首页 » 文章 » 文章详细信息
Advanced Science Volume 6 ,Issue 8 ,2019-02-22
ATG7 Promotes Bladder Cancer Invasion via Autophagy‐Mediated Increased ARHGDIB mRNA Stability
Full Papers
Junlan Zhu 1 Zhongxian Tian 1 Yang Li 2 Xiaohui Hua 2 Dongyun Zhang 2 Jingxia Li 2 Honglei Jin 1 Jiheng Xu 2 Wei Chen 3 Beifang Niu 3 Xue‐Ru Wu 4 , 5 Sergio Comincini 6 Haishan Huang 1 Chuanshu Huang 2
Show affiliations
DOI:10.1002/advs.201801927
Received 2018-10-29,
PDF
摘要

Abstract Since invasive bladder cancer (BC) can progress to life threatening metastases, understanding the molecular mechanisms underlying BC invasion is crucial for potentially decreasing the mortality of this disease. Herein, it is discovered that autophagy‐related gene 7 (ATG7) is remarkably overexpressed in human invasive BC tissues. The knockdown of ATG7 in human BC cells dramatically inhibits cancer cell invasion, revealing that ATG7 is a key player in regulating BC invasion. Mechanistic studies indicate that MIR190A is responsible for ATG7 mRNA stability and protein overexpression by directly binding to ATG7 mRNA 3′‐UTR. Furthermore, ATG7‐mediated autophagy promotes HNRNPD (ARE/poly(U)‐binding/degradation factor 1) protein degradation, and in turn reduces HNRNPD interaction with ARHGDIB mRNA, resulting in the elevation of ARHGDIB mRNA stability, and subsequently leading to BC cell invasion. The identification of the MIR190A/ATG7 autophagic mechanism regulation of HNRNPD/ARHGDIB expression provides an important insight into understanding the nature of BC invasion and suggests that autophagy may represent a potential therapeutic strategy for the treatment of human BC patients.

关键词

cancer invasion;bladder cancer;autophagy;ATG7;ARHGDIB

授权许可

© 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

图表

ATG7 was overexpressed in mouse invasive BCs, human invasive BC cells, and tissues. A) Western Blot assay was performed to detect the conversion of LC3 from LC3‐I to LC3‐II, ATG3 and ATG7 expression in mouse invasive BCs (n = 5). B) Western Blot was used to determine the conversion of LC3 from LC3‐I to LC3‐II and ATG7 protein expression, β‐Actin was used as a protein loading control. C) Real‐time PCR was performed to detect ATG7 mRNA expression, and the asterisk (*) indicates a significant increase from normal UROtsa cells (p < 0.05). D) UROtsa, T24, and UMUC3 cells were seeded into six‐well plates and the cells were then treated with or without 400 × 10−6 m of BBN for 24 h. The cell extracts were subjected to Western Blot for the determination of protein expression as indicated. GAPDH was used as a protein loading control. E) The GFP‐LC3 construct was stably transfected into UROtsa, T24, and UMUC3 cells, and then treated with 5 × 10−9 m Baf A1 for 12h. LC3 puncta formation was observed and images were captured using fluorescence microscopy. F,G) Percentage of GFP‐LC3 puncta cells (F) and the number of puncta per positive cell (G) were calculated. The asterisk (*) indicates a significant increase as comparison to UROtsa cells treated with Baf A1 (p < 0.05). H) Western Blot was performed to determine autophagy flux and ATG7 expression in presence of 5 × 10−9 m of Baf A1. I,J) Hematoxylin‐eosin (HE) and IHC staining were performed to evaluate morphology and ATG7 expression in 18 paired human BC tissues and their adjacent normal bladder tissues. The IHC images were captured using the AxioVision Rel.4.6 computerized image system. K) The ATG7 protein expression levels were analyzed by calculating the integrated IOD/area using Image‐Pro Plus version 6.0. Three independent experiments were performed, the Student's t‐test was utilized to determine the p‐value; and the asterisk (*) indicates a significant increase from the adjacent normal bladder tissues (*p < 0.05).

MIR190A stabilized ATG7 mRNA by direct binding to 3′‐UTR of ATG7 mRNA in human bladder cancer cells. A,B) The pGL3‐Basic vector versus human ATG7 promoter‐driven luciferase reporter (A) or pMIR‐report versus pMIR‐ATG7 3′‐UTR reporter (B) were transiently transfected into the indicated cells and luciferase activity was evaluated. Student's t‐test was utilized to calculate the p‐value, p > 0.05 (A), and *p < 0.05 (B). C) qPCR was performed to determine the effect of miRNA expression in the indicated cells (*p < 0.05). D) Quantitative Real‐time PCR analyses were used to determine MIR190A expression in human cancerous (T) and paired normal (N) tissues among 26 bladder cancer patients. Student's t‐test was utilized to determine the p‐value, *p = 0.016. E,F) UROtsa, T24, and UMUC3 cells were stably transfected with MIR190A constitutively expressed plasmids (E), while MIR190A antisense plasmids were stably transfected into T24 and UMUC3 cells (F). The asterisk (*) indicates a significant increase in comparison to UROtsa empty cells (*p < 0.05) (E), while the double asterisk (**) indicates a significant decrease in comparison to scramble vector control (**p < 0.05) (F). G,H) Cell lysates and total RNAs extracted from the indicated cells were subjected to either Western Blot (top panel) to determine ATG7 and PHLPP1 protein expression or RT‐PCR (bottom panel) to determine ATG7 mRNA expression, respectively. β‐Actin was used as a loading control. I–M) The ATG7 mRNA levels of indicated cells were evaluated by real‐time PCR (*p < 0.05, **p < 0.05). N) In the presence of Actinomycin D (Act D), ATG7 mRNA degradation rate in the indicated cell transfectants was determined for the indicated time, **p < 0.05. O) UMUC3(MIR190A) cells and its vector control transfectants were used to test the ATG7 mRNA degradation as described in (N), *p < 0.05. P) Schematic of the construction of the ATG7 mRNA 3′‐UTR luciferase reporter and its mutants was aligned with MIR190A. Q) Wild‐type and mutant of ATG7 3′‐UTR luciferase reporters were transiently cotransfected with pRL‐TK into the indicated cells. ATG7 3′‐UTR activity of each transfectant was determined (*p < 0.05, **p < 0.05).

ATG7 overexpression and its mediated autophagy were crucial for BC invasion. A,B) Knockdown constructs of ATG7 were stably transfected into T24 and UMUC3 cells, respectively. Western Blot was used to detect the knockdown efficiency of ATG7 protein and autophagy activity. C) The indicated cells were treated with or without Baf A1 for 24 h, and the cell extracts were subjected to Western Blot to determine protein expression, as indicated. D) The indicated cells were cultured in either 10% fetal bovine serum (FBS) medium (no starvation) or 0.1% FBS medium (starvation) for 24 h. The cell extracts were subjected to Western Blot to determine protein expression, as indicated. E,F) The invasive abilities of UMUC3 cells were determined in presence of 400 × 10−6 m of BBN or 5 × 10−9 m of Baf A1 using BD BioCoat Matrigel Invasion Chamber applied with the matrigel. After incubation for 24 h, the cells were fixed and stained as described in the Experimental Section. The migrated and invasive cells were photographed under an Olympus DP71 (E), and the number of the cells in each image was counted by the software “Image J.” The invasion rate was normalized with the insert control according to the manufacturer's instruction (F). The bars represent mean ± SD from three independent experiments. Student's t‐test was utilized to determine the p‐value; the asterisk (*) indicates a significant increase in comparison to vehicle control (*p < 0.05) (E), while the double asterisk (**) indicates a significant decrease in comparison to vehicle control (**p < 0.05). G–J) The invasion abilities of T24(shATG7), UMUC3(shATG7), and their nonsense transfectants were determined, **p < 0.05. K) UMUC3(Vector) and UMUC3(GFP‐ATG7) were treated with 5 × 10−9 m of Baf A1 for 12 h, and the cell extracts were subjected to Western Blot for determination of ATG7 overexpression and autophagic status. β‐Actin was used as a protein loading control. L,M) The invasion abilities of the indicated cells were determined in presence or absence of 5 × 10−9 m of Baf A1. The asterisk (*) indicates a significant increase in comparison to vector control transfectant (*p < 0.05), while the double asterisk (**) indicates a significant inhibition in comparison to vehicle control cells (**p < 0.05).

ATG7 was an MIR190A downstream effector responsible for BC invasion. A,B) The invasion abilities of the indicated cells were evaluated. Student's t‐test was utilized to determine the p‐value; the asterisk (*) indicates a significant increase in comparison to UMUC3(pLKO.1) transfectants (*p < 0.05) (B), while the double asterisk (**) indicates a significant decrease in comparison to UMUC3(LacZ) transfectants (**p < 0.05). C) ATG7 overexpressed plasmid was stably transfected into UMUC3(Anti‐MIR190A) cells. The overexpression efficiency of ATG7 protein was assessed by Western Blotting. β‐Actin was used as an internal protein loading control. D) The invasion abilities of UMUC3(Anti‐MIR190A) and UMUC3(Anti‐MIR190A/ATG7) cells were evaluated. Student's t‐test was utilized to determine the p‐value; the double asterisk (**) indicates a significant decrease in comparison to scramble vector transfectants (**p < 0.05), while the asterisk (*) indicates a significant increase in comparison to Anti‐MIR190A transfectants (*p < 0.05) (E).

ARHGDIB, but not RHOA, mediated ATG7 promotion of BC invasion. A,B) Western Blot was used to determine protein expression of ATG7, RHOA, RAC1,2,3, ARHGDIA, and ARHGDIB. β‐Actin was used as a protein loading control. C,D) Athymic nude mice were injected with UMUC3(Nonsense) cells (n = 5), UMUC3(shATG7#1) cells (n = 5), or UMUC3(shATG7#2) cells (n = 5), respectively. IHC staining was performed to evaluate ARHGDIB expression. The IHC images were captured using the AxioVision Rel.4.6 computerized image system and protein expression levels were analyzed by calculating the integrated IOD/area using Image‐Pro Plus version 6.0. Results are presented as the mean ± SD of five mice in each group. Student's t‐test was utilized to determine the p‐value, **p < 0.05. E) GFP‐RHOA expression constructs were stably transfected into UMUC3(shATG7#1) cells, and the stable transfectants were identified by Western Blotting. F,G) The invasion abilities of UMUC3(shATG7#1/Vector) cells and UMUC3(shATG7#1/GFP‐RHOA) cells were determined, as described in the Experimental Section. Results are presented as the mean ± SD from triplicate (p > 0.05). H) GFP‐ARHGDIB expression constructs were stably transfected into UMUC3(shATG7#1) cells and the stable transfectants were identified by Western Blotting. I,J) The invasion abilities of UMUC3(Nonsense), UMUC3(shATG7#1/Vector), and UMUC3(shATG7#1/GFP‐ARHGDIB) cells were determined, as described in the Experimental Section. Bars represent mean ± SD from three independent experiments. Student's t‐test was utilized to determine the p‐value. The double asterisk (**) indicates a significant decrease in comparison to scramble vector transfectants (**p < 0.05), while the asterisk (*) indicates a significant increase in comparison to UMUC3(shATG7#1/Vector) transfectants (*p < 0.05) (J).

HNRNPD was an ATG7 downstream effector and inhibited ARHGDIB mRNA stability and BC cell invasion. A) Real‐time PCR was used to determine ARHGDIB mRNA expression, and β‐Actin was used as an internal control, **p < 0.05. B) Human ARHGDIB promoter‐driven luciferase activity was evaluated in the indicated cells, p > 0.05. C) ARHGDIB mRNA stability was detected in the presence of Act D by using real‐time PCR, **p < 0.05. D) The indicated cell extracts were subjected to Western Blot for determination of NCL, ELAVL1, and HNRNPD protein expression. E,F) IHC staining was performed to detect HNRNPD expression in the tumor tissues obtained from the nude mice injected with UMUC3(shATG7#1), UMUC3(shATG7#2), or UMUC3(Nonsense) cells, *p < 0.05. G–I) HNRNPD knockdown constructs were stably transfected into UMUC3(shATG7#1). The HNRNPD knockdown efficiency was evaluated by Western Blotting (G). The stable transfectants were used to determine their invasion abilities in comparison to nonsense control transfectants (H and I). Student's t‐test was utilized to determine the p‐value, the double asterisk (**) indicates a significant decrease in comparison to scramble vector transfectants (**p < 0.05), while the asterisk (*) indicates a significant increase in comparison to UMUC3(shATG7#1/Nonsense) transfectants (*p < 0.05) (I). J) ARHGDIB mRNA stability was evaluated by real‐time PCR in the presence of Act D in UMUC3(shATG7#1/shHNRNPD) cells and its nonsense control, *p < 0.05. K,L) IHC staining was performed to evaluate HNRNPD expression in mouse highly invasive BCs, **p < 0.05. M) HA‐HNRNPD construct was transfected into 293T cells and HA‐HNRNPD protein was pulled down with anti‐HA beads. The mRNAs bound to HNRNPD protein were used to carry out RT‐PCR for determination of ARHGDIB mRNA expression.

ATG7 promoted autophagic removal of HNRNPD protein. A,B) Real‐time PCR was used to determine HNRNPD mRNA expression in the indicated cells, p > 0.05. C) HNRNPD protein stability was evaluated in the presence of Cycloheximide (CHX) in the indicated cells. D) The indicated cells were treated with or without Baf A1 for 24 h, and the cell extracts were subjected to Western Blot to determine protein expression. E) The indicated cells were cultured in either 10% FBS medium (no starvation) or 0.1% FBS medium (starvation) for 24 h. The cell extracts were subjected to Western Blot to determine protein expression.

MIR190A upregulation mediated ATG7 elevation, HNRNPD degradation, and ARHGDIB overexpression. A) UMUC3(pLKO.1), UMUC3(MIR190A), and UMUC3(MIR190A/shATG7) cell extracts were subjected to Western Blot to evaluate the expression of ATG7, LC3, HNRNPD, and ARHGDIB. GAPDH was used as a protein loading control. B) UMUC3(pLKO.1), UMUC3(MIR190A), and UMUC3(MIR190A/shATG7) cells were treated with or without Baf A1 for 24 h, and the cell extracts were subjected to Western Blot to determine protein expression, as indicated. C) UMUC3(pLKO.1), UMUC3(MIR190A), and UMUC3(MIR190A/shATG7) cells were cultured in either 10% FBS medium (no starvation) or 0.1% FBS medium (starvation) for 24 h. The cell extracts were then subjected to Western Blot to determine protein expression, as indicated. D–G) The xenograft tumor tissues obtained from athymic nude mice injected with UMUC3(pLKO.1) cells (n = 5), UMUC3(MIR190A) cells (n = 5), or UMUC3(MIR190A/shATG7) cells (n = 5) were subjected to IHC for evaluation of the expression of HNRNPD (D,E) and ARHGDIB (F,G), *p < 0.05,**p < 0.05. H,I) Athymic nude mice were subcutaneously injected into the right axillary region of each mouse with UMUC3(pLKO.1), UMUC3(MIR190A), and UMUC3(MIR190A/shATG7) transfectants (2 × 106 suspended in 100 µL PBS), as indicated in the Experimental Section. Four weeks after cell injection, the mice were sacrificed and the tumors were surgically removed and photographed (H,I), as well as weighed (J), p < 0.05, **p < 0.05. K) The proposed mechanisms underlying ATG7 overexpression in the promotion of human bladder cancer cells invasion: MIR190A upregulation promotes ATG7 overexpression, which further mediates the autophagic removal of HNRNPD, in turn increasing in ARHGDIB mRNA stability and protein expression, as well as BC invasion.

通讯作者

1. Haishan Huang.Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.haishan_333@163.com
2. Chuanshu Huang.Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10010, USA.haishan_333@163.com

推荐引用方式

Junlan Zhu,Zhongxian Tian,Yang Li,Xiaohui Hua,Dongyun Zhang,Jingxia Li,Honglei Jin,Jiheng Xu,Wei Chen,Beifang Niu,Xue‐Ru Wu,Sergio Comincini,Haishan Huang,Chuanshu Huang. ATG7 Promotes Bladder Cancer Invasion via Autophagy‐Mediated Increased ARHGDIB mRNA Stability. Advanced Science ,Vol.6, Issue 8(2019)

您觉得这篇文章对您有帮助吗?
分享和收藏
0

是否收藏?

参考文献
[1] H. Ishizaki, A. Togawa, M. Tanaka‐Okamoto, K. Hori, M. Nishimura, A. Hamaguchi, T. Imai, Y. Takai, J. Miyoshi, J. Immunol. 2006, 177, 8512.
[2] a) E. White, Nat. Rev. Cancer 2012, 12, 401;
[3] R. M. Hicks, Environ. Health Perspect. 1983, 50, 37.
[4] M. Catalano, G. D'Alessandro, F. Lepore, M. Corazzari, S. Caldarola, C. Valacca, F. Faienza, V. Esposito, C. Limatola, F. Cecconi, S. Di Bartolomeo, Mol. Oncol. 2015, 9, 1612.
[5] S. Rao, L. Tortola, T. Perlot, G. Wirnsberger, M. Novatchkova, R. Nitsch, P. Sykacek, L. Frank, D. Schramek, V. Komnenovic, V. Sigl, K. Aumayr, G. Schmauss, N. Fellner, S. Handschuh, M. Glosmann, P. Pasierbek, M. Schlederer, G. P. Resch, Y. Ma, H. Yang, H. Popper, L. Kenner, G. Kroemer, J. M. Penninger, Nat. Commun. 2014, 5, 3056.
[6] X. D. Liu, J. Yao, D. N. Tripathi, Z. Ding, Y. Xu, M. Sun, J. Zhang, S. Bai, P. German, A. Hoang, L. Zhou, D. Jonasch, X. Zhang, C. J. Conti, E. Efstathiou, N. M. Tannir, N. T. Eissa, G. B. Mills, C. L. Walker, E. Jonasch, Oncogene 2015, 34, 2450.
[7] J. Zhu, Y. Li, C. Chen, J. Ma, W. Sun, Z. Tian, J. Li, J. Xu, C. S. Liu, D. Zhang, C. Huang, H. Huang, Neoplasia 2017, 19, 672.
[8] G. Jiang, A. D. Wu, C. Huang, J. Gu, L. Zhang, H. Huang, X. Liao, J. Li, D. Zhang, X. Zeng, H. Jin, H. Huang, C. Huang, Cancer Prev. Res. (Phila) 2016, 9, 567.
[9] Y. Liang, J. Zhu, H. Huang, D. Xiang, Y. Li, D. Zhang, J. Li, Y. Wang, H. Jin, G. Jiang, Z. Liu, C. Huang, Autophagy 2016, 12, 1229.
[10] S. Comincini, G. Allavena, S. Palumbo, M. Morini, F. Durando, F. Angeletti, L. Pirtoli, C. Miracco, Cancer Biol. Ther. 2013, 14, 574.
[11] S. Tatarano, T. Chiyomaru, K. Kawakami, H. Enokida, H. Yoshino, H. Hidaka, N. Nohata, T. Yamasaki, T. Gotanda, T. Tachiwada, N. Seki, M. Nakagawa, Int. J. Oncol. 2012, 40, 951.
[12] J. Y. Guo, H. Y. Chen, R. Mathew, J. Fan, A. M. Strohecker, G. Karsli‐Uzunbas, J. J. Kamphorst, G. Chen, J. M. Lemons, V. Karantza, H. A. Coller, R. S. Dipaola, C. Gelinas, J. D. Rabinowitz, E. White, Genes Dev. 2011, 25, 460.
[13] Y. Xiu, Z. Liu, S. Xia, C. Jin, H. Yin, W. Zhao, Q. Wu, PLoS One 2014, 9, e109734.
[14] R. Lock, C. M. Kenific, A. M. Leidal, E. Salas, J. Debnath, Cancer Discovery 2014, 4, 466.
[15] R. Mathew, C. M. Karp, B. Beaudoin, N. Vuong, G. Chen, H. Y. Chen, K. Bray, A. Reddy, G. Bhanot, C. Gelinas, R. S. Dipaola, V. Karantza‐Wadsworth, E. White, Cell 2009, 137, 1062.
[16] H. Jin, Y. Yu, Y. Hu, C. Lu, J. Li, J. Gu, L. Zhang, H. Huang, D. Zhang, X. R. Wu, J. Gao, C. Huang, Oncotarget 2015, 6, 522.
[17] S. Liu, H. Cui, Q. Li, L. Zhang, Q. Na, C. Liu, Biol. Reprod. 2014, 90, 88.
[18] X. Wang, RNA 2008, 14, 1012.
[19] H. Huang, X. Pan, H. Jin, Y. Li, L. Zhang, C. Yang, P. Liu, Y. Liu, L. Chen, J. Li, J. Zhu, X. Zeng, K. Fu, G. Chen, J. Gao, C. Huang, Clin. Cancer Res. 2015, 21, 3783.
[20] A. Takamura, M. Komatsu, T. Hara, A. Sakamoto, C. Kishi, S. Waguri, Y. Eishi, O. Hino, K. Tanaka, N. Mizushima, Genes Dev. 2011, 25, 795.
[21] J. Mandelbaum, N. Rollins, P. Shah, D. Bowman, J. Y. Lee, O. Tayber, H. Bernard, P. LeRoy, P. Li, E. Koenig, J. E. Brownell, N. D'Amore, Autophagy 2015, 0.
[22] A. Krek, D. Grun, M. N. Poy, R. Wolf, L. Rosenberg, E. J. Epstein, P. MacMenamin, I. da Piedade, K. C. Gunsalus, M. Stoffel, N. Rajewsky, Nat. Genet. 2005, 37, 495.
[23] I. H. Lee, Y. Kawai, M. M. Fergusson, I. I. Rovira, A. J. Bishop, N. Motoyama, L. Cao, T. Finkel, Science 2012, 336, 225.
[24] B. P. Lewis, I. H. Shih, M. W. Jones‐Rhoades, D. P. Bartel, C. B. Burge, Cell 2003, 115, 787.
[25] P. Vishnu, J. Mathew, W. W. Tan, OncoTargets Ther. 2011, 4, 97.
[26] Y. Shi, S. H. Tan, S. Ng, J. Zhou, N. D. Yang, G. B. Koo, K. A. McMahon, R. G. Parton, M. M. Hill, M. A. Del Pozo, Y. S. Kim, H. M. Shen, Autophagy 2015, 11, 769.
[27] E. L. Eskelinen, P. Saftig, Biochim. Biophys. Acta 2009, 1793, 664.
[28] Y. Fang, Y. Wang, Y. Wang, Y. Meng, J. Zhu, H. Jin, J. Li, D. Zhang, Y. Yu, X. R. Wu, C. Huang, Biochem. J. 2014, 463, 383.
[29] X. Xie, J. Y. Koh, S. Price, E. White, J. M. Mehnert, Cancer Discovery 2015, 5, 410.
[30] L. Henckaerts, I. Cleynen, M. Brinar, J. M. John, K. Van Steen, P. Rutgeerts, S. Vermeire, Inflammatory Bowel Dis. 2011, 17, 1392.
[31] J. Ge, Z. Chen, J. Huang, J. Chen, W. Yuan, Z. Deng, PLoS One 2014, 9, e110293.
[32] U. Santanam, W. Banach‐Petrosky, C. Abate‐Shen, M. M. Shen, E. White, R. S. DiPaola, Genes Dev. 2016, 30, 399.
[33] J. Li, B. Yang, Q. Zhou, Y. Wu, D. Shang, Y. Guo, Z. Song, Q. Zheng, J. Xiong, Carcinogenesis 2013, 34, 1343.
[34] R. Mathew, S. Kongara, B. Beaudoin, C. M. Karp, K. Bray, K. Degenhardt, G. Chen, S. Jin, E. White, Genes Dev. 2007, 21, 1367.
[35] L. L. Fu, X. Wen, J. K. Bao, B. Liu, Int. J. Biochem. Cell Biol. 2012, 44, 733.
[36] Y. Wu, K. Moissoglu, H. Wang, X. Wang, H. F. Frierson, M. A. Schwartz, D. Theodorescu, Proc. Natl. Acad. Sci. USA 2009, 106, 5807.
[37] J. Marx, Science 2006, 312, 1160.
[38] J. Zhu, Y. Li, Z. Tian, X. Hua, J. Gu, J. Li, C. Liu, H. Jin, Y. Wang, G. Jiang, H. Huang, C. Huang, Mol. Ther.–Nucleic Acids 2017, 7, 299.
[39] Y. L. Liao, L. Y. Hu, K. W. Tsai, C. W. Wu, W. C. Chan, S. C. Li, C. H. Lai, M. R. Ho, W. L. Fang, K. H. Huang, W. C. Lin, Carcinogenesis 2012, 33, 760.
[40] J. Levy, W. Cacheux, M. A. Bara, A. L'Hermitte, P. Lepage, M. Fraudeau, C. Trentesaux, J. Lemarchand, A. Durand, A. M. Crain, C. Marchiol, G. Renault, F. Dumont, F. Letourneur, M. Delacre, A. Schmitt, B. Terris, C. Perret, M. Chamaillard, J. P. Couty, B. Romagnolo, Nat. Cell Biol. 2015, 17, 1062.
[41] R. Siegel, J. Ma, Z. Zou, A. Jemal, Ca‐Cancer J. Clin. 2014, 64, 9.
[42] B. Nyfeler, C. H. Eng, Autophagy 2016, 12, 1206.
[43] Y. Feng, Z. Yao, D. J. Klionsky, Trends Cell Biol. 2015, 25, 354.
[44] H. Zhu, H. Wu, X. Liu, B. Li, Y. Chen, X. Ren, C. G. Liu, J. M. Yang, Autophagy 2009, 5, 816.
[45] M. A. Harding, D. Theodorescu, Eur. J. Cancer 2010, 46, 1252.
[46] I. Tanida, M. Yamasaki, M. Komatsu, T. Ueno, Autophagy 2012, 8, 88.
[47] G. Korkmaz, C. le Sage, K. A. Tekirdag, R. Agami, D. Gozuacik, Autophagy 2012, 8, 165.
[48] J. Y. Guo, G. Karsli‐Uzunbas, R. Mathew, S. C. Aisner, J. J. Kamphorst, A. M. Strohecker, G. Chen, S. Price, W. Lu, X. Teng, E. Snyder, U. Santanam, R. S. Dipaola, T. Jacks, J. D. Rabinowitz, E. White, Genes Dev. 2013, 27, 1447.