 (HBP1) in oral cancer and its aggressiveness. First, in Chapter 1, we provided background information regarding the biological role of HBP1 in the control of cell cycle arrest, apoptosis, cell differentiation, and senescence, and its connection to tumorigenesis. The evidence for HBP1’s anti-cancer function is in the process of being accumulated, and more importantly, the implication of HBP1 in cancer treatment has begun receiving attention. It has been shown that EGCG, NAC, emodin, and radiation can inhibit tumor growth by up-regulating the expression of HBP1, and knocking down HBP1 often attenuates their effects.
In Chapter 2, we proposed that the role of HBP1 in the EGFR/PI3K/Akt signaling transduction pathway to be a key downstream effector in oral cancer. In this study, we used chemical inhibitors, expressing vectors, and siRNA to manipulate the expression or activity of EGFR, PI3K, and Akt to see if HBP1 expression is affected in oral cancer. As we predicted, suppression of EGFR/Pi3K/Akt activation resulted in inducing the expression of HBP1, and siRNA-mediated HBP1 knockdown potently attenuated the suppressive effect of erlotinib on the cell growth and the invasiveness of the HSC-3 oral cancer cell line. All told, our data indicated that HBP1 is a negative downstream mediator of the EGFR/PI3K/Akt signaling pathway-regulated aggressiveness in oral cancer.
Next, we asked how the EGFR/PI3K/Akt signaling pathway modulates HBP1 expression. Our review of the literature told us both that FOXO1 transcription factor is a downstream effector of the PI3K/Akt pathway and that it is associated with tumorigenesis. Therefore, in Chapter 3, we proposed and further identified HBP1 to be a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer. In searching for the potential FOXO1 binding sites in the HBP1 promoter, the use of the MAPPER Search Engine predicted two putative FOXO1 binding sites located in said HBP1 promoter: -132 to-125 bp and -343 to -336 bp. These binding sites were then confirmed by both reporter gene assays and an in-cellulo ChIP assay. Furthermore, HBP1 knockdown was found to potently promote malignant phenotypes of oral cancer and attenuate the suppressive effect of FOXO1 on cell growth, colony formation, and invasion in invasive oral cancer cells. Taken together, our data provide evidence for HBP1 as a novel downstream target of FOXO1 in oral cancer malignancy.
In Chapter 4, we asked what the downstream target of HBP1 regulation of oral cancer invasiveness might be. Microarray analysis in HBP1 knockdown cells revealed overall up-regulation of the matrix metalloproteinase (MMP) family member genes. Among all MMP members, we examined the effect of HBP1 on the activation of MMP-2, -9, and -13, all of which are highly associated with the aggressiveness of oral cancer. Our manipulation of HBP1 expression in oral cancer cell models consistently resulted in the reciprocal expression and activation of MMPs tested. Further, we demonstrated that MMP-13 is a direct target of HBP1 transcription repression as evidenced by the identification of an HBP1 binding site in the cis-proximal region of the MMP-13 promoter. Even more importantly, MMP-13 knockdown significantly alleviated HBP1 si-RNA-mediated promotion in cell invasion. Altogether, our study provides evidence supporting the idea that the HBP1-MMP-13 axis is a key regulator of the aggressiveness of oral cancer.
In conclusion, this study provides molecular evidence that supports the novel biological role of HBP1 as a downstream effector of the EGFR/PI3K/Akt/FOXO1 axis in oral tumorigenesis, as well as MMP-13 being a direct target of HBP1-mediated metastatic potential in oral cancer. Taken as a whole our data indicate that HBP1 is a tumor suppressor gene and an important anti-cancer target for oral cancer therapy strategies.

ACKNOWLEDGEMENTS 5
摘要 6
ABSTRACT 8
ABBREVIATION 11
CHAPTER 1 GENERAL INTRODUCTION 14
1.1 HBP1 ( HMG-box-containing protein 1) 15
1.2 HBP1, cell cycle regulation, and cancer 16
1.3 HBP1, cell apoptosis, and cancer 19
1.4 HBP1, cell differentiation, and cancer 22
1.5 HBP1 and cell development 24
1.6 HBP1, cellular senescence, and cancer 25
1.7 HBP1, microRNA, and cancer 28
1.8 HBP1 as an anti-cancer target 30
1.9 References 33
CHAPTER 2 Motivation 38
2.1 References 41
CHAPTER 3 HMG box-containing protein 1 (HBP1) functions as a downstream effector of the EGFR/PI3K/Akt signaling pathway in oral cancer 42
3.1 Abstract 43
3.2 Introduction 44
3.3 Materials and methods 46
3.3.1 Reagents and antibodies 46
3.3.2 Plasmids 46
3.3.3 Cell culture and treatment 46
3.3.4 Establishment of stable HBP1-knockdown cell lines 47
3.3.5 Cell cycle analysis 47
3.3.6 Colony formation assay 47
3.3.7 Reporter assay 48
3.3.8 Tissue sample preparation 48
3.3.9 Reverse transcription-polymerase chain reaction and real-time PCR 48
3.3.10 Matrigel invasion assay 49
3.3.11 Statistical analysis 49
3.4 Results 50
3.4.1 Low HBP1/high EGFR expression predicts malignancy of oral cancer 50
3.4.2 HBP1 functions as downstream mediator of the EGFR signaling 51
3.4.3 HBP1 functions as downstream mediator of the PI3k/Akt signaling 51
3.4.4 Erlotinib suppresses EGFR/Akt signaling pathway and cell growth in oral cancer cells 52
3.4.5 Erlotinib inhibits cell growth and invasion through HBP1 53
3.5 Discussion 54
3.6 Acknowledgments 57
3.7 Figure legends and figures 58
3.7.1 Impact of HBP1 on oral cancer malignancy. 58
3.7.2 Effect of HBP1 on aggressiveness of oral cancer cells. 62
3.7.3 Effects of EGFR activation and protein levels on HBP1 expression. 66
3.7.4 Effect of Akt activation and protein levels on HBP1 expression. 70
3.7.5 Effects of Akt activation and protein levels on HBP1 transcription. 73
3.7.6 Effect of erlotinib on cell growth and HBP1 expression in oral cancer cell lines. 76
3.7.7 HBP1 regulates erlotinib-mediated cell growth and invasion in oral cancer cells. 80
3.8 References 83
CHAPTER 4 Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer 86
4.1 Abstract 87
4.2 Introdution 88
4.3 Materials and methods 90
4.3.1 Reagents and antibodies 90
4.3.2 Plasmids 90
4.3.3 Cell culture and treatment 90
4.3.4 Colony formation assay 91
4.3.5 Reporter assay 91
4.3.6 Tissue sample preparation 91
4.3.7 Reverse transcription-polymerase chain reaction, real-time PCR, and PCR 92
4.3.8 Matrigel invasion assay 93
4.3.9 Colony formation in soft agar 93
4.3.10 Chromatin immunoprecipitation (ChIP) assays 93
4.3.11 Statistical analysis 94
4.4 Results 95
4.4.1 Low FOXO1/low HBP1 expression predicts invasiveness of oral cancer 95
4.4.2 FOXO1 transcriptionally induces HBP1 expression 96
4.4.3 FOXO1 activity is essential for the FOXO1-mediated HBP1 expression 97
4.4.4 Identification of the FOXO1 response elements in the HBP1 promoter 98
4.4.5 FOXO1-mediated activation of HBP1 expression suppresses tumor cell proliferation and invasion 99
4.5 Discussion 101
4.6 Acknowledgments 104
4.7 Figure legends and figures 105
4.7.1 Coordinate down-regulation of FOXO1 and HBP1 in oral cancer. 105
4.7.2 FOXO1 induces HBP1 gene expression in oral cancer. 108
4.7.3 HBP1 expression is regulated by FOXO1 activity. 113
4.7.4 Identification of FOXO1 response elements in the HBP1 promoter. 119
4.7.5 FOXO1 occupies its consensus binding sites in the endogenous HBP1 promoter. 122
4.7.6 The role of FOXO1-mediated HBP1 expression in oral cancer malignancy. 125
4.8 References 130
CHAPTER 5 HMG box-containing protein 1 (HBP1) modulates cell invasion via Matrix metalloproteinase-13 (MMP-13) in human oral cancer cells 133
5.1 Abstract 134
5.2 Introduction 135
5.3 Materials and Methods 137
5.3.1 Reagents and antibodies 137
5.3.2 Plasmids 137
5.3.3 Cell culture and treatment 137
5.3.4 Reporter gene assay 138
5.3.5 Zymography assay 138
5.3.6 Tissue sample preparation 138
5.3.7 Reverse transcription-polymerase chain reaction and real-time PCR 139
5.3.8 Wound-healing assay 139
5.3.9 Matrigel invasion assay 140
5.3.10 Statistical analysis 140
5.4 Results 141
5.4.1 HBP1 expression level affects invasiveness of oral cancer 141
5.4.2 HBP1 regulates the epithelial-mesenchymal transition (EMT) 141
5.4.3 HBP1 modulates the activation of matrix metalloproteinases (MMPs) 142
5.4.4 HBP1 modulates MMP-13 promoter activity 143
5.4.5 MMP-13 is crucial in an HBP1-mediated invasion 144
5.4.6 Low HBP1/high MMP-13 expression predicts malignancy of oral cancer 144
5.5 Discussion 146
5.6 Acknowledgements 150
5.7 Figure legends and figures 151
5.7.1 Effect of HBP1 expression level on cell migration and invasion. 151
5.7.2 HBP1 modulates the aggressive phenotype of oral cancer cells. 155
5.7.3 HBP1 regulates the expression and activity of MMPs. 157
5.7.4 MMP-13 regulates invasion in oral cancer cells. 160
5.7.5 HBP1 regulates MMP-13 expression through transcription. 163
5.7.6 The HBP1 DNA binding domain is necessary for the transcription repression of MMP-13 gene. 167
5.7.7 MMP-13 is involved in HBP1-mediated invasion in oral cancer cells. 169
5.7.8 Impact of HBP1 and MMP-13 on oral cancer malignancy. 171
5.8 References 174
CHAPTER 6 Discussion 178
6.1 Figure legends and figures 184
6.2 References 188
CHAPTER 7 Conclusion 190

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63.Kim J, Zhang X, Rieger-Christ KM, Summerhayes IC, Wazer DE, Paulson KE, et al. Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J Biol Chem. 2006;281:10865-75.
64.Pooja T, Karunagaran D. Emodin suppresses Wnt signaling in human colorectal cancer cells SW480 and SW620. Eur J Pharmacol. 2014;742:55-64.
65.Raghu D, Karunagaran D. Plumbagin downregulates Wnt signaling independent of p53 in human colorectal cancer cells. J Nat Prod. 2014;77:1130-4.
66.Lee MF, Hsieh NT, Huang CY, Li CI. All Trans-Retinoic Acid Mediates MED28/HMG Box-Containing Protein 1 (HBP1)/beta-Catenin Signaling in Human Colorectal Cancer Cells. J Cell Physiol. 2016;231:1796-803.
67.Feng YM, Feng CW, Chen SY, Hsieh HY, Chen YH, Hsu CD. Cyproheptadine, an antihistaminic drug, inhibits proliferation of hepatocellular carcinoma cells by blocking cell cycle progression through the activation of P38 MAP kinase. BMC Cancer. 2015;15:134.
1.Sheu JJ, Hua CH, Wan L, Lin YJ, Lai MT, Tseng HC, et al. Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma. Cancer Res. 2009;69:2568-76.
2.Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol. 2006;24:4170-6.
3.Temam S, Kawaguchi H, El-Naggar AK, Jelinek J, Tang H, Liu DD, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol. 2007;25:2164-70.
4.Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS. Targeting EGFR resistance networks in head and neck cancer. Cell Signal. 2009;21:1255-68.
5.Modjtahedi H, Essapen S. Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs. 2009;20:851-5.
6.Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284:31-53.
7.Burtness B. The role of cetuximab in the treatment of squamous cell cancer of the head and neck. Expert Opin Biol Ther. 2005;5:1085-93.
8.Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005;23:8646-54.
9.Dobelbower MC, Russo SM, Raisch KP, Seay LL, Clemons LK, Suter S, et al. Epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, and concurrent 5-fluorouracil, cisplatin and radiotherapy for patients with esophageal cancer: a phase I study. Anticancer Drugs. 2006;17:95-102.
10.Yee AS, Paulson EK, McDevitt MA, Rieger-Christ K, Summerhayes I, Berasi SP, et al. The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. Gene. 2004;336:1-13.
11.Zhang X, Kim J, Ruthazer R, McDevitt MA, Wazer DE, Paulson KE, et al. The HBP1 transcriptional repressor participates in RAS-induced premature senescence. Mol Cell Biol. 2006;26:8252-66.
12.Wang W, Pan K, Chen Y, Huang C, Zhang X. The acetylation of transcription factor HBP1 by p300/CBP enhances p16INK4A expression. Nucleic acids research. 2012;40:981-95.
13.Pan K, Chen Y, Roth M, Wang W, Wang S, Yee AS, et al. HBP1-mediated transcriptional regulation of DNA methyltransferase 1 and its impact on cell senescence. Mol Cell Biol. 2013;33:887-903.
14.Tevosian SG, Shih HH, Mendelson KG, Sheppard KA, Paulson KE, Yee AS. HBP1: a HMG box transcriptional repressor that is targeted by the retinoblastoma family. Genes Dev. 1997;11:383-96.
15.Shih HH, Tevosian SG, Yee AS. Regulation of differentiation by HBP1, a target of the retinoblastoma protein. Mol Cell Biol. 1998;18:4732-43.
16.Berasi SP, Xiu M, Yee AS, Paulson KE. HBP1 repression of the p47phox gene: cell cycle regulation via the NADPH oxidase. Mol Cell Biol. 2004;24:3011-24.
17.Chen YC, Zhang XW, Niu XH, Xin DQ, Zhao WP, Na YQ, et al. Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer. Oncogene. 2010;29:3067-78.
18.Lin KM, Zhao WG, Bhatnagar J, Zhao WD, Lu JP, Simko S, et al. Cloning and expression of human HBP1, a high mobility group protein that enhances myeloperoxidase (MPO) promoter activity. Leukemia. 2001;15:601-12.
19.Paulson KE, Rieger-Christ K, McDevitt MA, Kuperwasser C, Kim J, Unanue VE, et al. Alterations of the HBP1 transcriptional repressor are associated with invasive breast cancer. Cancer research. 2007;67:6136-45.
20.Yao CJ, Works K, Romagnoli PA, Austin GE. Effects of overexpression of HBP1 upon growth and differentiation of leukemic myeloid cells. Leukemia. 2005;19:1958-68.
21.Kim J, Zhang X, Rieger-Christ KM, Summerhayes IC, Wazer DE, Paulson KE, et al. Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J Biol Chem. 2006;281:10865-75.
22.Paulson KE, Rieger-Christ K, McDevitt MA, Kuperwasser C, Kim J, Unanue VE, et al. Alterations of the HBP1 transcriptional repressor are associated with invasive breast cancer. Cancer Res. 2007;67:6136-45.
23.Lee MF, Chan CY, Hung HC, Chou IT, Yee AS, Huang CY. N-acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box-containing protein 1 (HBP1) signaling pathway in invasive oral cancer. Oral Oncol. 2013;49:129-35.
24.Xiu M, Kim J, Sampson E, Huang CY, Davis RJ, Paulson KE, et al. The transcriptional repressor HBP1 is a target of the p38 mitogen-activated protein kinase pathway in cell cycle regulation. Mol Cell Biol. 2003;23:8890-901.
25.Huang CY, Chou YH, Hsieh NT, Chen HH, Lee MF. MED28 regulates MEK1-dependent cellular migration in human breast cancer cells. J Cell Physiol. 2012;227:3820-7.
26.Rubin Grandis J, Melhem MF, Barnes EL, Tweardy DJ. Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer. 1996;78:1284-92.
27.Lee MF, Chan CY, Hung HC, Chou IT, Yee AS, Huang CY. N-acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box-containing protein 1 (HBP1) signaling pathway in invasive oral cancer. Oral Oncol. 2012.
28.Kozaki K, Imoto I, Pimkhaokham A, Hasegawa S, Tsuda H, Omura K, et al. PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma. Cancer Sci. 2006;97:1351-8.
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31.Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003;22:2812-22.
32.Di Gennaro E, Barbarino M, Bruzzese F, De Lorenzo S, Caraglia M, Abbruzzese A, et al. Critical role of both p27KIP1 and p21CIP1/WAF1 in the antiproliferative effect of ZD1839 (''Iressa''), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells. J Cell Physiol. 2003;195:139-50.
33.Escamilla-Powers JR, Daniel CJ, Farrell A, Taylor K, Zhang X, Byers S, et al. The tumor suppressor protein HBP1 is a novel c-myc-binding protein that negatively regulates c-myc transcriptional activity. J Biol Chem. 2010;285:4847-58.
1.Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410-25.
2.Zhao Y, Wang Y, Zhu WG. Applications of post-translational modifications of FoxO family proteins in biological functions. J Mol Cell Biol. 2011.
3.Kim SY, Yoon J, Ko YS, Chang MS, Park JW, Lee HE, et al. Constitutive phosphorylation of the FOXO1 transcription factor in gastric cancer cells correlates with microvessel area and the expressions of angiogenesis-related molecules. BMC Cancer. 2011;11:264.
4.Katayama K, Nakamura A, Sugimoto Y, Tsuruo T, Fujita N. FOXO transcription factor-dependent p15(INK4b) and p19(INK4d) expression. Oncogene. 2008;27:1677-86.
5.Valis K, Prochazka L, Boura E, Chladova J, Obsil T, Rohlena J, et al. Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner. Cancer Res. 2011;71:946-54.
6.Suhara T, Kim HS, Kirshenbaum LA, Walsh K. Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation. Mol Cell Biol. 2002;22:680-91.
7.Maiese K, Chong ZZ, Shang YC. OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. Trends Mol Med. 2008;14:219-27.
8.Yee AS, Paulson EK, McDevitt MA, Rieger-Christ K, Summerhayes I, Berasi SP, et al. The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. Gene. 2004;336:1-13.
9.Tevosian SG, Shih HH, Mendelson KG, Sheppard KA, Paulson KE, Yee AS. HBP1: a HMG box transcriptional repressor that is targeted by the retinoblastoma family. Genes Dev. 1997;11:383-96.
10.Lin KM, Zhao WG, Bhatnagar J, Zhao WD, Lu JP, Simko S, et al. Cloning and expression of human HBP1, a high mobility group protein that enhances myeloperoxidase (MPO) promoter activity. Leukemia. 2001;15:601-12.
11.Paulson KE, Rieger-Christ K, McDevitt MA, Kuperwasser C, Kim J, Unanue VE, et al. Alterations of the HBP1 transcriptional repressor are associated with invasive breast cancer. Cancer Res. 2007;67:6136-45.
12.Yao CJ, Works K, Romagnoli PA, Austin GE. Effects of overexpression of HBP1 upon growth and differentiation of leukemic myeloid cells. Leukemia. 2005;19:1958-68.
13.Kim J, Zhang X, Rieger-Christ KM, Summerhayes IC, Wazer DE, Paulson KE, et al. Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J Biol Chem. 2006;281:10865-75.
14.Chen YC, Zhang XW, Niu XH, Xin DQ, Zhao WP, Na YQ, et al. Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer. Oncogene. 2010;29:3067-78.
15.Lee MF, Chan CY, Hung HC, Chou IT, Yee AS, Huang CY. N-acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box-containing protein 1 (HBP1) signaling pathway in invasive oral cancer. Oral Oncol. 2013;49:129-35.
16.Shih HH, Tevosian SG, Yee AS. Regulation of differentiation by HBP1, a target of the retinoblastoma protein. Mol Cell Biol. 1998;18:4732-43.
17.Berasi SP, Xiu M, Yee AS, Paulson KE. HBP1 repression of the p47phox gene: cell cycle regulation via the NADPH oxidase. Mol Cell Biol. 2004;24:3011-24.
18.Coomans de Brachene A, Bollaert E, Eijkelenboom A, de Rocca Serra A, van der Vos KE, Burgering BM, et al. The expression of the tumour suppressor HBP1 is down-regulated by growth factors via the PI3K/PKB/FOXO pathway. Biochem J. 2014;460:25-34.
19.Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, et al. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999;96:2110-5.
20.Sheu JJ, Hua CH, Wan L, Lin YJ, Lai MT, Tseng HC, et al. Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma. Cancer Res. 2009;69:2568-76.
21.Huang CY, Chou YH, Hsieh NT, Chen HH, Lee MF. MED28 regulates MEK1-dependent cellular migration in human breast cancer cells. J Cell Physiol. 2012;227:3820-7.
22.Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857-68.
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24.Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS. Targeting EGFR resistance networks in head and neck cancer. Cell Signal. 2009;21:1255-68.
25.Rubin Grandis J, Melhem MF, Barnes EL, Tweardy DJ. Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer. 1996;78:1284-92.
26.Huang CY, Chan CY, Chou IT, Lien CH, Hung HC, Lee MF. Quercetin induces growth arrest through activation of FOXO1 transcription factor in EGFR-overexpressing oral cancer cells. J Nutr Biochem. 2013;24:1596-603.
27.Armoni M, Harel C, Karni S, Chen H, Bar-Yoseph F, Ver MR, et al. FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity. J Biol Chem. 2006;281:19881-91.
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29.Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489-501.
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32.Kaestner KH, Knochel W, Martinez DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 2000;14:142-6.
33.Ramaswamy S, Nakamura N, Sansal I, Bergeron L, Sellers WR. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell. 2002;2:81-91.
34.Chen J, Yusuf I, Andersen HM, Fruman DA. FOXO transcription factors cooperate with delta EF1 to activate growth suppressive genes in B lymphocytes. J Immunol. 2006;176:2711-21.
35.Zhang H, Pan Y, Zheng L, Choe C, Lindgren B, Jensen ED, et al. FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion. Cancer Res. 2011;71:3257-67.
36.Wu Y, Elshimali Y, Sarkissyan M, Mohamed H, Clayton S, Vadgama JV. Expression of FOXO1 is associated with GATA3 and Annexin-1 and predicts disease-free survival in breast cancer. Am J Cancer Res. 2012;2:104-15.
Chan CY, Huang SY, Sheu JJ, Roth MM, Chou IT, Lien CH, et al. Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer. Oncotarget. 2017.
2.Sheu JJ, Hua CH, Wan L, Lin YJ, Lai MT, Tseng HC, et al. Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma. Cancer Res. 2009;69:2568-76.
3.Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol. 2006;24:4170-6.
4.Temam S, Kawaguchi H, El-Naggar AK, Jelinek J, Tang H, Liu DD, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol. 2007;25:2164-70.
5.Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS. Targeting EGFR resistance networks in head and neck cancer. Cell Signal. 2009;21:1255-68.
6.Modjtahedi H, Essapen S. Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs. 2009;20:851-5.
7.Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284:31-53.
8.Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. Journal of the National Cancer Institute. 1997;89:1260-70.
9.Culhaci N, Metin K, Copcu E, Dikicioglu E. Elevated expression of MMP-13 and TIMP-1 in head and neck squamous cell carcinomas may reflect increased tumor invasiveness. BMC cancer. 2004;4:42.
10.Komatsu K, Nakanishi Y, Nemoto N, Hori T, Sawada T, Kobayashi M. Expression and quantitative analysis of matrix metalloproteinase-2 and -9 in human gliomas. Brain tumor pathology. 2004;21:105-12.
11.Johansson N, Airola K, Grenman R, Kariniemi AL, Saarialho-Kere U, Kahari VM. Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. Am J Pathol. 1997;151:499-508.
12.Kawamata H, Nakashiro K, Uchida D, Harada K, Yoshida H, Sato M. Possible contribution of active MMP2 to lymph-node metastasis and secreted cathepsin L to bone invasion of newly established human oral-squamous-cancer cell lines. Int J Cancer. 1997;70:120-7.
13.Ruokolainen H, Paakko P, Turpeenniemi-Hujanen T. Serum matrix metalloproteinase-9 in head and neck squamous cell carcinoma is a prognostic marker. Int J Cancer. 2005;116:422-7.
14.Kusukawa J, Harada H, Shima I, Sasaguri Y, Kameyama T, Morimatsu M. The significance of epidermal growth factor receptor and matrix metalloproteinase-3 in squamous cell carcinoma of the oral cavity. European journal of cancer Part B, Oral oncology. 1996;32B:217-21.
15.Yee AS, Paulson EK, McDevitt MA, Rieger-Christ K, Summerhayes I, Berasi SP, et al. The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. Gene. 2004;336:1-13.
16.Zhang X, Kim J, Ruthazer R, McDevitt MA, Wazer DE, Paulson KE, et al. The HBP1 transcriptional repressor participates in RAS-induced premature senescence. Mol Cell Biol. 2006;26:8252-66.
17.Wang W, Pan K, Chen Y, Huang C, Zhang X. The acetylation of transcription factor HBP1 by p300/CBP enhances p16INK4A expression. Nucleic acids research. 2012;40:981-95.
18.Pan K, Chen Y, Roth M, Wang W, Wang S, Yee AS, et al. HBP1-mediated transcriptional regulation of DNA methyltransferase 1 and its impact on cell senescence. Mol Cell Biol. 2013;33:887-903.
19.Tevosian SG, Shih HH, Mendelson KG, Sheppard KA, Paulson KE, Yee AS. HBP1: a HMG box transcriptional repressor that is targeted by the retinoblastoma family. Genes Dev. 1997;11:383-96.
20.Shih HH, Tevosian SG, Yee AS. Regulation of differentiation by HBP1, a target of the retinoblastoma protein. Mol Cell Biol. 1998;18:4732-43.
21.Berasi SP, Xiu M, Yee AS, Paulson KE. HBP1 repression of the p47phox gene: cell cycle regulation via the NADPH oxidase. Mol Cell Biol. 2004;24:3011-24.
22.Chen YC, Zhang XW, Niu XH, Xin DQ, Zhao WP, Na YQ, et al. Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer. Oncogene. 2010;29:3067-78.
23.Lin KM, Zhao WG, Bhatnagar J, Zhao WD, Lu JP, Simko S, et al. Cloning and expression of human HBP1, a high mobility group protein that enhances myeloperoxidase (MPO) promoter activity. Leukemia. 2001;15:601-12.
24.Paulson KE, Rieger-Christ K, McDevitt MA, Kuperwasser C, Kim J, Unanue VE, et al. Alterations of the HBP1 transcriptional repressor are associated with invasive breast cancer. Cancer Res. 2007;67:6136-45.
25.Yao CJ, Works K, Romagnoli PA, Austin GE. Effects of overexpression of HBP1 upon growth and differentiation of leukemic myeloid cells. Leukemia. 2005;19:1958-68.
26.Kim J, Zhang X, Rieger-Christ KM, Summerhayes IC, Wazer DE, Paulson KE, et al. Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J Biol Chem. 2006;281:10865-75.
27.Li H, Bian C, Liao L, Li J, Zhao RC. miR-17-5p promotes human breast cancer cell migration and invasion through suppression of HBP1. Breast Cancer Res Treat. 2011;126:565-75.
28.Mengshol JA, Vincenti MP, Brinckerhoff CE. IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAPK and JNK pathways. Nucleic Acids Res. 2001;29:4361-72.
29.Huang CY, Chou YH, Hsieh NT, Chen HH, Lee MF. MED28 regulates MEK1-dependent cellular migration in human breast cancer cells. J Cell Physiol. 2012;227:3820-7.
30.Chan CY, Lien CH, Lee MF, Huang CY. Quercetin suppresses cellular migration and invasion in human head and neck squamous cell carcinoma (HNSCC). Biomedicine (Taipei). 2016;6:15.
31.Rubin Grandis J, Melhem MF, Barnes EL, Tweardy DJ. Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer. 1996;78:1284-92.
32.Lee MF, Chan CY, Hung HC, Chou IT, Yee AS, Huang CY. N-acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box-containing protein 1 (HBP1) signaling pathway in invasive oral cancer. Oral Oncol. 2012.
33.Kozaki K, Imoto I, Pimkhaokham A, Hasegawa S, Tsuda H, Omura K, et al. PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma. Cancer Sci. 2006;97:1351-8.
34.Gavert N, Ben-Ze''ev A. Epithelial-mesenchymal transition and the invasive potential of tumors. Trends Mol Med. 2008;14:199-209.
1.Chan CY, Huang SY, Sheu JJ, Roth MM, Chou IT, Lien CH, et al. Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer. Oncotarget. 2017.
2.Sheu JJ, Hua CH, Wan L, Lin YJ, Lai MT, Tseng HC, et al. Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma. Cancer Res. 2009;69:2568-76.
3.Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol. 2006;24:4170-6.
4.Temam S, Kawaguchi H, El-Naggar AK, Jelinek J, Tang H, Liu DD, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol. 2007;25:2164-70.
5.Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS. Targeting EGFR resistance networks in head and neck cancer. Cell Signal. 2009;21:1255-68.
6.Modjtahedi H, Essapen S. Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs. 2009;20:851-5.
7.Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284:31-53.
8.Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. Journal of the National Cancer Institute. 1997;89:1260-70.
9.Culhaci N, Metin K, Copcu E, Dikicioglu E. Elevated expression of MMP-13 and TIMP-1 in head and neck squamous cell carcinomas may reflect increased tumor invasiveness. BMC cancer. 2004;4:42.
10.Komatsu K, Nakanishi Y, Nemoto N, Hori T, Sawada T, Kobayashi M. Expression and quantitative analysis of matrix metalloproteinase-2 and -9 in human gliomas. Brain tumor pathology. 2004;21:105-12.
11.Johansson N, Airola K, Grenman R, Kariniemi AL, Saarialho-Kere U, Kahari VM. Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. Am J Pathol. 1997;151:499-508.
12.Kawamata H, Nakashiro K, Uchida D, Harada K, Yoshida H, Sato M. Possible contribution of active MMP2 to lymph-node metastasis and secreted cathepsin L to bone invasion of newly established human oral-squamous-cancer cell lines. Int J Cancer. 1997;70:120-7.
13.Ruokolainen H, Paakko P, Turpeenniemi-Hujanen T. Serum matrix metalloproteinase-9 in head and neck squamous cell carcinoma is a prognostic marker. Int J Cancer. 2005;116:422-7.
14.Kusukawa J, Harada H, Shima I, Sasaguri Y, Kameyama T, Morimatsu M. The significance of epidermal growth factor receptor and matrix metalloproteinase-3 in squamous cell carcinoma of the oral cavity. European journal of cancer Part B, Oral oncology. 1996;32B:217-21.
15.Yee AS, Paulson EK, McDevitt MA, Rieger-Christ K, Summerhayes I, Berasi SP, et al. The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. Gene. 2004;336:1-13.
16.Zhang X, Kim J, Ruthazer R, McDevitt MA, Wazer DE, Paulson KE, et al. The HBP1 transcriptional repressor participates in RAS-induced premature senescence. Mol Cell Biol. 2006;26:8252-66.
17.Wang W, Pan K, Chen Y, Huang C, Zhang X. The acetylation of transcription factor HBP1 by p300/CBP enhances p16INK4A expression. Nucleic acids research. 2012;40:981-95.
18.Pan K, Chen Y, Roth M, Wang W, Wang S, Yee AS, et al. HBP1-mediated transcriptional regulation of DNA methyltransferase 1 and its impact on cell senescence. Mol Cell Biol. 2013;33:887-903.
19.Tevosian SG, Shih HH, Mendelson KG, Sheppard KA, Paulson KE, Yee AS. HBP1: a HMG box transcriptional repressor that is targeted by the retinoblastoma family. Genes Dev. 1997;11:383-96.
20.Shih HH, Tevosian SG, Yee AS. Regulation of differentiation by HBP1, a target of the retinoblastoma protein. Mol Cell Biol. 1998;18:4732-43.
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