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研究生：	陳佳文 Chen, Jia-Wen
論文名稱：	自噬反應經由Rab37主導之TIMP1分泌參與肺癌細胞之癌化現象 Autophagy participates in lung cancer cell tumorigenesis through Rab37-mediated TIMP1 secretion
指導教授：	劉校生 Liu, Hsiao-Sheng
學位類別：	碩士 Master
系所名稱：	醫學院 - 微生物及免疫學研究所 Department of Microbiology & Immunology
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	70
中文關鍵詞：	自噬反應、Rab37 、金屬蛋白酶的組織抑製劑1 、肺癌、小鼠Lung-to-lung轉移模式
外文關鍵詞：	Autophagy, Rab37, TIMP1, lung cancer, Lung-to-lung metastasis in mice model
相關次數：	點閱：50 下載：0
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Rab小GTPase蛋白家族主要負責細胞膜、胞器間以及胞內小腔室間之交通以及胞內物質之運送。金屬蛋白酶的組織抑製劑1（TIMP1）是一種分泌型醣蛋白，能抑制細胞外基質的轉換。TIMP1會存在於Rab37攜帶之囊泡中而被運送至胞外。Rab37在細胞飢餓的刺激下會被活化，進而促進TIMP1分泌至胞外並抑制肺癌細胞的轉移。細胞飢餓也可誘導自噬反應活性。我們已經證明在細胞飢餓狀態下活化的Rab37或活化形式的突變型Rab37（Q89L）均能增加TIMP1的分泌量以及自噬反應LC3II蛋白表現量。因此，我們假設Rab37和自噬反應均參與TIMP1分泌並抑制TIMP1介導的腫瘤轉移。我們發現表現活化態Rab37的CL1-5 Q89L細胞中TIMP1分泌增加伴隨著LC3II之表現量增加。若抑制肺癌H460細胞中的Rab37基因表現，Rab37和LC3II表現量以及TIMP1分泌量均減少。而在此Rab37被抑制之H460細胞中，若以自噬反應誘導劑amiodarone誘發自噬反應活性卻無法增加TIMP1之分泌。將細胞轉殖入正常之Rab37基因也會增加LC3II的水平。若於CL1-5 Q89L肺癌細胞中沈默自噬反應必需基因Atg5或Atg7的表達，可減少自噬活性以及TIMP1之分泌。以上結果顯示Rab37是自噬反應促進TIMP1分泌的上游調節者並能直接促進LC3II之表現量。細胞功能研究之結果顯示沈默Atg5或Atg7表現量時，CL1-5 Q89L細胞爬行（migration）和侵襲（invasion）能力均增加。由於H460細胞在飢餓的刺激下TIMP1分泌增加，進一步研究發現TIMP1在細胞內的積累量也增加。但CL1-5細胞中的活化態的Rab37對細胞增生（proliferation）和群落形成（colony-forming）沒有影響。在小鼠”肺對肺”癌細胞轉移模式中，在抑制Rab37表現量的條件下，自噬反應對TIMP1分泌量以及肺癌細胞的轉移沒有影響。而當Rab37表現量高或於活化態時，若以amiodarone誘發小鼠自噬反應活性， TIMP1表現量增加伴隨著左肺組織轉移減少。反之，在沈默Atg5或Atg7基因CL1-5 Q89L細胞的小鼠中，肺癌細胞的轉移增加。小鼠肺組織之分析結果顯示，降低Atg5或Atg7基因表現導致自噬反應活性下降以及TIMP1分泌量減少。綜述之，上述細胞和動物實驗均證實活化態之Rab37主導之TIMP1分泌以及抑制癌細胞之轉移，LC3II之表現量同時上升伴隨著自噬反應的增加。而自噬反應需要在Rab37的參與下，才有促進TIMP1分泌之功能。最後，我們舊藥新用將另一自噬反應誘導劑“Niclosamide”結合表達NanoLuc® luciferase基因的H460細胞株，利用IVIS系統監測小鼠肺癌細胞轉移。所獲結果與amiodarone處理一致。

Rab small GTPases are major regulators of membrane trafficking and vesicle targeting. Tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted glycoprotein, inhibits extracellular matrix turnover, and is the cargo of human Rab37 protein. Rab37 secrets TIMP1 under starvation conditions and leads to suppression of lung cancer cell metastasis. Starvation also induces autophagic activity. We have demonstrated that both of starvation or active form Rab37 (mutant Q89L) increase TIMP1 secretion and LC3II protein level. Therefore, we hypothesize that both of Rab37 and autophagy participate in the TIMP1 secretion and inhibit TIMP1-mediated tumor metastasis. We demonstrated that active form Rab37 in CL1-5 Q89L cells increased TIMP1 secretion and further increase LC3II expression induced autophagy. Furthermore, wild type Rab37 transgene increases the level of LC3II. Silencing Rab37 gene expression in lung cancer H460 cells leads to decreased Rab37, LC3II expression and TIMP1 secretion. Notably, in the Rab37 silenced H460 cells, induction of autophagic activity could not increase TIMP1 secretion. Tsai et al. report that the migration and invasion of H460 cells decrease when the Rab37 is activated (mutant Q89L). Silencing autophagy Atg 5 or Atg 7 gene in CL1-5 Q89L lung cancer cells lead to decreased autophagy activity and TIMP1 secretion. These data indicate that Rab37 is at the up-stream of autophagic pathway and TIMP1 secretion. Functional studies reveal that the migration and invasion of active-form CL1-5 Q89L cells increased when the Atg 5 or Atg 7 was silenced. Because starvation increased TIMP1 secretion in H460 cells, we clarifed whether starvation affects TIMP1 biosynthesis. We found that starvation increased both of TIMP1 secretion and intracellular accumulation. However, active-form Rab37 in CL1-5 Q89L cells has no effect on cell proliferation and colony-forming. In our lung to lung metastasis mice model, induction of autophagic activity by autophagy inducer amiodarone under Rab37 silencing conditions. TIMP1 expression and lung cancer cell metastasis of the amiodarone-treated mice were not affected comparing to the non-treatment group. However, TIMP1 expression increased accompanied with decreased the metastasis of the CL1-5-Q89L cells when the mice autophagic activity was induced by amiodarone. Similarly, decreased autophagic activity by silencing Atg 5 or Atg 7 gene in CL1-5 Q89L cell inoculated mice, increased lung cancer cells metastasis comparing to the control group. Mice lung tissue analysis demonstrate decreased TIMP1 secretion accompanied with decreased autophagy activity compared to the control group by IHC and IFA. Altogether, our in vitro and in vivo data reveal that active-form Rab37 mediated TIMP1 secretion and suppression of metastasis, while autophagy plays a promoting role. However, autophagy alone could not induce TIMP1 secretion. Furthermore, active-form Rab37 could increase autophagosome marker protein LC3II to increase autophagic activity. Finally, we utilized another use off-label use drug “Niclosamide” together with the H460 cells in mice expressing NanoLu® luciferase(NLuc) gene to monitor the tumor growth and metastasis under the IVIS imaging system. The results are consistent with the findings of amiodarone.

中文摘要......I
Abstract......III
Acknowledgements......V
Abbreviation......X
Introduction......1
I.	Lung cancer......1
II.	Rab small GTPase family proteins......1
III.	Traditional autophagy: selective and non-selective autophagy......3
IV.	Non-canonical secretory autophagy......4
V.	Rab and cancer......5
VI.	Autophagy and lung cancer......6
VII.	Secretory autophagy and cancer......7
VIII.	Autophagic inducer......7
IX.	TIMP1 in cancer......8
Materials and Methods......10
I.	Cell lines and Media......10
II.	Small hairpin RNA (shRNA) lentiviral infection system......10
III.	Establishment of CL1-5 Q89L of Atg5 knockout cell lines by CRISPR/Cas9 system......11
IV.	Western blotting......11
V.	Preparation of conditional medium (CM)......12
VI.	Coomassie brilliant blue solution......12
VII.	Cell migration and invasion assay......12
VIII.	Cell proliferation......13
IX.	Colony formation assay......13
X.	Cell death analysis......14
XI.	Lung-to-lung metastasis assay in vivo......14
XII.	Immunohistochemistry (IHC)......16
XIII.	Immunofluorescent assay (IFA)......17
XIV.	Transient transfection of cells with plasmid DNA......17
XV.	Luciferase reporter assay......17
XVI.	IVIS Spectrum......18
XVII.	Statistical analysis......18
Results......19
I.	Rab37 is an up-stream regulator of autophagy and TIMP1 secretion.......19
II.	Autophagy promotes active-form Rab37-mediated TIMP1 secretion and negatively regulates migration and invasion of lung cancer cells.......19
III.	Starvation increased TIMP1 secretion was associated with an intracellular accumulation of TIMP1......21
IV.	Rab37 expression level and status does not affect cell proliferation and colony formation.......21
V.	Autophagy has no effect on TIMP1 secretion and cancer cell metastasis is in a Rab37 independent manner.......22
VI.	Increase of autophagic activity promotes Rab37-mediated TIMP1 secretion and suppression of cancer cell metastasis in vivo.......23
VII.	Suppression of autophagic activity attenuates Rab37-mediated TIMP1 secretion and increase of lung cancer cell metastasis in vivo.......24
VIII.	Using off-label use drug “Niclosamide” to induce autophagy and lead to increased TIMP1 secretion.......25
IX.	The lung cancer cell lines H460-NLuc which stably express luciferase reporter gene were established and observed tumor formation and metastasis in mice by using IVIS system.......25
Discussion......27
References......33
Curriculum Vitae......70
Figure List
Figure 1. LC3 II protein and TIMP1 secretion decreased in lung cancer H460 cells stably expressing lentiviral Rab37 shRNA.......41
Figure 2. Autophagy promotrs active-form Rab37-mediated TIMP1 secretion and negatively regulates lung cancer cells migration and invasion.......45
Figure 3. Starvation increased TIMP1 secretion was associated with an intracellular accumulation of TIMP1.......47
Figure 4. Rab37 expression level and status have no effect on cell growth and colony formation.......49
Figure 5. Autophagy has no effect on TIMP1 secretion and metastasis in lung cancer H460 cells under Rab37 silencing conditions.......52
Figure 6. Increase of autophagic activity suppressed metastasis of CL1-5 cancer cells through promoting the secretion of tumor suppressor TIMP1.......55
Figure 7. Decrease of autophagic activity attenuates Rab37-mediated TIMP1 secretion and increases of the metastasis of lung cancer CL1-5 derivated cells in vivo.......58
Figure 8. Using off-label use drug “Niclosamide” induces autophagy and leads to increased TIMP1 secretion.......60
Figure 9. The lung cancer cell lines H460-NLuc which stably express luciferase reporter gene were established and observed tumor formation and metastasis in mice by using IVIS system.......63
Figure 10. A schematic hypothesis that autophagy positively regulates Rab37-mediated exocytosis of TIMP1, which leads to suppression of lung cancer cell migration and metastasis in vivo......65
Appendix 1. Active Rab37 increases LC3 protein lipidation in vitro.......67
Appendix 2. Autophagy positively regulates Rab37-mediated TIMP1 secretion of lung cancer CL1-5 cells.......69
                                    

1 Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet‐Tieulent, J. & Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87-108 (2015).
2 Molina, J. R., Yang, P., Cassivi, S. D., Schild, S. E. & Adjei, A. A. in Mayo Clin. Proc. 584-594 (Elsevier).
3 Herbst, R. S., Morgensztern, D. & Boshoff, C. The biology and management of non-small cell lung cancer. Nature 553, 446 (2018).
4 Chambers, A. F., Groom, A. C. & MacDonald, I. C. Metastasis: dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563 (2002).
5 Perlikos, F., Harrington, K. J. & Syrigos, K. N. Key molecular mechanisms in lung cancer invasion and metastasis: a comprehensive review. Crit. Rev. Oncol. Hematol. 87, 1-11 (2013).
6 Deryugina, E. I. & Quigley, J. P. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25, 9-34 (2006).
7 Ronzone, E., Wesolowski, J. & Paumet, F. in Chlamydia (InTech, 2012).
8 Hutagalung, A. H. & Novick, P. J. Role of Rab GTPases in membrane traffic and cell physiology. Physiol. Rev. 91, 119-149 (2011).
9 Stenmark, H. & Olkkonen, V. M. The rab gtpase family. Genome Biol. 2, reviews3007. 3001 (2001).
10 Pfeffer, S. R. Rab GTPases: specifying and deciphering organelle identity and function. Trends Cell Biol. 11, 487-491 (2001).
11 Segev, N. Ypt and Rab GTPases: insight into functions through novel interactions. Curr. Opin. Cell Biol. 13, 500-511 (2001).
12 Ao, X., Zou, L. & Wu, Y. Regulation of autophagy by the Rab GTPase network. Cell Death Differ. 21, 348 (2014).
13 Dupont, N., Jiang, S., Pilli, M., Ornatowski, W., Bhattacharya, D. & Deretic, V. Autophagy‐based unconventional secretory pathway for extracellular delivery of IL‐1β. EMBO J. 30, 4701-4711 (2011).
14 Awan, M. U. F. & Deng, Y. Role of autophagy and its significance in cellular homeostasis. Appl. Microbiol. Biotechnol. 98, 5319-5328 (2014).
15 Wirawan, E., Berghe, T. V., Lippens, S., Agostinis, P. & Vandenabeele, P. Autophagy: for better or for worse. Cell Res. 22, 43 (2012).
16 Yu, L., Chen, Y. & Tooze, S. A. Autophagy pathway: Cellular and molecular mechanisms. Autophagy 14, 207-215 (2018).
17 Bento, C. F., Renna, M., Ghislat, G., Puri, C., Ashkenazi, A., Vicinanza, M., Menzies, F. M. & Rubinsztein, D. C. Mammalian autophagy: how does it work? Annu. Rev. Biochem. 85, 685-713 (2016).
18 Glick, D., Barth, S. & Macleod, K. F. Autophagy: cellular and molecular mechanisms. J pathol. 221, 3-12 (2010).
19 Shorter, J., Watson, R., Giannakou, M. E., Clarke, M., Warren, G. & Barr, F. A. GRASP55, a second mammalian GRASP protein involved in the stacking of Golgi cisternae in a cell‐free system. EMBO J. 18, 4949-4960 (1999).
20 Jiang, S., Dupont, N., Castillo, E. F. & Deretic, V. Secretory versus degradative autophagy: unconventional secretion of inflammatory mediators. J. Innate Immun. 5, 471-479 (2013).
21 Ponpuak, M., Mandell, M. A., Kimura, T., Chauhan, S., Cleyrat, C. & Deretic, V. Secretory autophagy. Curr. Opin. Cell Biol. 35, 106-116 (2015).
22 Viotti, C. in Unconventional Protein Secretion 3-29 (Springer, 2016).
23 Pilli, M., Arko-Mensah, J., Ponpuak, M., Roberts, E., Master, S., Mandell, M. A., Dupont, N., Ornatowski, W., Jiang, S. & Bradfute, S. B. TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity 37, 223-234 (2012).
24 Nickel, W. & Rabouille, C. Mechanisms of regulated unconventional protein secretion. Nat rev Mol Cell Biol. 10, 148 (2009).
25 Deretic, V., Jiang, S. & Dupont, N. Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation. Trends Cell Biol. 22, 397-406 (2012).
26 Tzeng, H.-T. & Wang, Y.-C. Rab-mediated vesicle trafficking in cancer. J. Biomed. Sci. 23, 70 (2016).
27 Bravo‐Cordero, J. J., Marrero‐Diaz, R., Megías, D., Genís, L., García‐Grande, A., García, M. A., Arroyo, A. G. & Montoya, M. C. MT1‐MMP proinvasive activity is regulated by a novel Rab8‐dependent exocytic pathway. EMBO J. 26, 1499-1510 (2007).
28 Caswell, P. T., Spence, H. J., Parsons, M., White, D. P., Clark, K., Cheng, K. W., Mills, G. B., Humphries, M. J., Messent, A. J. & Anderson, K. I. Rab25 associates with α5β1 integrin to promote invasive migration in 3D microenvironments. Dev. Cell 13, 496-510 (2007).
29 Cheng, K. W., Lahad, J. P., Kuo, W.-l., Lapuk, A., Yamada, K., Auersperg, N., Liu, J., Smith-McCune, K., Lu, K. H. & Fishman, D. The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat. Med. 10, 1251 (2004).
30 Hendrix, A., Maynard, D., Pauwels, P., Braems, G., Denys, H., Van den Broecke, R., Lambert, J., Van Belle, S., Cocquyt, V. & Gespach, C. Effect of the secretory small GTPase Rab27B on breast cancer growth, invasion, and metastasis. JNCI-J. Natl. Cancer Inst. 102, 866-880 (2010).
31 Hou, Q., Wu, Y. H., Grabsch, H., Zhu, Y., Leong, S. H., Ganesan, K., Cross, D., Tan, L. K., Tao, J. & Gopalakrishnan, V. Integrative genomics identifies RAB23 as an invasion mediator gene in diffuse-type gastric cancer. Cancer Res. 68, 4623-4630 (2008).
32 Pellinen, T., Arjonen, A., Vuoriluoto, K., Kallio, K., Fransen, J. A. & Ivaska, J. Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of β1-integrins. J. Cell Biol. 173, 767-780 (2006).
33 Yoon, S.-O., Shin, S. & Mercurio, A. M. Hypoxia stimulates carcinoma invasion by stabilizing microtubules and promoting the Rab11 trafficking of the α6β4 integrin. Cancer Res. 65, 2761-2769 (2005).
34 Tsai, C.-H., Cheng, H.-C., Wang, Y.-S., Lin, P., Jen, J., Kuo, I.-Y., Chang, Y.-H., Liao, P.-C., Chen, R.-H. & Yuan, W.-C. Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis. Nat Commun. 5, 4804 (2014).
35 Kroemer, G., Mariño, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280-293 (2010).
36 Liu, G., Pei, F., Yang, F., Li, L., Amin, A. D., Liu, S., Buchan, J. R. & Cho, W. C. Role of autophagy and apoptosis in non-small-cell lung cancer. Int. J. Mol. Sci. 18, 367 (2017).
37 Dang, S., Yu, Z.-m., Zhang, C.-y., Zheng, J., Li, K.-l., Wu, Y., Qian, L.-l., Yang, Z.-y., Li, X.-r. & Zhang, Y. Autophagy promotes apoptosis of mesenchymal stem cells under inflammatory microenvironment. Stem Cell. Res. Ther. 6, 247 (2015).
38 White, E. The role for autophagy in cancer. J Clin Invest. 125, 42-46 (2015).
39 Ye, M.-X., Li, Y., Yin, H. & Zhang, J. Curcumin: updated molecular mechanisms and intervention targets in human lung cancer. Int. J. Mol. Sci. 13, 3959-3978 (2012).
40 New, J., Arnold, L., Ananth, M., Alvi, S., Thornton, M., Werner, L., Tawfik, O., Dai, H., Shnayder, Y. & Kakarala, K. Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target. Cancer Res. 77, 6679-6691 (2017).
41 Rybstein, M. D., Bravo-San Pedro, J. M., Kroemer, G. & Galluzzi, L. The autophagic network and cancer. Nat. Cell Biol. 20, 243 (2018).
42 Hernandez-Fernaud, J. R., Ruengeler, E., Casazza, A., Neilson, L. J., Pulleine, E., Santi, A., Ismail, S., Lilla, S., Dhayade, S. & MacPherson, I. R. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity. Nat Commun. 8, 14206 (2017).
43 Zahoor, M. & Farhan, H. Crosstalk of Autophagy and the Secretory Pathway and Its Role in Diseases. Int. Rev. Cell Mol. Biol. (2018).
44 New, J., Arnold, L., Ananth, M., Alvi, S., Thornton, M., Werner, L., Tawfik, O., Dai, H., Shnayder, Y. & Kakarala, K. Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target. Cancer Res. (2017).
45 Balgi, A. D., Fonseca, B. D., Donohue, E., Tsang, T. C., Lajoie, P., Proud, C. G., Nabi, I. R. & Roberge, M. Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One 4, e7124 (2009).
46 Kodama, I., Kamiya, K. & Toyama, J. Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent. Am. J. Cardiol. 84, 20-28 (1999).
47 Chauffert, B., Martin, M., Hammann, A., Michel, M. F. & Martin, F. Amiodarone-induced enhancement of doxorubicin and 4′-deoxydoxorubicin cytotoxicity to rat colon cancer cells in vitro and in vivo. Cancer Res. 46, 825-830 (1986).
48 Boulin, M., Ciboulet, A., Guiu, B., Maillard, E., Bonnetain, F., Minello, A., Gagnaire, A., Lepage, C., Krause, D. & Hillon, P. Randomised controlled trial of lipiodol transarterial chemoembolisation with or without amiodarone for unresectable hepatocellular carcinoma. Dig. Liver Dis. 43, 905-911 (2011).
49 Guiu, B., Colin, C., Cercueil, J.-P., Loffroy, R., Guiu, S., Ferrant, E., Jouve, J.-L., Bonnetain, F., Boulin, M. & Ghiringhelli, F. Pilot study of transarterial chemoembolization with pirarubicin and amiodarone for unresectable hepatocellular carcinoma. Am. J. Clin. Oncol. 32, 238-244 (2009).
50 Lan, S. H., Wu, S. Y., Zuchini, R., Lin, X. Z., Su, I. J., Tsai, T. F., Lin, Y. J., Wu, C. T. & Liu, H. S. Autophagy suppresses tumorigenesis of hepatitis B virus‐associated hepatocellular carcinoma through degradation of microRNA‐224. Hepatology 59, 505-517 (2014).
51 Lan, S.-H., Wu, S.-Y., Zuchini, R., Lin, X.-Z., Su, I.-J., Tsai, T.-F., Lin, Y.-J., Wu, C.-T. & Liu, H.-S. Autophagy-preferential degradation of MIR224 participates in hepatocellular carcinoma tumorigenesis. Autophagy 10, 1687-1689 (2014).
52 Pan, J.-X., Ding, K. & Wang, C.-Y. Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells. Chin. J. Cancer 31, 178 (2012).
53 Sack, U., Walther, W., Scudiero, D., Selby, M., Kobelt, D., Lemm, M., Fichtner, I., Schlag, P. M., Shoemaker, R. H. & Stein, U. Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer. J. Natl. Cancer Inst. 103, 1018-1036 (2011).
54 Grum-Schwensen, B., Klingelhofer, J., Berg, C. H., El-Naaman, C., Grigorian, M., Lukanidin, E. & Ambartsumian, N. Suppression of tumor development and metastasis formation in mice lacking the S100A4 (mts1) gene. Cancer Res. 65, 3772-3780 (2005).
55 Stetler-Stevenson, W. G. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal. 1, re6-re6 (2008).
56 Jung, K. K., Liu, X. W., Chirco, R., Fridman, R. & Kim, H. R. C. Identification of CD63 as a tissue inhibitor of metalloproteinase‐1 interacting cell surface protein. EMBO J. 25, 3934-3942 (2006).
57 Toricelli, M., Melo, F. H., Peres, G. B., Silva, D. C. & Jasiulionis, M. G. Timp1 interacts with beta-1 integrin and CD63 along melanoma genesis and confers anoikis resistance by activating PI3-K signaling pathway independently of Akt phosphorylation. Mol. Cancer 12, 1095 (2013).
58 Lee, S. Y., Kim, J. M., Cho, S. Y., Kim, H. S., Shin, H. S., Jeon, J. Y., Kausar, R., Jeong, S. Y., Lee, Y. S. & Lee, M. A. TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling. Biochem. J. 459, 565-576 (2014).
59 D'Angelo, R. C., Liu, X.-W., Najy, A. J., Jung, Y. S., Won, J., Chai, K. X., Fridman, R. & Kim, H.-R. C. TIMP-1 via TWIST1 induces EMT phenotypes in human breast epithelial cells. Mol. Cancer Res. 12, 1324-1333 (2014).
60 Brew, K. & Nagase, H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim. Biophys. Acta-Mol. cell res. 1803, 55-71 (2010).
61 Seubert, B., Grünwald, B., Kobuch, J., Cui, H., Schelter, F., Schaten, S., Siveke, J. T., Lim, N. H., Nagase, H. & Simonavicius, N. Tissue inhibitor of metalloproteinases (TIMP)‐1 creates a premetastatic niche in the liver through SDF‐1/CXCR4‐dependent neutrophil recruitment in mice. Hepatology 61, 238-248 (2015).
62 Schrohl, A.-S., Holten-Andersen, M. N., Peters, H. A., Look, M. P., Meijer-van Gelder, M. E., Klijn, J. G., Brünner, N. & Foekens, J. A. Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer. Clin. Cancer Res. 10, 2289-2298 (2004).
63 Birgisson, H., Nielsen, H. J., Christensen, I. J., Glimelius, B. & Brünner, N. Preoperative plasma TIMP-1 is an independent prognostic indicator in patients with primary colorectal cancer: a prospective validation study. Eur. J. Cancer 46, 3323-3331 (2010).
64 Roy, R., Zurakowski, D., Wischhusen, J., Frauenhoffer, C., Hooshmand, S., Kulke, M. & Moses, M. Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies. Br. J. Cancer 111, 1772 (2014).
65 Botta, G. P., Reichert, M., Reginato, M. J., Heeg, S., Rustgi, A. K. & Lelkes, P. I. ERK2-regulated TIMP1 induces hyperproliferation of K-RasG12D-transformed pancreatic ductal cells. Neoplasia 15, IN1 (2013).
66 Schroeder, B., Schulze, R. J., Weller, S. G., Sletten, A. C., Casey, C. A. & McNiven, M. A. The small GTPase Rab7 as a central regulator of hepatocellular lipophagy. Hepatology 61, 1896-1907 (2015).
67 Scott, R. C., Schuldiner, O. & Neufeld, T. P. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167-178 (2004).
68 Guo, H., Chitiprolu, M., Roncevic, L., Javalet, C., Hemming, F. J., Trung, M. T., Meng, L., Latreille, E., de Souza, C. T. & McCulloch, D. Atg5 disassociates the V 1 V 0-ATPase to promote exosome production and tumor metastasis independent of canonical macroautophagy. Dev. Cell 43, 716-730. e717 (2017).
69 D'Costa, Z., Jones, K., Azad, A., van Stiphout, R., Lim, S. Y., Gomes, A. L., Kinchesh, P., Smart, S. C., McKenna, W. G. & Buffa, F. M. Gemcitabine-induced TIMP1 attenuates therapy response and promotes tumor growth and liver metastasis in pancreatic cancer. Cancer Res. 77, 5952-5962 (2017).
70 Zeng, Z.-s., Cohen, A. M., Zhang, Z.-f., Stetler-Stevenson, W. & Guillem, J. G. Elevated tissue inhibitor of metalloproteinase 1 RNA in colorectal cancer stroma correlates with lymph node and distant metastases. Clin. Cancer Res. 1, 899-906 (1995).
71 Urbanski, S., Edwards, D., Hershfield, N., Huchcroft, S., Shaffer, E., Sutherland, L. & Kossakowska, A. Expression pattern of metalloproteinases and their inhibitors changes with the progression of human sporadic colorectal neoplasia. Diagn Mol Pathol. 2, 81-89 (1993).
72 Avalos, B. R., Kaufman, S. E., Tomonaga, M., Williams, R. E., Golde, D. W. & Gasson, J. C. K562 cells produce and respond to human erythroid-potentiating activity. Blood 71, 1720-1725 (1988).
73 Chen, N. & Karantza-Wadsworth, V. Role and regulation of autophagy in cancer. Biochim. Biophys. Acta-Mol. cell res. 1793, 1516-1523 (2009).
74 White, E. & DiPaola, R. S. The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res. 15, 5308-5316 (2009).
75 Kondo, Y., Kanzawa, T., Sawaya, R. & Kondo, S. The role of autophagy in cancer development and response to therapy. Nat. Rev. Cancer 5, 726 (2005).
76 Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nat. Rev. Cancer 7, 961 (2007).
77 Lum, J. J., Bauer, D. E., Kong, M., Harris, M. H., Li, C., Lindsten, T. & Thompson, C. B. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237-248 (2005).
78 Lin, C.-W., Chen, Y.-S., Lin, C.-C., Chen, Y.-J., Lo, G.-H., Lee, P.-H., Kuo, P.-L., Dai, C.-Y., Huang, J.-F. & Chung, W.-L. Amiodarone as an autophagy promoter reduces liver injury and enhances liver regeneration and survival in mice after partial hepatectomy. Sci. Rep. 5, 15807 (2015).
79 Lee, K.-Y., Oh, S., Choi, Y.-J., Oh, S.-H., Yang, Y.-S., Yang, M.-J., Lee, K. & Lee, B.-H. Activation of autophagy rescues amiodarone-induced apoptosis of lung epithelial cells and pulmonary toxicity in rats. Toxicol. Sci. 136, 193-204 (2013).
80 Wu, S. Y., Lan, S. H., Wu, S. R., Chiu, Y. C., Lin, X. Z., Su, I. J., Tsai, T. F., Yen, C. J., Lu, T. H. & Liang, F. W. Hepatocellular carcinoma‐related cyclin D1 is selectively regulated by autophagy degradation system. Hepatology (2018).

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