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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Colorectal Cancer | Research

IPO5 promotes the proliferation and tumourigenicity of colorectal cancer cells by mediating RASAL2 nuclear transportation

Authors: Wenjuan Zhang, Yanxia Lu, Xiaomin Li, Jianming Zhang, Weihao Lin, Wei Zhang, Lin Zheng, Xuenong Li

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

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Abstract

Background

Karyopherin nuclear transport receptors play important roles in tumour development and drug resistance and have been reported as potential biomarkers and therapeutic targets for tumour treatment. However, IPO5, one of the karyopherin nuclear transport receptor family members, remains largely uncharacterized in tumour progression.

Methods

The TCGA data, quantitative reverse transcription-PCR (qRT-PCR), western blotting, and IHC analyses were used to detect IPO5 expression in CRC tissues. A series of in vivo and in vitro experiments was utilized to demonstrate the function of IPO5 in CRC tissues. Mass spectrometry (MS), CO-IP technology, subcellular fractionation, and immunofluorescence were utilized to investigate the possible mechanisms of CRC.

Results

IPO5 was highly expressed and positively correlated with the clinicopathological characteristics of colorectal cancer tissues. Functional experiments indicated that IPO5 could promote the development of CRC. Mechanistically, we screened RASAL2, one cargo of IPO5, and further confirmed that IPO5 bound to the NLS sequence of RASAL2, mediating RASAL2 nuclear translocation and inducing RAS signal activation, thereby promoting the progression of CRC.

Conclusions

Together, our results indicate that IPO5 is overexpressed in colorectal cancer cells. By transporting RASAL2, IPO5 may play a crucial role in CRC.
Appendix
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Literature
1.
2.
3.
Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U. Nuclear export of microRNA precursors. Science. 2004;303:95–8.PubMedCrossRef
4.
Silver PA, Kau TR, Way JC. Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer. 2004;4:106–17.PubMedCrossRef
5.
Tran EJ, King MC, Corbett AH. Macromolecular transport between the nucleus and the cytoplasm: advances in mechanism and emerging links to disease. Biochim Biophys Acta. 2014;1843:2784–95.PubMedPubMedCentralCrossRef
6.
Senapedis WT, Baloglu E, Landesman Y. Clinical translation of nuclear export inhibitors in cancer. Semin Cancer Biol. 2014;27:74–86.PubMedCrossRef
7.
Kimura M, Imamoto N. Biological significance of the importin-beta family-dependent nucleocytoplasmic transport pathways. Traffic. 2014;15:727–48.PubMedCrossRef
8.
9.
Shigeyasu K, Okugawa Y, Toden S, Boland CR, Goel A. Exportin-5 functions as an oncogene and a potential therapeutic target in colorectal cancer. Clin Cancer Res. 2017;23:1312–22.PubMedCrossRef
10.
Kim J, McMillan E, Kim HS, Venkateswaran N, Makkar G, Rodriguez-Canales J, et al. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature. 2016;538:114–7.PubMedPubMedCentralCrossRef
11.
Vuorinen EM, Rajala N, Rauhala HE, Kallioniemi A. Abstract 76: KPNA7 nuclear import protein - a critical regulator of cancer cell growth. Cancer Res. 2016;76:76.
12.
Qi L, Ding Y. Construction of key signal regulatory network in metastatic colorectal cancer. Oncotarget. 2018;9:6086–94.PubMed
13.
Lin C, Zhang J, Lu Y, Li X, Zhang W, Zhang W, et al. NIT1 suppresses tumour proliferation by activating the TGFβ1–Smad2/3 signalling pathway in colorectal cancer. Cell Death Dis. 2018;9:263.
14.
Zeng Z, Li Y, Pan Y, Lan X, Song F, Sun J, et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun. 2018;9:5395.
15.
Weis K. Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell. 2003;112:441–51.PubMedCrossRef
16.
Beck M, Schirmacher P, Singer S. Alterations of the nuclear transport system in hepatocellular carcinoma - new basis for therapeutic strategies. J Hepatol. 2017;67:1051–61.PubMedCrossRef
17.
Zhao X, Chen Y, Tan X, Zhang L, Zhang H, Li Z, et al. Advanced glycation end-products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of  transcription factor EB. J Pathol. 2018;245:235-48.PubMedPubMedCentralCrossRef
18.
Yan D, Pomicter AD, Tantravahi S, Mason CC, Senina AV, Ahmann JM, et al. Nuclear-cytoplasmic transport is a therapeutic target in myelofibrosis. Clin Cancer Res. 2018;25:2323-35.PubMedCrossRef
19.
Kau TR, Silver PA. Nuclear transport as a target for cell growth. Drug Discov Today. 2003;8:78–85.PubMedCrossRef
20.
van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D, et al. The Karyopherin proteins, Crm1 and Karyopherin β1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer. 2009;124:1829–40.PubMedCrossRef
21.
Angus L, van der Watt PJ, Leaner VD. Inhibition of the nuclear transporter, Kpnβ1, results in prolonged mitotic arrest and activation of the intrinsic apoptotic pathway in cervical cancer cells. Carcinogenesis. 2014;35:1121–31.PubMedCrossRef
22.
Zhang Y, Zhang M, Yu F, Lu S, Sun H, Tang H, et al. Karyopherin alpha 2 is a novel prognostic marker and a potential therapeutic target for colon cancer. J Exp Clin Cancer Res. 2015;34:145.PubMedPubMedCentralCrossRef
23.
Li J, Liu Q, Liu Z, Xia Q, Zhang Z, Zhang R, et al. KPNA2 promotes metabolic reprogramming in glioblastomas by regulation of c-myc. J Exp Clin Cancer Res. 2018;37:194.PubMedPubMedCentralCrossRef
24.
Kojima K, Kornblau SM, Ruvolo V, Dilip A, Duvvuri S, Davis RE, et al. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood. 2013;121:4166–74.PubMedPubMedCentralCrossRef
25.
Yang X, Cheng L, Yao L, Ren H, Zhang S, Min X, et al. Involvement of chromosome region maintenance 1 (CRM1) in the formation and progression of esophageal squamous cell carcinoma. Med Oncol. 2014;31:1–13.
26.
Yang J, Lu C, Wei J, Guo Y, Liu W, Luo L, et al. Inhibition of KPNA4 attenuates prostate cancer metastasis. Oncogene. 2017;36:2868–78.PubMedCrossRef
27.
Krawczyk E, Hanover JA, Schlegel R, Suprynowicz FA. Karyopherin beta3: a new cellular target for the HPV-16 E5 oncoprotein. Biochem Biophys Res Commun. 2008;371:684–8.PubMedPubMedCentralCrossRef
28.
Quan L, Qiu T, Liang J, Li M, Zhang Y, Tao K. Identification of target genes regulated by KSHV miRNAs in KSHV-infected lymphoma cells. Pathol Oncol Res. 2015;21:875–80.PubMedCrossRef
29.
30.
Baas R, Sijm A, van Teeffelen HA, van Es R, Vos HR, Marc TH. Quantitative proteomics of the SMAD (suppressor of mothers against decapentaplegic) transcription factor family identifies importin 5 as a bone morphogenic protein receptor SMAD-specific importin. J Biol Chem. 2016;291:24121–32.PubMedPubMedCentralCrossRef
31.
Vuorinen EM, Rajala NK, Rauhala HE, Nurminen AT, Hytonen VP, Kallioniemi A. Search for KPNA7 cargo proteins in human cells reveals MVP and ZNF414 as novel regulators of cancer cell growth. Biochim Biophys Acta Mol basis Dis. 2017;1863:211–9.PubMedCrossRef
32.
Wang CI, Chien KY, Wang CL, Liu HP, Cheng CC, Chang YS, et al. Quantitative proteomics reveals regulation of karyopherin subunit alpha-2 (KPNA2) and its potential novel cargo proteins in nonsmall cell lung cancer. Mol Cell Proteomics. 2012;11:1105–22.PubMedPubMedCentralCrossRef
33.
Alshareeda AT, Negm OH, Green AR, Nolan CC, Tighe P, Albarakati N, et al. KPNA2 is a nuclear export protein that contributes to aberrant localisation of key proteins and poor prognosis of breast cancer. Br J Cancer. 2015;112:1929–37.PubMedPubMedCentralCrossRef
34.
35.
Li K, Mo C, Gong D, Chen Y, Huang Z, Li Y, et al. DDX17 nucleocytoplasmic shuttling promotes acquired gefitinib resistance in non-small cell lung cancer cells via activation of β-catenin. Cancer Lett. 2017;400:194–202.PubMedCrossRef
36.
McLaughlin SK, Olsen SN, Dake B, De Raedt T, Lim E, Bronson RT, et al. The RasGAP gene, RASAL2, is a tumor and metastasis suppressor. Cancer Cell. 2013;24:365–78.PubMedCrossRef
37.
Shen J, Wang Y, Hung MC. RASAL2: wrestling in the combat of Ras activation. Cancer Cell. 2013;24:277–9.PubMedCrossRef
38.
Olsen SN, Wronski A, Castano Z, Dake B, Malone C, De Raedt T, et al. Loss of RasGAP tumor suppressors underlies the aggressive nature of luminal B breast cancers. Cancer Discov. 2017;7:202–17.PubMedCrossRef
39.
Hui K, Gao Y, Huang J, Xu S, Wang B, Zeng J, et al. RASAL2, a RAS GTPase-activating protein, inhibits stemness and epithelial-mesenchymal transition via MAPK/SOX2 pathway in bladder cancer. Cell Death Dis. 2017;8:e2600.PubMedPubMedCentralCrossRef
40.
Friedrich B, Quensel C, Sommer T, Hartmann E, Kohler M. Nuclear localization signal and protein context both mediate importin alpha specificity of nuclear import substrates. Mol Cell Biol. 2006;26:8697–709.PubMedPubMedCentralCrossRef
41.
Duan J, Tang Z, Mu H, Zhang G. [retracted] nuclear import of prototype foamy virus transactivator bel1 is mediated by KPNA1, KPNA6 and KPNA7. Int J Mol Med. 2017;39:771.PubMedPubMedCentralCrossRef
42.
Ishizawa J, Kojima K, Hail NJ, Tabe Y, Andreeff M. Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein. Pharmacol Ther. 2015;153:25–35.PubMedPubMedCentralCrossRef
43.
Mahipal A, Malafa M. Importins and exportins as therapeutic targets in cancer. Pharmacol Ther. 2016;164:135–43.PubMedCrossRef
44.
Mutka SC, Yang WQ, Dong SD, Ward SL, Craig DA, Timmermans PB, et al. Identification of nuclear export inhibitors with potent anticancer activity in vivo. Cancer Res. 2009;69:510–7.PubMedPubMedCentralCrossRef
45.
Tai YT, Landesman Y, Acharya C, Calle Y, Zhong MY, Cea M, et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia. 2014;28:155–65.PubMedCrossRef
46.
Hing ZA, Fung HY, Ranganathan P, Mitchell S, El-Gamal D, Woyach JA, et al. Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia. 2016;30:2364–72.PubMedPubMedCentralCrossRef
47.
Walker CJ, Oaks JJ, Santhanam R, Neviani P, Harb JG, Ferenchak G, et al. Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood. 2013;122:3034–44.PubMedPubMedCentralCrossRef
48.
van der Watt PJ, Chi A, Stelma T, Stowell C, Strydom E, Carden S, et al. Targeting the nuclear import receptor Kpnbeta1 as an anticancer therapeutic. Mol Cancer Ther. 2016;15:560–73.PubMedCrossRef
Metadata
Title
IPO5 promotes the proliferation and tumourigenicity of colorectal cancer cells by mediating RASAL2 nuclear transportation
Authors
Wenjuan Zhang
Yanxia Lu
Xiaomin Li
Jianming Zhang
Weihao Lin
Wei Zhang
Lin Zheng
Xuenong Li
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1290-0

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