Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Overexpression of p62 Induces Autophagy and Promotes Proliferation, Migration and Invasion of Nasopharyngeal Carcinoma Cells through Promoting ERK Signaling Pathway

Author(s): Qiong Wu, Manlin Xiang, Kun Wang, Zhen Chen, Lu Long, Ya Tao, Yunlai Liang, Yahui Yan, Zhiqiang Xiao, Shiyang Qiu and Bin Yi*

Volume 20, Issue 8, 2020

Page: [624 - 637] Pages: 14

DOI: 10.2174/1568009620666200424145122

Price: $65

Abstract

Background: Increasing evidence has shown that p62 plays an important role in tumorigenesis. However, relatively little is known about the association between p62 and tumor invasion and metastasis; in addition, its role in NPC (nasopharyngeal carcinoma, NPC) has been rarely investigated.

Objective: To investigate the effect of p62 on tumorigenesis and metastasis in nasopharyngeal carcinoma.

Methods: Western blotting, immunofluorescent staining and immunohistochemistry were used to evaluate p62 protein expression. Subsequently, cell viability, colony formation, migration, invasion and autophagy assays were performed. anti-p62 autoantibodies in sera were detected by ELISA. These data were correlated with clinicopathological parameters.

Results: We confirmed that p62 was significantly up-regulated in NPC tissues. Furthermore, high expression of p62 was observed in NPC cell lines, and especially in the highly metastatic 5-8F cells. In vitro, down-regulation of p62 inhibited proliferation, clone forming ability, autophagy, migration, and invasion in 5-8F cells, whereas p62 overexpression resulted in the opposite effects in 6-10B cells. Moreover, we confirmed that p62 promotes NPC cell proliferation, migration, and invasion by activating ERK (extracellular signal-regulated kinase, ERK). Clinical analysis indicated that high p62 expression correlates with lymph node and distant metastasis (P<0.05). Serum anti-p62 autoantibodies were increased in NPC patients and levels were associated with metastasis.

Conclusion: Our data establish p62 targeting ERK as potential determinant in the NPC, which supplies a new pathway to treat NPC. Furthermore, p62 is a potential biomarker which might be closely related to the tumorigenesis and metastasis in NPC.

Keywords: Nasopharyngeal carcinoma, p62, metastasis, autophagy, autoantibody, ERK, EMT.

« Previous Next »
Graphical Abstract

[1]
He, M.L.; Luo, M.X.; Lin, M.C.; Kung, H.F. MicroRNAs: Potential diagnostic markers and therapeutic targets for EBV-associated nasopharyngeal carcinoma. Biochim. Biophys. Acta, 2012, 1825(1), 1-10.
[PMID: 21958739]
[2]
Chen, M.Y.; Jiang, R.; Guo, L.; Zou, X.; Liu, Q.; Sun, R.; Qiu, F.; Xia, Z.J.; Huang, H.Q.; Zhang, L.; Hong, M.H.; Mai, H.Q.; Qian, C.N. Locoregional radiotherapy in patients with distant metastases of nasopharyngeal carcinoma at diagnosis. Chin. J. Cancer, 2013, 32(11), 604-613.
[http://dx.doi.org/10.5732/cjc.013.10148] [PMID: 24206918]
[3]
Lin, D.C.; Meng, X.; Hazawa, M.; Nagata, Y.; Varela, A.M.; Xu, L.; Sato, Y.; Liu, L.Z.; Ding, L.W.; Sharma, A.; Goh, B.C.; Lee, S.C.; Petersson, B.F.; Yu, F.G.; Macary, P.; Oo, M.Z.; Ha, C.S.; Yang, H.; Ogawa, S.; Loh, K.S.; Koeffler, H.P. The genomic landscape of nasopharyngeal carcinoma. Nat. Genet., 2014, 46(8), 866-871.
[http://dx.doi.org/10.1038/ng.3006] [PMID: 24952746]
[4]
Hwang, C.F.; Chien, C.Y.; Huang, S.C.; Yin, Y.F.; Huang, C.C.; Fang, F.M.; Tsai, H.T.; Su, L.J.; Chen, C.H. Fibulin-3 is associated with tumour progression and a poor prognosis in nasopharyngeal carcinomas and inhibits cell migration and invasion via suppressed AKT activity. J. Pathol., 2010, 222(4), 367-379.
[http://dx.doi.org/10.1002/path.2776] [PMID: 20927779]
[5]
Tao, Q.; Chan, A.T. Nasopharyngeal carcinoma: Molecular pathogenesis and therapeutic developments. Expert Rev. Mol. Med., 2007, 9(12), 1-24.
[http://dx.doi.org/10.1017/S1462399407000312] [PMID: 17477889]
[6]
Zhang, L.; Chen, Q.Y.; Liu, H.; Tang, L.Q.; Mai, H.Q. Emerging treatment options for nasopharyngeal carcinoma. Drug Des. Devel. Ther., 2013, 7, 37-52.
[PMID: 23403548]
[7]
Moscat, J.; Diaz-Meco, M.T. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell, 2009, 137(6), 1001-1004.
[http://dx.doi.org/10.1016/j.cell.2009.05.023] [PMID: 19524504]
[8]
Moscat, J.; Diaz-Meco, M.T.; Albert, A.; Campuzano, S. Cell signaling and function organized by PB1 domain interactions. Mol. Cell, 2006, 23(5), 631-640.
[http://dx.doi.org/10.1016/j.molcel.2006.08.002] [PMID: 16949360]
[9]
Pankiv, S.; Clausen, T.H.; Lamark, T.; Brech, A.; Bruun, J.A.; Outzen, H.; Øvervatn, A.; Bjørkøy, G.; Johansen, T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem., 2007, 282(33), 24131-24145.
[http://dx.doi.org/10.1074/jbc.M702824200] [PMID: 17580304]
[10]
Komatsu, M.; Kurokawa, H.; Waguri, S.; Taguchi, K.; Kobayashi, A.; Ichimura, Y.; Sou, Y.S.; Ueno, I.; Sakamoto, A.; Tong, K.I.; Kim, M.; Nishito, Y.; Iemura, S.; Natsume, T.; Ueno, T.; Kominami, E.; Motohashi, H.; Tanaka, K.; Yamamoto, M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol., 2010, 12(3), 213-223.
[http://dx.doi.org/10.1038/ncb2021] [PMID: 20173742]
[11]
Duran, A.; Linares, J.F.; Galvez, A.S.; Wikenheiser, K.; Flores, J.M.; Diaz-Meco, M.T.; Moscat, J. The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell, 2008, 13(4), 343-354.
[http://dx.doi.org/10.1016/j.ccr.2008.02.001] [PMID: 18394557]
[12]
Lu, M.; Nakamura, R.M.; Dent, E.D.; Zhang, J.Y.; Nielsen, F.C.; Christiansen, J.; Chan, E.K.; Tan, E.M. Aberrant expression of fetal RNA-binding protein p62 in liver cancer and liver cirrhosis. Am. J. Pathol., 2001, 159(3), 945-953.
[http://dx.doi.org/10.1016/S0002-9440(10)61770-1] [PMID: 11549587]
[13]
Thompson, H.G.; Harris, J.W.; Wold, B.J.; Lin, F.; Brody, J.P. p62 overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells. Oncogene, 2003, 22(15), 2322-2333.
[http://dx.doi.org/10.1038/sj.onc.1206325] [PMID: 12700667]
[14]
Inoue, D.; Suzuki, T.; Mitsuishi, Y.; Miki, Y.; Suzuki, S.; Sugawara, S.; Watanabe, M.; Sakurada, A.; Endo, C.; Uruno, A.; Sasano, H.; Nakagawa, T.; Satoh, K.; Tanaka, N.; Kubo, H.; Motohashi, H.; Yamamoto, M. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma. Cancer Sci., 2012, 103(4), 760-766.
[http://dx.doi.org/10.1111/j.1349-7006.2012.02216.x] [PMID: 22320446]
[15]
Qian, H.L.; Peng, X.X.; Chen, S.H.; Ye, H.M.; Qiu, J.H. p62 Expression in primary carcinomas of the digestive system. World J. Gastroenterol., 2005, 11(12), 1788-1792.
[http://dx.doi.org/10.3748/wjg.v11.i12.1788] [PMID: 15793865]
[16]
Rolland, P.; Madjd, Z.; Durrant, L.; Ellis, I.O.; Layfield, R.; Spendlove, I. The ubiquitin-binding protein p62 is expressed in breast cancers showing features of aggressive disease. Endocr. Relat. Cancer, 2007, 14(1), 73-80.
[http://dx.doi.org/10.1677/erc.1.01312] [PMID: 17395976]
[17]
Chen, Z.; Long, L.; Wang, K.; Cui, F.; Zhu, L.; Tao, Y.; Wu, Q.; Xiang, M.; Liang, Y.; Qiu, S.; Xiao, Z.; Yi, B. Identification of nasopharyngeal carcinoma metastasis-related biomarkers by iTRAQ combined with 2D-LC-MS/MS. Oncotarget, 2016, 7(23), 34022-34037.
[http://dx.doi.org/10.18632/oncotarget.9067] [PMID: 27145374]
[18]
Shanmugaratnam, K.; Sobin, L.H. The World Health Organization histological classification of tumours of the upper respiratory tract and ear. A commentary on the second edition. In: Cancer 1993 71, pp. 2689-2697.
[19]
Qian, C.N.; Guo, X.; Cao, B.; Kort, E.J.; Lee, C.C.; Chen, J.; Wang, L.M.; Mai, W.Y.; Min, H.Q.; Hong, M.H.; Vande Woude, G.F.; Resau, J.H.; Teh, B.T. Met protein expression level correlates with survival in patients with late-stage nasopharyngeal carcinoma. Cancer Res., 2002, 62(2), 589-596.
[PMID: 11809714]
[20]
Lee, A.W.; Poon, Y.F.; Foo, W.; Law, S.C.; Cheung, F.K.; Chan, D.K.; Tung, S.Y.; Thaw, M.; Ho, J.H. Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985: overall survival and patterns of failure. Int. J. Radiat. Oncol. Biol. Phys., 1992, 23(2), 261-270.
[http://dx.doi.org/10.1016/0360-3016(92)90740-9] [PMID: 1587745]
[21]
Xu, T.; Shen, C.; Zhu, G.; Hu, C. Omission of chemotherapy in early stage nasopharyngeal carcinoma treated with IMRT: A paired cohort study. Medicine (Baltimore), 2015, 94(39), e1457.
[http://dx.doi.org/10.1097/MD.0000000000001457] [PMID: 26426610]
[22]
Lee, Y.E.; He, H.L.; Chen, T.J.; Lee, S.W.; Chang, I.W.; Hsing, C.H.; Li, C.F. The prognostic impact of RAP2A expression in patients with early and locoregionally advanced nasopharyngeal carcinoma in an endemic area. Am. J. Transl. Res., 2015, 7(5), 912-921.
[PMID: 26175852]
[23]
Ke, L.; Xiang, Y.; Xia, W.; Yang, J.; Yu, Y.; Ye, Y.; Liang, H.; Guo, X.; Lv, X. A prognostic model predicts the risk of distant metastasis and death for patients with nasopharyngeal carcinoma based on pre-treatment interleukin 6 and clinical stage. Clin. Immunol., 2016, 164, 45-51.
[http://dx.doi.org/10.1016/j.clim.2016.01.004] [PMID: 26780676]
[24]
Xiao, W.; Xu, A.; Han, F.; Lin, X.; Lu, L.; Shen, G.; Huang, S.; Fan, W.; Deng, X.; Zhao, C. Positron emission tomography-computed tomography before treatment is highly prognostic of distant metastasis in nasopharyngeal carcinoma patients after intensity-modulated radiotherapy treatment: A prospective study with long-term follow-up. Oral Oncol., 2015, 51(4), 363-369.
[http://dx.doi.org/10.1016/j.oraloncology.2015.01.009] [PMID: 25655559]
[25]
Liao, L.; Yan, W.J.; Tian, C.M.; Li, M.Y.; Tian, Y.Q.; Zeng, G.Q. Knockdown of annexin A1 enhances radioresistance and inhibits apoptosis in nasopharyngeal carcinoma. Technol. Cancer Res. Treat., 2018.171533034617750309
[http://dx.doi.org/10.1177/1533034617750309] [PMID: 29357787]
[26]
Wang, K.; Chen, Z.; Long, L.; Tao, Y.; Wu, Q.; Xiang, M.; Liang, Y.; Xie, X.; Jiang, Y.; Xiao, Z.; Yan, Y.; Qiu, S.; Yi, B. iTRAQ-based quantitative proteomic analysis of differentially expressed proteins in chemoresistant nasopharyngeal carcinoma. Cancer Biol. Ther., 2018, 19(9), 809-824.
[http://dx.doi.org/10.1080/15384047.2018.1472192] [PMID: 30067426]
[27]
Feng, X.; Lv, W.; Wang, S.; He, Q. miR-495 enhances the efficacy of radiotherapy by targeting GRP78 to regulate EMT in nasopharyngeal carcinoma cells. Oncol. Rep., 2018, 40(3), 1223-1232.
[http://dx.doi.org/10.3892/or.2018.6538] [PMID: 30015969]
[28]
Shi, C.; Guan, Y.; Zeng, L.; Liu, G.; Zhu, Y.; Xu, H.; Lu, Y.; Liu, J.; Guo, J.; Feng, X.; Zhao, X.; Jiang, W.; Li, G.; Li, G.; Dai, Y.; Jin, F.; Li, W.; Zhou, W. High COX-2 expression contributes to a poor prognosis through the inhibition of chemotherapy-induced senescence in nasopharyngeal carcinoma. Int. J. Oncol., 2018, 53(3), 1138-1148.
[http://dx.doi.org/10.3892/ijo.2018.4462] [PMID: 29956730]
[29]
Liu, W.; Liu, X.; Wang, L.; Zhu, B.; Zhang, C.; Jia, W.; Zhu, H.; Liu, X.; Zhong, M.; Xie, D.; Liu, Y.; Li, S.; Shi, J.; Lin, J.; Xia, X.; Jiang, X.; Ren, C. PLCD3, a flotillin2-interacting protein, is involved in proliferation, migration and invasion of nasopharyngeal carcinoma cells. Oncol. Rep., 2018, 39(1), 45-52.
[PMID: 29115528]
[30]
Stumptner, C.; Heid, H.; Fuchsbichler, A.; Hauser, H.; Mischinger, H.J.; Zatloukal, K.; Denk, H. Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. Demonstration of p62 as major constituent. Am. J. Pathol., 1999, 154(6), 1701-1710.
[http://dx.doi.org/10.1016/S0002-9440(10)65426-0] [PMID: 10362795]
[31]
Su, Y.; Qian, H.; Zhang, J.; Wang, S.; Shi, P.; Peng, X. The diversity expression of p62 in digestive system cancers. Clin. Immunol., 2005, 116(2), 118-123.
[http://dx.doi.org/10.1016/j.clim.2005.04.004] [PMID: 15886058]
[32]
Ren, F.; Shu, G.; Liu, G.; Liu, D.; Zhou, J.; Yuan, L.; Zhou, J. Knockdown of p62/sequestosome 1 attenuates autophagy and inhibits colorectal cancer cell growth. Mol. Cell. Biochem., 2014, 385(1-2), 95-102.
[http://dx.doi.org/10.1007/s11010-013-1818-0] [PMID: 24065390]
[33]
Lv, Q.; Wang, W.; Xue, J.; Hua, F.; Mu, R.; Lin, H.; Yan, J.; Lv, X.; Chen, X.; Hu, Z.W. DEDD interacts with PI3KC3 to activate autophagy and attenuate epithelial-mesenchymal transition in human breast cancer. Cancer Res., 2012, 72(13), 3238-3250.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-3832] [PMID: 22719072]
[34]
Bertrand, M.; Petit, V.; Jain, A.; Amsellem, R.; Johansen, T.; Larue, L.; Codogno, P.; Beau, I. SQSTM1/p62 regulates the expression of junctional proteins through epithelial-mesenchymal transition factors. Cell Cycle, 2015, 14(3), 364-374.
[http://dx.doi.org/10.4161/15384101.2014.987619] [PMID: 25496309]
[35]
Komatsu, M.; Kageyama, S.; Ichimura, Y. p62/SQSTM1/A170: physiology and pathology. Pharmacol. Res., 2012, 66(6), 457-462.
[http://dx.doi.org/10.1016/j.phrs.2012.07.004] [PMID: 22841931]
[36]
Johansen, T.; Lamark, T. Selective autophagy mediated by autophagic adapter proteins. Autophagy, 2011, 7(3), 279-296.
[http://dx.doi.org/10.4161/auto.7.3.14487] [PMID: 21189453]
[37]
Kirkin, V.; McEwan, D.G.; Novak, I.; Dikic, I. A role for ubiquitin in selective autophagy. Mol. Cell, 2009, 34(3), 259-269.
[http://dx.doi.org/10.1016/j.molcel.2009.04.026] [PMID: 19450525]
[38]
Duran, A.; Amanchy, R.; Linares, J.F.; Joshi, J.; Abu-Baker, S.; Porollo, A.; Hansen, M.; Moscat, J.; Diaz-Meco, M.T. p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol. Cell, 2011, 44(1), 134-146.
[http://dx.doi.org/10.1016/j.molcel.2011.06.038] [PMID: 21981924]
[39]
Mathew, R.; Karp, C.M.; Beaudoin, B.; Vuong, N.; Chen, G.; Chen, H.Y.; Bray, K.; Reddy, A.; Bhanot, G.; Gelinas, C.; Dipaola, R.S.; Karantza-Wadsworth, V.; White, E. Autophagy suppresses tumorigenesis through elimination of p62. Cell, 2009, 137(6), 1062-1075.
[http://dx.doi.org/10.1016/j.cell.2009.03.048] [PMID: 19524509]
[40]
Puissant, A.; Fenouille, N.; Auberger, P. When autophagy meets cancer through p62/SQSTM1. Am. J. Cancer Res., 2012, 2(4), 397-413.
[PMID: 22860231]
[41]
Zhong, L.; Coe, S.P.; Stromberg, A.J.; Khattar, N.H.; Jett, J.R.; Hirschowitz, E.A. Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. J. Thorac. Oncol., 2006, 1(6), 513-519.
[http://dx.doi.org/10.1097/01243894-200607000-00003] [PMID: 17409910]
[42]
Storr, S.J.; Chakrabarti, J.; Barnes, A.; Murray, A.; Chapman, C.J.; Robertson, J.F. Use of autoantibodies in breast cancer screening and diagnosis. Expert Rev. Anticancer Ther., 2006, 6(8), 1215-1223.
[http://dx.doi.org/10.1586/14737140.6.8.1215] [PMID: 16925487]
[43]
Covini, G.; Chan, E.K.; Nishioka, M.; Morshed, S.A.; Reed, S.I.; Tan, E.M. Immune response to cyclin B1 in hepatocellular carcinoma. Hepatology, 1997, 25(1), 75-80.
[http://dx.doi.org/10.1002/hep.510250114] [PMID: 8985268]
[44]
Shi, F.D.; Zhang, J.Y.; Liu, D.; Rearden, A.; Elliot, M.; Nachtsheim, D.; Daniels, T.; Casiano, C.A.; Heeb, M.J.; Chan, E.K.; Tan, E.M. Preferential humoral immune response in prostate cancer to cellular proteins p90 and p62 in a panel of tumor-associated antigens. Prostate, 2005, 63(3), 252-258.
[http://dx.doi.org/10.1002/pros.20181] [PMID: 15538718]
[45]
Zhang, J.Y.; Chan, E.K.; Peng, X.X.; Tan, E.M. A novel cytoplasmic protein with RNA-binding motifs is an autoantigen in human hepatocellular carcinoma. J. Exp. Med., 1999, 189(7), 1101-1110.
[http://dx.doi.org/10.1084/jem.189.7.1101] [PMID: 10190901]
[46]
Anderson, K.S.; LaBaer, J. The sentinel within: Exploiting the immune system for cancer biomarkers. J. Proteome Res., 2005, 4(4), 1123-1133.
[http://dx.doi.org/10.1021/pr0500814] [PMID: 16083262]

Rights & Permissions Print Cite
Article Metrics
76
3
© 2024 Bentham Science Publishers | Privacy Policy