XPO1-Mediated EIF1AX Cytoplasmic Relocation Promotes Tumor Migration and Invasion in Endometrial Carcinoma

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2023 Jan 2

PMID 36589683

Authors

Yuhong Ye

Chengyu Lv

Jiandong Sun

Zihang Lin

Yue Liu

Yuxiu Huang

Yupeng Chen

Hua Li

Xiuli Lian

Xia Jiang

Sheng Zhang

Shie Wang

Affiliations

Soon will be listed here.

Abstract

Dysregulation of eukaryotic translation initiation factor 1A, X-linked (), has been implicated in the pathogenesis of some cancers. However, the role of in endometrial carcinoma (EC) remains unknown. We investigated the expression in EC patients and assessed its tumorigenesis-associated function and nucleocytoplasmic transport mechanism and . The results indicated that the cytoplasmic EIF1AX expression showed a gradual increase when going from endometrium normal tissue, simple endometrial hyperplasia, complex endometrial hyperplasia, and endometrial atypical hyperplasia to EC, while vice versa for the nuclear EIF1AX expression. In addition, the cytoplasmic EIF1AX expression was positively correlated with histologic type, high International Federation of Gynecology and Obstetrics (FIGO) grade, advanced FIGO stage, deeper infiltration, high Ki67 index, and shorter recurrence-free survival in EC patients. , short hairpin RNA-mediated depletion or SV40NLS-mediated EIF1AX import into the nucleus in multiple human EC cells potently suppressed cell migration and invasion, epithelial-mesenchymal transition, and lung metastasis. Moreover, exportin 1 induced the transport of EIF1AX from the nucleus to the cytoplasm that could be inhibited by leptomycin B treatment or the mutation in the location sequence. These results demonstrate that cytoplasmic EIF1AX may play a key role in the incidence and promotion of EC, and thus, targeting EIF1AX or its nucleocytoplasmic transport process may offer an effective new therapeutic approach to EC.

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References

Wen Q, Wang W, Luo J, Chu S, Chen L, Xu L . CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway. Oncotarget. 2016; 7(19):27787-801. PMC: 5053688. DOI: 10.18632/oncotarget.8497. View

Kunstman J, Juhlin C, Goh G, Brown T, Stenman A, Healy J . Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing. Hum Mol Genet. 2015; 24(8):2318-29. PMC: 4380073. DOI: 10.1093/hmg/ddu749. View

Felix A, Yang H, Bell D, Sherman M . Epidemiology of Endometrial Carcinoma: Etiologic Importance of Hormonal and Metabolic Influences. Adv Exp Med Biol. 2016; 943:3-46. DOI: 10.1007/978-3-319-43139-0_1. View

Yi T, Arthanari H, Akabayov B, Song H, Papadopoulos E, Qi H . eIF1A augments Ago2-mediated Dicer-independent miRNA biogenesis and RNA interference. Nat Commun. 2015; 6:7194. PMC: 4448125. DOI: 10.1038/ncomms8194. View

Li Y, Guo L, Ying S, Feng G, Zhang Y . Transcriptional repression of p21 by EIF1AX promotes the proliferation of breast cancer cells. Cell Prolif. 2020; 53(10):e12903. PMC: 7574879. DOI: 10.1111/cpr.12903. View

Gorlich D, Kutay U . Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol. 1999; 15:607-60. DOI: 10.1146/annurev.cellbio.15.1.607. View

Wang C, Cigliano A, Jiang L, Li X, Fan B, Pilo M . 4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice. Hepatology. 2014; 61(1):200-13. PMC: 4280310. DOI: 10.1002/hep.27396. View

Simoes-Pereira J, Moura M, Marques I, Rito M, Cabrera R, Leite V . The role of EIF1AX in thyroid cancer tumourigenesis and progression. J Endocrinol Invest. 2018; 42(3):313-318. DOI: 10.1007/s40618-018-0919-8. View

Mitamura T, Dong P, Ihira K, Kudo M, Watari H . Molecular-targeted therapies and precision medicine for endometrial cancer. Jpn J Clin Oncol. 2018; 49(2):108-120. DOI: 10.1093/jjco/hyy159. View

10.

Kosugi S, Hasebe M, Tomita M, Yanagawa H . Systematic identification of cell cycle-dependent yeast nucleocytoplasmic shuttling proteins by prediction of composite motifs. Proc Natl Acad Sci U S A. 2009; 106(25):10171-6. PMC: 2695404. DOI: 10.1073/pnas.0900604106. View

11.

. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014; 159(3):676-90. PMC: 4243044. DOI: 10.1016/j.cell.2014.09.050. View

12.

Lindeberg M, Hovatta O, Ahrlund-Richter L . Real-time reverse transcription-polymerase chain reaction analysis of translation initiation factor 1A (eIF-1A) in human and mouse preimplantation embryos. Reprod Biomed Online. 2004; 8(3):338-43. DOI: 10.1016/s1472-6483(10)60914-5. View

13.

Lortet-Tieulent J, Ferlay J, Bray F, Jemal A . International Patterns and Trends in Endometrial Cancer Incidence, 1978-2013. J Natl Cancer Inst. 2017; 110(4):354-361. DOI: 10.1093/jnci/djx214. View

14.

Ewens K, Kanetsky P, Richards-Yutz J, Purrazzella J, Shields C, Ganguly T . Chromosome 3 status combined with BAP1 and EIF1AX mutation profiles are associated with metastasis in uveal melanoma. Invest Ophthalmol Vis Sci. 2014; 55(8):5160-7. DOI: 10.1167/iovs.14-14550. View

15.

Jaafar Z, Oguro A, Nakamura Y, Kieft J . Translation initiation by the hepatitis C virus IRES requires eIF1A and ribosomal complex remodeling. Elife. 2016; 5. PMC: 5238962. DOI: 10.7554/eLife.21198. View

16.

Garzon R, Savona M, Baz R, Andreeff M, Gabrail N, Gutierrez M . A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. Blood. 2017; 129(24):3165-3174. PMC: 5524530. DOI: 10.1182/blood-2016-11-750158. View

17.

Monecke T, Dickmanns A, Ficner R . Allosteric control of the exportin CRM1 unraveled by crystal structure analysis. FEBS J. 2014; 281(18):4179-94. PMC: 4231977. DOI: 10.1111/febs.12842. View

18.

Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y . Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood. 2012; 120(23):4621-34. PMC: 3512237. DOI: 10.1182/blood-2012-05-429506. View

19.

Hao P, Yu J, Ward R, Liu Y, Hao Q, An S . Eukaryotic translation initiation factors as promising targets in cancer therapy. Cell Commun Signal. 2020; 18(1):175. PMC: 7640403. DOI: 10.1186/s12964-020-00607-9. View

20.

Karunamurthy A, Panebianco F, Hsiao S, Vorhauer J, Nikiforova M, Chiosea S . Prevalence and phenotypic correlations of EIF1AX mutations in thyroid nodules. Endocr Relat Cancer. 2016; 23(4):295-301. PMC: 5494715. DOI: 10.1530/ERC-16-0043. View