神經母細胞瘤（Neuroblastoma, NB）為兒童最常見之顱外固態腫瘤（extracranial solid tumor）。其成因被認為主要由於神經嵴前驅細胞（neural crest progenitors）分化失敗並異常增生所導致。然而此疾病異質性極高，致病機制也尚未明瞭，故高風險神經母細胞瘤患者即使經強力治療後，其長期存活率仍低於四成。目前MYCN基因擴增為神經母細胞瘤最重要的不良預後因子，因此科學家在尋找高風險神經母細胞瘤之治療標的時，對MYCN基因上下游調控網路特別感興趣。
　　由本實驗室有關神經母細胞瘤與微核醣核酸（microRNA, miRNA）之系列研究發現神經母細胞瘤腫瘤中若表現較高的miR-125b，則病患之長期存活率顯著較好。於MYCN擴增之神經母細胞瘤細胞株過表現miR-125b會導致細胞分化、細胞週期停滯、降低細胞遷移與侵襲能力，顯示miR-125b於此疾病扮演抑癌之角色。我們由微陣列（microarray）分析有無過表現miR-125b神經母細胞瘤細胞之差異表現基因，其中包括LIN28B和PODXL。
　　Podocalyxin-Like Protein 1（PODXL）屬於CD34家族成員，是細胞表面高度糖化的穿膜蛋白。過往文獻提及，PODXL於多種癌症中有過表現的情況，並與較具侵襲性之腫瘤以及預後不良相關；亦有研究指出PODXL之高表現與癌細胞之遷移、侵襲、上皮－間質轉換（epithelial-mesenchymal transition, EMT）和轉移有關。在閉塞性動脈硬化（atherosclerosis obliterans）相關研究中亦已證實miR-125b可直接負調控PODXL表現並影響人類主動脈血管平滑肌細胞（human aortic vascular smooth muscle cells, HAVSMCs）之增生與移動，本研究的目的為於神經母細胞瘤中確認miR-125b／PODXL調控路徑之存在，並探討PODXL在神經母細胞瘤腫瘤生成與發展中扮演之角色。
　　我們在神經母細胞瘤SK-N-DZ細胞株中過表現miR-125b，會導致其PODXL表現減弱，顯示神經母細胞瘤系統中PODXL基因受miR-125b之負向調控。且於四十位神經母細胞瘤病人臨床檢體中，miR-125b與PODXL基因表現量呈負相關。此外，以公開的R2資料庫內三個神經母細胞瘤資料集（Versteeg-88, NRC-283, TARGET-249）進行分析，發現PODXL高表現之病患存活率顯著較差；且高風險分期病患之PODXL表現顯著高於低風險分期者。接著我們利用慢病毒（lentivirus）將shPODXL送入SK-N-DZ細胞干擾PODXL表現，藉此探究PODXL對於癌症表現型的影響。抑制PODXL的SK-N-DZ細胞，其遷移、侵襲，與非貼附生長能力皆顯著降低；而其增生則不受影響。有趣的是，我們發現抑制PODXL能使間質細胞表型的標記－vimentin以及N-cadherin蛋白質表現降低，暗示著PODXL的表現可能參與調節細胞的EMT。
　　綜合本研究所得之結果推論PODXL可能會透過促進腫瘤細胞遷移與侵襲，而對神經母細胞瘤之腫瘤侵襲性（tumor aggressiveness）有所貢獻。且於神經母細胞瘤中，PODXL的表現受miR-125b負向調控。此外，PODXL高表現之神經母細胞瘤病患預後較差。因此在未來，原發腫瘤中PODXL之表現可望成為惡性神經母細胞瘤重要的分子標記之一，探討PODXL相關網路的調控有助於研發高風險性神經母細胞瘤之治療標的。

　　Neuroblastoma (NB) is the most common extracranial solid tumor in pediatric malignancies. It is thought to be derived from the failure of differentiation and abnormal proliferation of neural crest progenitors. Neuroblastoma is characterized by the heterogeneity in clinical behavior and unclear pathogenesis. The long-term survival of high-risk neuroblastoma is still under 40 percent after intensive therapy. MYCN amplification is the most important inferior prognostic factor of NB. Regulatory networks upstream or downstream of MYCN are of particular interest in searching for the therapeutic target in high-risk neuroblastoma.
　　We previously found that higher miR-125b expression level in the tumor was associated with better long-term survival in neuroblastoma. Overexpression of miR-125b in MYCN-amplified NB cells led to cell differentiation, cell cycle arrest, reduced cell growth, anchorage-independent cell growth, cell migration and invasion suggested miR-125b plays as a tumor suppressor in neuroblastoma. Microarray analysis of miR-125b-overexpressed versus control NB cells revealed several candidate targets, including LIN28B and PODXL.
　　Podocalyxin-like protein 1 (PODXL), is a transmembrane glycoprotein of the CD34 family. PODXL was found being overexpressed in several kinds of carcinoma and was associated with more aggressive tumors and poorer prognosis. High PODXL expression was related to tumor migration, invasion, epithelial-mesenchymal transition (EMT), and metastasis. PODXL was shown to be a direct target of miR-125b that mediate the proliferation and migration of human aortic vascular smooth muscle cells (HAVSMCs). In this study, we aim to confirm the miR-125b/PODXL regulatory pathway and to investigate the role of PODXL in neuroblastoma tumorigenesis and development.
　　Expression of PODXL was suppressed in response to miR-125b overexpression in SK-N-DZ NB cells, indicated that PODXL was negatively regulated by miR-125b in neuroblastoma. Also, in a cohort of 40 NB patients, the expression of PODXL and miR-125b in tumor samples showed a negative correlation. In addition, by analyzing three neuroblastoma datasets（Versteeg-88, NRC-283, TARGET-249）in the public R2 database, it was found that high PODXL expression was significantly correlated with the poor survival of patients. PODXL expression is higher in the tumor of advanced stages. We used lentivirus to deliver shPODXL into SK-N-DZ cells to elucidate the role of PODXL plays in oncogenic phenotypes. In PODXL repressed SK-N-DZ cells, the capabilities of migration, invasion, and anchorage-independent cell growth were significantly reduced while the proliferative expansion of the cells was not affected. Interestingly, expression of vimentin and N-cadherin were downregulated in response to PODXL repression, suggesting PODXL may participate in the regulation of EMT.
　　In summary, PODXL may promote tumor migration and invasion, thus contributes to tumor aggressiveness in neuroblastoma, while its expression was negatively regulated by miR-125b. High level of PODXL was associated with poor prognosis in neuroblastoma. PODXL expression in the primary tumor might serve as a molecular marker in advanced NB. In depth research of the regulatory network implicated in PODXL-mediated aggressive phenotypes may help to define potential therapeutic targets for advanced neuroblastoma.

致謝 I
摘要 II
Abstract IV
縮寫表 VI
目錄 XI
圖目錄 XV
表目錄 XVII
附錄目錄 XVIII
第一章 緒論 1
1.1 神經母細胞瘤 1
1.1.1　神經母細胞瘤簡介 1
1.1.2　神經母細胞瘤之致病機轉 1
1.1.3　神經母細胞瘤之臨床表現 2
1.1.4　神經母細胞瘤之病理特徵與分類 3
1.1.5　神經母細胞瘤之疾病診斷與分期 4
1.1.6　神經母細胞瘤之分子標記及預後指標 5
1.1.7　神經母細胞瘤之治療策略 8
1.2 PODXL基因 10
1.2.1　PODXL基因簡介 10
1.2.2　PODXL基因與癌症 12
1.2.3　PODXL基因與微核醣核酸 14
1.3 微核醣核酸 15
1.3.1 　微核醣核酸簡介 15
1.3.2　微核醣核酸之生理功能與意義 16
1.3.3　微核醣核酸與癌症 17
1.3.4　微核醣核酸-125b簡介 18
1.3.5　微核醣核酸-125b與癌症 19
1.3.6　微核醣核酸-125b在神經母細胞瘤中之抑癌作用 21
1.4 研究動機與假說 22
第二章 研究目的與實驗設計 23
2.1 研究目的 23
2.2 實驗設計 23
第三章 材料與方法 25
3.1 實驗材料 25
3.1.1　R2資料庫 25
3.1.2　細胞株 25
3.1.3　臨床檢體 26
3.1.4　試藥、試劑清單 26
3.1.5　試劑套組 29
3.1.6　抗體清單 30
3.1.7　溶液試劑配方 30
3.1.8　實驗儀器 37
3.1.9　質體 38
3.1.10　引子序列 38
3.1.11　軟體與網路工具 39
3.2 實驗方法 40
3.2.1　解凍細胞、繼代培養、凍存細胞 40
3.2.2　慢病毒製備 41
3.2.3　慢病毒濃縮 41
3.2.4　測試病毒力價（titer） 42
3.2.5　慢病毒轉導（lentiviral transduction） 43
3.2.6　酸性磷酸酶試驗（Acid phosphatase assay, ACP assay） 43
3.2.7　細胞生長與活性分析 43
3.2.8　遷移能力試驗（Migration assay） 44
3.2.9　侵襲能力試驗（Invasion assay） 44
3.2.10　非貼附生長能力試驗（anchorage-independent growth ability assay） 45
3.2.11　核醣核酸萃取（Total RNA extraction） 46
3.2.12　核醣核酸相對表現量（RNA relative expression） 46
3.2.13　微核醣核酸相對表現量（miRNA relative expression） 49
3.2.14　西方墨點法（Western blot） 50
3.2.15　數據統計及分析 53
第四章 結果 54
4.1 PODXL基因與miR-125b表現量於神經母細胞瘤中呈現負相關 54
4.1.1　台大醫院臨床檢體 54
4.1.2　神經母細胞瘤細胞株 54
4.2 分析PODXL基因表現量與病患存活率及臨床特徵之相關性 55
4.2.1　R2資料庫－Versteeg-88 dataset 55
4.2.2　R2資料庫－NRC-283 dataset 56
4.2.3　R2資料庫－TARGET-249 dataset 56
4.2.4　台大醫院神經母細胞瘤臨床檢體 57
4.3 在神經母細胞瘤細胞株抑制PODXL基因表現對細胞表型之影響 59
4.3.1　神經母細胞瘤細胞株之PODXL基因表現量 59
4.3.2　利用shRNA抑制神經母細胞瘤細胞株之PODXL基因表現 59
4.3.3　抑制PODXL基因表現不影響神經母細胞瘤細胞株之生長與存活率 59
4.3.4　抑制PODXL基因表現能減緩神經母細胞瘤細胞株之惡性度 60
4.3.5　抑制PODXL基因表現對神經母細胞瘤細胞株EMT之影響 62
第五章 討論 63
參考文獻 68
圖 91
表 115
附錄 117

1Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F, et al., and Steliarova-Foucher E. International incidence of childhood cancer, 2001-10: a population-based registry study. The Lancet Oncology 18, 719-731, (2017).
2National Cancer Institute. Unusual Cancers of Childhood Treatment (PDQ®)–Health Professional Version, <https://www.cancer.gov/types/childhood-cancers/hp/unusual-cancers-childhood-pdq> (2019).
3Maris JM, Hogarty MD, Bagatell R & Cohn SL. Neuroblastoma. Lancet 369, 2106-2120, (2007).
4Stewart BW & Wild CP. World Cancer Report. (2014).
5中華民國兒童癌症基金會. 兒童神經母細胞瘤疾病簡介, <http://www.ccfroc.org.tw/content_sub2.php?id=358&level1ID=2&level2ID=16&level3ID=1&level4ID=1> (2019).
6National Cancer Institute. Neuroblastoma Treatment (PDQ®)–Health Professional Version, <https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq> (2019).
7中華民國兒童癌症基金會. 2010-2017 年台灣兒童癌症診斷人數, <http://www.ccfroc.org.tw/upload/files/Newsletter/2017/2017.pdf> (2017).
8Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, et al., and Maris JM. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455, 930, (2008).
9Machin GA. Histogenesis and histopathology of neuroblastoma. Clinical and Biological Manifestations, 195-231, (1982).
10Hoehner JC, Gestblom C, Hedborg F, Sandstedt B, Olsen L & Påhlman S. A developmental model of neuroblastoma: differentiating stroma-poor tumors'' progress along an extra-adrenal chromaffin lineage. Laboratory investigation; a journal of technical methods and pathology 75, 659-675, (1996).
11Ratner N, Brodeur GM, Dale RC & Schor NF. The “neuro” of neuroblastoma: Neuroblastoma as a neurodevelopmental disorder. Annals of Neurology 80, 13-23, (2016).
12Bresler Scott C, Weiser Daniel A, Huwe Peter J, Park Jin H, Krytska K, Ryles H, et al., and Mossé Yaël P. ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma. Cancer Cell 26, 682-694, (2014).
13Weiss WA, Aldape K, Mohapatra G, Feuerstein BG & Bishop JM. Targeted expression of MYCN causes neuroblastoma in transgenic mice. The EMBO journal 16, 2985-2995, (1997).
14Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nature reviews cancer 3, 203-216, (2003).
15Brodeur GM & Nakagawara A. Molecular basis of clinical heterogeneity in neuroblastoma. The American journal of pediatric hematology/oncology 14, 111-116, (1992).
16Maris JM. Recent Advances in Neuroblastoma. New England Journal of Medicine 362, 2202-2211, (2010).
17Kushner BH & Cheung N-KV. Neuroblastoma--from genetic profiles to clinical challenge. The New England journal of medicine 353, 2215-2217, (2005).
18Bernardi BD, Pianca C, Pistamiglio P, Veneselli E, Viscardi E, Pession A, et al., and Bruzzi P. Neuroblastoma With Symptomatic Spinal Cord Compression at Diagnosis: Treatment and Results With 76 Cases. Journal of Clinical Oncology 19, 183-190, (2001).
19Plantaz D, Rubie H, Michon J, Mechinaud F, Coze C, Chastagner P, et al., and Hartmann O. The treatment of neuroblastoma with intraspinal extension with chemotherapy followed by surgical removal of residual disease: A prospective study of 42 patients--Results of the NBL 90 study of the French Society of Pediatric Oncology. Cancer 78, 311-319, (1996).
20Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al., and et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 11, 1466-1477, (1993).
21Matthay KK. Stage 4S neuroblastoma: what makes it special? Journal of Clinical Oncology 16, 2003-2006, (1998).
22Shimada H, Umehara S, Monobe Y, Hachitanda Y, Nakagawa A, Goto S, et al., and Matthay KK. International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children''s Cancer Group. Cancer 92, 2451-2461, (2001).
23Park JR, Eggert A & Caron H. Neuroblastoma: Biology, Prognosis, and Treatment. Pediatric Clinics of North America 55, 97-120, (2008).
24Rufini V, Fisher GA, Shulkin BL, Sisson JC & Shapiro B. Iodine-123-MIBG imaging of neuroblastoma: utility of SPECT and delayed imaging. The Journal of Nuclear Medicine 37, 1464, (1996).
25Geatti O, Shapiro B, Sisson JC, Hutchinson RJ, Mallette S, Eyre P & Beierwaltes WH. Iodine-131 metaiodobenzylguanidine scintigraphy for the location of neuroblastoma: preliminary experience in ten cases. Journal of Nuclear Medicine 26, 736-742, (1985).
26Joyner BD. Neuroblastoma Workup, <https://emedicine.medscape.com/article/439263-workup#c4> (2017).
27American Cancer Society. Neuroblastoma Stages and Prognostic Markers, <https://www.cancer.org/cancer/neuroblastoma/detection-diagnosis-staging/staging.html> (Last Revised: March 19, 2018).
28National Institutes of Health U.S. National Library of Medicine. MYCN gene, <https://ghr.nlm.nih.gov/gene/MYCN#location> (Last Revised: May 14, 2019).
29Giannini G, Cerignoli F, Mellone M, Massimi I, Ambrosi C, Rinaldi C, et al., and Gulino A. High Mobility Group A1 Is a Molecular Target for MYCN in Human Neuroblastoma. Cancer Research 65, 8308, (2005).
30Lasorella A, Boldrini R, Dominici C, Donfrancesco A, Yokota Y, Inserra A & Iavarone A. Id2 Is Critical for Cellular Proliferation and Is the Oncogenic Effector of N-Myc in Human Neuroblastoma. Cancer Research 62, 301, (2002).
31Hogarty MD, Norris MD, Davis K, Liu X, Evageliou NF, Hayes CS, et al., and Haber M. ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma. Cancer Research 68, 9735-9745, (2008).
32Chen L, Iraci N, Gherardi S, Gamble LD, Wood KM, Perini G, et al., and Tweddle DA. p53 is a direct transcriptional target of MYCN in neuroblastoma. Cancer Research 70, 1377-1388, (2010).
33Hatzi E, Murphy C, Zoephel A, Ahorn H, Tontsch U, Bamberger A-M, et al., and Fotsis T. N-myc oncogene overexpression down-regulates leukemia inhibitory factor in neuroblastoma. European Journal of Biochemistry 269, 3732-3741, (2002).
34Brodeur GM, Seeger RC, Schwab M, Varmus HE & Bishop JM. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224, 1121-1124, (1984).
35Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY & Hammond D. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. New England Journal of Medicine 313, 1111-1116, (1985).
36Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A, et al., and Maris JM. International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. British Journal of Cancer 100, 1471, (2009).
37Sawai S, Shimono A, Wakamatsu Y, Palmes C, Hanaoka K & Kondoh HJD. Defects of embryonic organogenesis resulting from targeted disruption of the N-myc gene in the mouse. Development 117, 1445-1455, (1993).
38Sawai S, Shimono A, Hanaoka K & Kondoh H. Embryonic lethality resulting from disruption of both N-myc alleles in mouse zygotes. The New biologist 3, 861-869, (1991).
39White PS, Maris JM, Beltinger C, Sulman E, Marshall HN, Fujimori M, et al., and Hilliard CJPotNAoS. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36. 2-36.3. PNAS 92, 5520-5524, (1995).
40Attiyeh EF, London WB, Mossé YP, Wang Q, Winter C, Khazi D, et al., and Shimada H. Chromosome 1p and 11q deletions and outcome in neuroblastoma. New England Journal of Medicine 353, 2243-2253, (2005).
41White PS, Thompson PM, Gotoh T, Okawa ER, Igarashi J, Kok M, et al., and Brodeur GM. Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma. Oncogene 24, 2684-2694, (2005).
42Caron H, van Sluis P, de Kraker J, Bökkerink J, Egeler M, Laureys G, et al., and Versteeg R. Allelic Loss of Chromosome 1p as a Predictor of Unfavorable Outcome in Patients with Neuroblastoma. The New England journal of medicine 334, 225-230, (1996).
43Mlakar V, Jurkovic Mlakar S, Lopez G, Maris JM, Ansari M & Gumy-Pause F. 11q deletion in neuroblastoma: a review of biological and clinical implications. Molecular Cancer 16, 114, (2017).
44Carén H, Kryh H, Nethander M, Sjöberg R-M, Träger C, Nilsson S, et al., and Martinsson T. High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. Proceedings of the National Academy of Sciences of the United States of America 107, 4323-4328, (2010).
45Schleiermacher G, Janoueix-Lerosey I & Delattre O. Recent insights into the biology of neuroblastoma. International Journal of Cancer 135, 2249-2261, (2014).
46Bown N, Cotterill S, Łastowska M, O''Neill S, Pearson ADJ, Plantaz D, et al., and Speleman F. Gain of Chromosome Arm 17q and Adverse Outcome in Patients with Neuroblastoma. New England Journal of Medicine 340, 1954-1961, (1999).
47Janoueix-Lerosey I, Schleiermacher G, Michels E, Mosseri V, Ribeiro A, Lequin D, et al., and delattre O. Overall Genomic Pattern Is a Predictor of Outcome in Neuroblastoma. Journal of Clinical Oncology 27, 1026-1033, (2009).
48Kaneko Y, Kanda N, Maseki N, Sakurai M, Tsuchida Y, Takeda T, et al., and Sakurai M. Different Karyotypic Patterns in Early and Advanced Stage Neuroblastomas. Cancer Research 47, 311, (1987).
49Joshi VV, Cantor AB, Brodeur GM, Look AT, Shuster JJ, Altshuler G, et al., and et al. Correlation between morphologic and other prognostic markers of neuroblastoma. A study of histologic grade, DNA index, N-myc gene copy number, and lactic dehydrogenase in patients in the Pediatric Oncology Group. Cancer 71, 3173-3181, (1993).
50Look AT, Hayes FA, Nitschke R, McWilliams NB & Green AA. Cellular DNA Content as a Predictor of Response to Chemotherapy in Infants with Unresectable Neuroblastoma. New England Journal of Medicine 311, 231-235, (1984).
51Brodeur GM, Minturn JE, Ho R, Simpson AM, Iyer R, Varela CR, et al., and Evans AE. Trk Receptor Expression and Inhibition in Neuroblastomas. Clinical Cancer Research 15, 3244, (2009).
52Nakagawara A, Azar CG, Scavarda NJ & Brodeur GM. Expression and function of TRK-B and BDNF in human neuroblastomas. Molecular and Cellular Biology 14, 759, (1994).
53Rydén M, Sehgal R, Dominici C, Schilling FH, Ibáñez CF & Kogner P. Expression of mRNA for the neurotrophin receptor trkC in neuroblastomas with favourable tumour stage and good prognosis. British Journal of Cancer 74, 773-779, (1996).
54Schulz G, Cheresh DA, Varki NM, Yu A, Staffileno LK & Reisfeld RA. Detection of Ganglioside GD2 in Tumor Tissues and Sera of Neuroblastoma Patients. Cancer Research 44, 5914, (1984).
55Hung J-T & Yu AL. in Neuroblastoma (ed Swapan K. Ray) 63-78 (Academic Press, 2019).
56Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, et al., and Matthay KK. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. Journal of Clinical Oncology 27, 289-297, (2009).
57Kembhavi SA, Shah S, Rangarajan V, Qureshi S, Popat P & Kurkure P. Imaging in neuroblastoma: An update. Indian Journal of Radiology & Imaging 25, 129-136, (2015).
58Strother DR, London WB, Schmidt ML, Brodeur GM, Shimada H, Thorner P, et al., and Cohn SL. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children''s Oncology Group study P9641. Journal of Clinical Oncology 30, 1842-1848, (2012).
59American Cancer Society. Neuroblastoma Survival Rates by Risk Group, <https://www.cancer.org/cancer/neuroblastoma/detection-diagnosis-staging/survival-rates.html> (Last Revised: March 19, 2018).
60Baker DL, Schmidt ML, Cohn SL, Maris JM, London WB, Buxton A, et al., and Matthay KK. Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma. New England Journal of Medicine 363, 1313-1323, (2010).
61Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, et al., and Reynolds CP. Treatment of High-Risk Neuroblastoma with Intensive Chemotherapy, Radiotherapy, Autologous Bone Marrow Transplantation, and 13-cis-Retinoic Acid. The New England journal of medicine 341, 1165-1173, (1999).
62De Bernardi B, Nicolas B, Boni L, Indolfi P, Carli M, Cordero Di Montezemolo L, et al., and Bruzzi P. Disseminated neuroblastoma in children older than one year at diagnosis: comparable results with three consecutive high-dose protocols adopted by the Italian Co-Operative Group for Neuroblastoma. Journal of Clinical Oncology 21, 1592-1601, (2003).
63Kerjaschki D, Sharkey DJ & Farquhar MG. Identification and characterization of podocalyxin--the major sialoprotein of the renal glomerular epithelial cell. The Journal of cell biology 98, 1591-1596, (1984).
64Doyonnas R, Nielsen JS, Chelliah S, Drew E, Hara T, Miyajima A & McNagny KM. Podocalyxin is a CD34-related marker of murine hematopoietic stem cells and embryonic erythroid cells. Blood 105, 4170, (2005).
65Kershaw DB, Thomas PE, Wharram BL, Goyal M, Wiggins JE, Whiteside CI & Wiggins RC. Molecular Cloning, Expression, and Characterization of Podocalyxin-like Protein 1 from Rabbit as a Transmembrane Protein of Glomerular Podocytes and Vascular Endothelium. Journal of Biological Chemistry 270, 29439-29446, (1995).
66Vitureira N, Andrés R, Pérez-Martínez E, Martínez A, Bribián A, Blasi J, et al., and Burgaya F. Podocalyxin is a novel polysialylated neural adhesion protein with multiple roles in neural development and synapse formation. PloS One 5, e12003, (2010).
67Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al., and Uhlen M. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Molecular & Cellular Proteomics 13, 397-406, (2014).
68Nielsen JS & McNagny KM. The role of podocalyxin in health and disease. American Society of Nephrology 20, 1669-1676, (2009).
69Turunen O, Wahlström T & Vaheri A. Ezrin has a COOH-terminal actin-binding site that is conserved in the ezrin protein family. The Journal of Cell Biology 126, 1445, (1994).
70Tsukita S, Yonemura S & Tsukita S. ERM (ezrin/radixin/moesin) family: from cytoskeleton to signal transduction. Current Opinion in Cell Biology 9, 70-75, (1997).
71Vaheri A, Carpén O, Heiska L, Helander TS, Jääskeläinen J, Majander-Nordenswan P, et al., and Turunen O. The ezrin protein family: membrane-cytoskeleton interactions and disease associations. Current Opinion in Cell Biology 9, 659-666, (1997).
72Li Y, Li J, Straight SW & Kershaw DB. PDZ domain-mediated interaction of rabbit podocalyxin and Na+/H+ exchange regulatory factor-2. American Journal of Physiology-Renal Physiology 282, F1129-F1139, (2002).
73Takeda T. Podocyte cytoskeleton is connected to the integral membrane protein podocalyxin through Na+/H+-exchanger regulatory factor 2 and ezrin. Clinical and Experimental Nephrology 7, 260-269, (2003).
74Schmieder S, Nagai M, Orlando RA, Takeda T & Farquhar MG. Podocalyxin activates RhoA and induces actin reorganization through NHERF1 and Ezrin in MDCK cells. American Society of Nephrology 15, 2289-2298, (2004).
75Tan PC, Furness SG, Merkens H, Lin S, McCoy ML, Roskelley CD, et al., and McNagny KM. Na+/H+ exchanger regulatory factor-1 is a hematopoietic ligand for a subset of the CD34 family of stem cell surface proteins. Stem Cells 24, 1150-1161, (2006).
76Sassetti C, Tangemann K, Singer MS, Kershaw DB & Rosen SD. Identification of podocalyxin-like protein as a high endothelial venule ligand for L-selectin: parallels to CD34. Journal of Experimental Medicine 187, 1965-1975, (1998).
77Thomas SN, Schnaar RL & Konstantopoulos K. Podocalyxin-like protein is an E-/L-selectin ligand on colon carcinoma cells: comparative biochemical properties of selectin ligands in host and tumor cells. American journal of physiology-Cell physiology 296, C505-C513, (2009).
78Dallas MR, Chen S-H, Streppel MM, Sharma S, Maitra A & Konstantopoulos K. Sialofucosylated podocalyxin is a functional E- and L-selectin ligand expressed by metastatic pancreatic cancer cells. American Journal of Physiology - Cell Physiology 303, C616, (2012).
79Ley K. The role of selectins in inflammation and disease. Trends in Molecular Medicine 9, 263-268, (2003).
80Barthel SR, Gavino JD, Descheny L & Dimitroff CJ. Targeting selectins and selectin ligands in inflammation and cancer. Expert Opinion on Therapeutic Targets 11, 1473-1491, (2007).
81Boman K, Larsson AH, Segersten U, Kuteeva E, Johannesson H, Nodin B, et al., and Jirstrom K. Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer. British Journal of Cancer 108, 2321-2328, (2013).
82Laitinen A, Böckelman C, Hagström J, Kokkola A, Fermér C, Nilsson O & Haglund C. Podocalyxin as a prognostic marker in gastric cancer. PloS One 10, e0145079, (2015).
83Borg D, Hedner C, Nodin B, Larsson A, Johnsson A, Eberhard J & Jirström K. Expression of podocalyxin-like protein is an independent prognostic biomarker in resected esophageal and gastric adenocarcinoma. BMC Clinical Pathology 16, 13, (2016).
84Kaprio T, Fermér C, Hagström J, Mustonen H, Böckelman C, Nilsson O & Haglund C. Podocalyxin is a marker of poor prognosis in colorectal cancer. BMC Cancer 14, 493, (2014).
85Larsson AH, Lehn S, Wangefjord S, Karnevi E, Kuteeva E, Sundström M, et al., and Birgisson H. Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer. Journal of Translational Medicine 14, 128, (2016).
86Saukkonen K, Hagström J, Mustonen H, Juuti A, Nordling S, Fermér C, et al., and Haglund C. Podocalyxin Is a Marker of Poor Prognosis in Pancreatic Ductal Adenocarcinoma. PloS One 10, e0129012, (2015).
87Taniuchi K, Furihata M, Naganuma S, Dabanaka K, Hanazaki K & Saibara T. Podocalyxin-like protein, linked to poor prognosis of pancreatic cancers, promotes cell invasion by binding to gelsolin. Cancer Science 107, 1430-1442, (2016).
88Flores-Téllez TN, Lopez TV, Garzón VRV & Villa-Treviño S. Co-expression of ezrin-CLIC5-podocalyxin is associated with migration and invasiveness in hepatocellular carcinoma. PloS One 10, e0131605, (2015).
89Somasiri A, Nielsen JS, Makretsov N, McCoy ML, Prentice L, Gilks CB, et al., and Roskelley CD. Overexpression of the anti-adhesin podocalyxin is an independent predictor of breast cancer progression. Cancer Research
64, 5068-5073, (2004).
90McNagny KM, Pettersson I, Rossi F, Flamme I, Shevchenko A, Mann M & Graf T. Thrombomucin, a novel cell surface protein that defines thrombocytes and multipotent hematopoietic progenitors. The Journal of cell biology 138, 1395-1407, (1997).
91Kelley TW, Huntsman D, McNagny KM, Roskelley CD & Hsix ED. Podocalyxin: a marker of blasts in acute leukemia. American Journal of Clinical Pathology 124, 134-142, (2005).
92Riccioni R, Calzolari A, Biffoni M, Senese M, Riti V, Petrucci E, et al., and Diverio D. Podocalyxin is expressed in normal and leukemic monocytes. Blood Cells, Molecules, and Diseases 37, 218-225, (2006).
93Lin C-W, Sun M-S, Liao M-Y, Chung C-H, Chi Y-H, Chiou L-T, et al., and Wu H-C. Podocalyxin-like 1 promotes invadopodia formation and metastasis through activation of Rac1/Cdc42/cortactin signaling in breast cancer cells. Carcinogenesis 35, 2425-2435, (2014).
94Meng X, Ezzati P & Wilkins JA. Requirement of podocalyxin in TGF-beta induced epithelial mesenchymal transition. PloS One 6, e18715, (2011).
95Zhang J, Zhu Z, Wu H, Yu Z, Rong Z, Luo Z, et al., and Huang C. PODXL, negatively regulated by KLF4, promotes the EMT and metastasis and serves as a novel prognostic indicator of gastric cancer. Gastric Cancer 22, 48-59, (2019).
96Lin CW, Sun MS & Wu HC. Podocalyxin-like 1 is associated with tumor aggressiveness and metastatic gene expression in human oral squamous cell carcinoma. International Journal of Oncology 45, 710-718, (2014).
97Zhang J, Zhu Z, Sheng J, Yu Z, Yao B, Huang K, et al., and Huang C. miR-509-3-5P inhibits the invasion and lymphatic metastasis by targeting PODXL and serves as a novel prognostic indicator for gastric cancer. Oncotarget 8, 34867, (2017).
98Favreau AJ, Cross E & Sathyanarayana P. miR-199b-5p directly targets PODXL and DDR1 and decreased levels of miR-199b-5p correlate with elevated expressions of PODXL and DDR1 in acute myeloid leukemia. American Journal of Hematology 87, 442, (2012).
99Chijiiwa Y, Moriyama T, Ohuchida K, Nabae T, Ohtsuka T, Miyasaka Y, et al., and Nakamura M. Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL. International Journal of Oncology 48, 1688-1700, (2016).
100Li X, Yao N, Zhang J & Liu Z. MicroRNA-125b is involved in atherosclerosis obliterans in vitro by targeting podocalyxin. Molecular Medicine Reports 12, 561-568, (2015).
101Lee RC, Feinbaum RL & Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843-854, (1993).
102Wightman B, Ha I & Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855-862, (1993).
103He L & Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nature Reviews Genetics 5, 522-531, (2004).
104Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nature Reviews Molecular Cell Biology 6, 376-385, (2005).
105Winter J, Jung S, Keller S, Gregory RI & Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nature Cell Biology 11, 228, (2009).
106Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 136, 215-233, (2009).
107Reinhart BJ, Weinstein EG, Rhoades MW, Bartel B & Bartel DP. MicroRNAs in plants. Genes and Development 16, 1616-1626, (2002).
108Golden TA, Schauer SE, Lang JD, Pien S, Mushegian AR, Grossniklaus U, et al., and Ray A. Short Integuments1/suspensor1/carpel Factory a Dicer Homolog, Is a Maternal Effect Gene Required for Embryo Development in Arabidopsis. Plant Physiology 130, 808, (2002).
109Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, Li MZ, et al., and Hannon GJ. Dicer is essential for mouse development. Nature Genetics 35, 215-217, (2003).
110Wang Y, Medvid R, Melton C, Jaenisch R & Blelloch RJNg. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nature Genetics 39, 380, (2007).
111Makeyev EV, Zhang J, Carrasco MA & Maniatis T. The MicroRNA miR-124 Promotes Neuronal Differentiation by Triggering Brain-Specific Alternative Pre-mRNA Splicing. Molecular Cell 27, 435-448, (2007).
112Yu J-Y, Chung K-H, Deo M, Thompson RC & Turner DL. MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation. Experimental Cell Research 314, 2618-2633, (2008).
113Cordes KR & Srivastava D. MicroRNA regulation of cardiovascular development. Circulation Research 104, 724-732, (2009).
114Callis TE, Chen J-F & Wang D-Z. MicroRNAs in skeletal and cardiac muscle development. DNA and Cell Biology 26, 219-225, (2007).
115Lawrie C, Saunders N, Soneji S, Palazzo S, Dunlop H, Cooper C, et al., and Enver T. MicroRNA expression in lymphocyte development and malignancy. Leukemia 22, 1440, (2008).
116Sayed D & Abdellatif M. MicroRNAs in Development and Disease. Physiological Reviews 91, 827-887, (2011).
117Esquela-Kerscher A & Slack FJJNrc. Oncomirs—microRNAs with a role in cancer. nature reviews cancer 6, 259, (2006).
118Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al., and Rai KJPotNAoS. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. PNAS 99, 15524-15529, (2002).
119Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, et al., and Dono MJPotNAoS. miR-15 and miR-16 induce apoptosis by targeting BCL2. PNAS 102, 13944-13949, (2005).
120Iorio MV, Ferracin M, Liu C-G, Veronese A, Spizzo R, Sabbioni S, et al., and Croce CM. MicroRNA gene expression deregulation in human breast cancer. Cancer Research 65, 7065, (2005).
121Chan JA, Krichevsky AM & Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer research
65, 6029-6033, (2005).
122Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, et al., and Harris CC. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9, 189-198, (2006).
123Connolly E, Melegari M, Landgraf P, Tchaikovskaya T, Tennant BC, Slagle BL, et al., and Rogler CE. Elevated expression of the miR-17–92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype. The American journal of pathology 173, 856-864, (2008).
124Slaby O, Svoboda M, Fabian P, Smerdova T, Knoflickova D, Bednarikova M, et al., and Vyzula R. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology 72, 397-402, (2007).
125Meng F, Henson R, Wehbe–Janek H, Ghoshal K, Jacob ST & Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133, 647-658, (2007).
126Asangani IA, Rasheed SA, Nikolova D, Leupold J, Colburn N, Post S & Allgayer H. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27, 2128, (2008).
127Liang L, Wong CM, Ying Q, Fan DNY, Huang S, Ding J, et al., and Yao M. MicroRNA‐125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B. Hepatology 52, 1731-1740, (2010).
128Bousquet M, Harris MH, Zhou B & Lodish HF. MicroRNA miR-125b causes leukemia. Proceedings of the National Academy of Sciences 107, 21558-21563, (2010).
129Enomoto Y, Kitaura J, Hatakeyama K, Watanuki J, Akasaka T, Kato N, et al., and Taniwaki M. Eμ/miR-125b transgenic mice develop lethal B-cell malignancies. Leukemia 25, 1849, (2011).
130Leung YY, Kuksa PP, Amlie-Wolf A, Valladares O, Ungar LH, Kannan S, et al., and Wang L-S. DASHR: database of small human noncoding RNAs. Nucleic Acids Research 44, D216-D222, (2015).
131Le MT, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V, et al., and Lim B. MicroRNA-125b is a novel negative regulator of p53. Genes and Development 23, 862-876, (2009).
132Wu L & Belasco JG. Micro-RNA Regulation of the Mammalian lin-28 Gene during Neuronal Differentiation of Embryonal Carcinoma Cells. Molecular and Cellular Biology 25, 9198, (2005).
133Le MT, Xie H, Zhou B, Chia PH, Rizk P, Um M, et al., and Lodish HF. MicroRNA-125b promotes neuronal differentiation in human cells by repressing multiple targets. Molecular and Cellular Biology 29, 5290-5305, (2009).
134Visone R, Pallante P, Vecchione A, Cirombella R, Ferracin M, Ferraro A, et al., and Borbone E. Specific microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene 26, 7590, (2007).
135Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, et al., and Kim S. MicroRNA expression profiles in serous ovarian carcinoma. Clinical Cancer Research 14, 2690-2695, (2008).
136Hui AB, Lenarduzzi M, Krushel T, Waldron L, Pintilie M, Shi W, et al., and Waldron J. Comprehensive MicroRNA profiling for head and neck squamous cell carcinomas. Clinical Cancer Research 16, 1129-1139, (2010).
137Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS & Benz CC. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. Journal of Biological Chemistry 282, 1479-1486, (2007).
138Lee YS, Kim HK, Chung S, Kim K-S & Dutta A. Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation. Journal of Biological Chemistry 280, 16635-16641, (2005).
139Zhang Y, Yan L-X, Wu Q-N, Du Z-M, Chen J, Liao D-Z, et al., and Zeng M-S. miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. Cancer Research 71, 3552-3562, (2011).
140Xu N, Zhang L, Meisgen F, Harada M, Heilborn J, Homey B, et al., and Pivarcsi A. MicroRNA-125b down-regulates matrix metallopeptidase 13 and inhibits cutaneous squamous cell carcinoma cell proliferation, migration, and invasion. Journal of Biological Chemistry 287, 29899-29908, (2012).
141Cui F, Li X, Zhu X, Huang L, Huang Y, Mao C, et al., and Shi H. MiR-125b inhibits tumor growth and promotes apoptosis of cervical cancer cells by targeting phosphoinositide 3-kinase catalytic subunit delta. Cellular Physiology and Biochemistry 30, 1310-1318, (2012).
142Wu N, Xiao L, Zhao X, Zhao J, Wang J, Wang F, et al., and Lin X. miR‐125b regulates the proliferation of glioblastoma stem cells by targeting E2F2. FEBS Letters 586, 3831-3839, (2012).
143Shiiba M, Shinozuka K, Saito K, Fushimi K, Kasamatsu A, Ogawara K, et al., and Tanzawa H. MicroRNA-125b regulates proliferation and radioresistance of oral squamous cell carcinoma. British Journal of Cancer 108, 1817, (2013).
144Bhattacharjya S, Nath S, Ghose J, Maiti G, Biswas N, Bandyopadhyay S, et al., and Roychoudhury S. miR-125b promotes cell death by targeting spindle assembly checkpoint gene MAD1 and modulating mitotic progression. Cell Death and Differentiation 20, 430, (2013).
145張勝凱. I.探討微核醣核酸-125b/LIN28B調控神經母細胞瘤惡性度之角色II.建立微核醣核酸-125b基因剔除小鼠 博士 thesis, 國立臺灣大學, (2013).
146Molenaar JJ, Domingo-Fernández R, Ebus ME, Lindner S, Koster J, Drabek K, et al., and Van Nes J. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nature Genetics 44, 1199, (2012).
147Bousquet M, Quelen C, Rosati R, Mansat-De Mas V, La Starza R, Bastard C, et al., and Leroux D. Myeloid cell differentiation arrest by miR-125b-1 in myelodysplasic syndrome and acute myeloid leukemia with the t (2; 11)(p21; q23) translocation. Journal of Experimental Medicine 205, 2499-2506, (2008).
148Chapiro E, Russell L, Struski S, Cave H, Radford-Weiss I, Valle V, et al., and Harrison C. A new recurrent translocation t (11; 14)(q24; q32) involving IGH@ and miR-125b-1 in B-cell progenitor acute lymphoblastic leukemia. Leukemia 24, 1362, (2010).
149Shi X-B, Xue L, Yang J, Ma A-H, Zhao J, Xu M, et al., and deVere White RW. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proceedings of the National Academy of Sciences 104, 19983-19988, (2007).
150Shi XB, Xue L, Ma AH, Tepper CG, Kung HJ & White RWD. miR‐125b promotes growth of prostate cancer xenograft tumor through targeting pro‐apoptotic genes. The Prostate 71, 538-549, (2011).
151Mestdagh P, Fredlund E, Pattyn F, Schulte J, Muth D, Vermeulen J, et al., and Van Roy NJO. MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors. Oncogene 29, 1394, (2010).
152Bray I, Bryan K, Prenter S, Buckley PG, Foley NH, Murphy DM, et al., and Stallings RL. Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival. PloS One 4, e7850, (2009).
153Chang T-C, Yu D, Lee Y-S, Wentzel EA, Arking DE, West KM, et al., and Mendell JTJNg. Widespread microRNA repression by Myc contributes to tumorigenesis. Nature Genetics 40, 43, (2008).
154Lovén J, Zinin N, Wahlström T, Müller I, Brodin P, Fredlund E, et al., and Henriksson MJPotNAoS. MYCN-regulated microRNAs repress estrogen receptor-α (ESR1) expression and neuronal differentiation in human neuroblastoma. PNAS 107, 1553-1558, (2010).
155Laneve P, Di Marcotullio L, Gioia U, Fiori ME, Ferretti E, Gulino A, et al., and Caffarelli EJPotNAoS. The interplay between microRNAs and the neurotrophin receptor tropomyosin-related kinase C controls proliferation of human neuroblastoma cells. PNAS 104, 7957-7962, (2007).
156蔡明憲. 探討LIN28B在神經母細胞瘤中之角色 碩士 thesis, 國立臺灣大學, (2012).
157Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, et al., and Maris JM. The genetic landscape of high-risk neuroblastoma. Nature Genetics 45, 279, (2013).
158Itai S, Yamada S, Kaneko MK, Sano M, Nakamura T, Yanaka M, et al., and Furusawa Y. Podocalyxin is crucial for the growth of oral squamous cell carcinoma cell line HSC-2. Biochemistry and biophysics reports 15, 93-96, (2018).
159George RE, London WB, Cohn SL, Maris JM, Kretschmar C, Diller L, et al., and Look AT. Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 23, 6466-6473, (2005).
160Toyoda H, Nagai Y, Kojima A & Kinoshita-Toyoda A. Podocalyxin as a major pluripotent marker and novel keratan sulfate proteoglycan in human embryonic and induced pluripotent stem cells. Glycoconjugate Journal 34, 817-823, (2017).
161Frose J, Chen MB, Hebron KE, Reinhardt F, Hajal C, Zijlstra A, et al., and Weinberg RA. Epithelial-Mesenchymal Transition Induces Podocalyxin to Promote Extravasation via Ezrin Signaling. Cell Reports 24, 962-972, (2018).
162Gao C-F, Xie Q, Su Y-L, Koeman J, Khoo SK, Gustafson M, et al., and Woude GFV. Proliferation and invasion: plasticity in tumor cells. Proceedings of the National Academy of Sciences 102, 10528-10533, (2005).
163Mori S, Chang JT, Andrechek ER, Matsumura N, Baba T, Yao G, et al., and Nevins JR. Anchorage-independent cell growth signature identifies tumors with metastatic potential. Oncogene 28, 2796-2805, (2009).
164Greenburg G & Hay EDJTJocb. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. The Journal of Cell Biology 95, 333-339, (1982).
165Kalluri R & Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. Journal of Clinical Investigation 112, 1776-1784, (2003).
166Kalluri R & Weinberg RA. The basics of epithelial-mesenchymal transition. The Journal of clinical investigation 119, 1420-1428, (2009).
167Sha Y, Haensel D, Gutierrez G, Du H, Dai X & Nie Q. Intermediate cell states in epithelial-to-mesenchymal transition. Physical Biology 16, (2019).
168Lamouille S, Xu J & Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nature reviews Molecular cell biology 15, 178, (2014).
169Nieto MA, Huang Ruby Y-J, Jackson Rebecca A & Thiery Jean P. EMT: 2016. Cell 166, 21-45, (2016).
170Díaz-López A, Moreno-Bueno G & Cano A. Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives. Cancer Management and Research 6, 205-216, (2014).
171Bedi U, Mishra VK, Wasilewski D, Scheel C & Johnsen SA. Epigenetic plasticity: a central regulator of epithelial-to-mesenchymal transition in cancer. Oncotarget 5, 2016, (2014).
172Kohl NE, Gee CE & Alt FW. Activated expression of the N-myc gene in human neuroblastomas and related tumors. Science 226, 1335-1337, (1984).
173Padovan-Merhar OM, Raman P, Ostrovnaya I, Kalletla K, Rubnitz KR, Sanford EM, et al., and Granger MP. Enrichment of targetable mutations in the relapsed neuroblastoma genome. Plos Genetics 12, e1006501, (2016).
174Mitra SK, Hanson DA & Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nature Reviews Molecular Cell Biology 6, 56-68, (2005).
175Serrels A, Canel M, Brunton VG & Frame MC. Src/FAK-mediated regulation of E-cadherin as a mechanism for controlling collective cell movement: insights from in vivo imaging. Cell adhesion & migration 5, 360-365, (2011).
176Negishi M & Katoh H. Rho Family GTPases as Key Regulators for Neuronal Network Formation. The Journal of Biochemistry 132, 157-166, (2002).
177Dyberg C, Fransson S, Andonova T, Sveinbjörnsson B, Lännerholm-Palm J, Olsen TK, et al., and Brodin B. Rho-associated kinase is a therapeutic target in neuroblastoma. Proceedings of the National Academy of Sciences 114, E6603-E6612, (2017).
178Rath N & Olson MF. Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy. EMBO Reports 13, 900-908, (2012).
179Martín-Villar E, Megías D, Castel S, Yurrita MM, Vilaró S & Quintanilla M. Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. Journal of Cell Science 119, 4541-4553, (2006).