Low Expression of PEBP1P2 Promotes Metastasis of Clear Cell Renal Cell Carcinoma by Post-transcriptional Regulation of PEBP1 and KLF13 MRNA

Overview

Journal Exp Hematol Oncol

Publisher Biomed Central

Specialty Hematology

Date 2022 Nov 9

PMID 36348434

Authors

Lei Yang

Haoli Yin

Yi Chen

Chun Pan

Hexing Hang

Yanwen Lu

Wenliang Ma

Xin Li

Weidong Gan

Hongqian Guo

Dongmei Li

Affiliations

Soon will be listed here.

Abstract

Background: Pseudogenes play an essential role in tumor occurrence and progression. However, the functions and mechanisms of pseudogenes in clear cell renal cell carcinoma (ccRCC) remain largely elusive.

Methods: We quantified PEBP1P2 expression in ccRCC tissues and cells using fluorescence in situ hybridization and real-time PCR. Besides, we evaluated the role of PEBP1P2 in ccRCC using a lung metastasis model and a transwell assay. Finally, we documented the interactions between PEBP1P2, PEBP1, and KLF13 by performing luciferase, RNA immunoprecipitation, RNA pulldown, and targeted RNA demethylation assays.

Results: Low PEBP1P2 expression correlates significantly with advanced stages and poor prognosis in ccRCC patients. Besides, PEBP1P2 overexpression inhibits ccRCC metastasis formation in vivo and in vitro. Interestingly, PEBP1P2 directly interacted with 5-methylcytosine (mC)-containing PEBP1 mRNA and recruited the YBX1/ELAVL1 complex, stabilizing PEBP1 mRNA. In addition, PEBP1P2 increased KLF13 mRNA levels by acting as a sponge for miR-296, miR-616, and miR-3194.

Conclusions: PEBP1P2 inhibits ccRCC metastasis formation and regulates both PEBP1 and KLF13. Therefore, molecular therapies targeting PEBP1P2 might be an effective treatment strategy against ccRCC and other cancers with low PEBP1P2 levels.

Citing Articles

Detection, molecular function and mechanisms of m5C in cancer.

Zhang L, Li Y, Li L, Yao F, Cai M, Ye D Clin Transl Med. 2025; 15(3):e70239.

PMID: 40008496 PMC: 11862898. DOI: 10.1002/ctm2.70239.

NXPH4 mediated by mC contributes to the malignant characteristics of colorectal cancer via inhibiting HIF1A degradation.

Yang L, Shi J, Zhong M, Sun P, Zhang X, Lian Z Cell Mol Biol Lett. 2024; 29(1):111.

PMID: 39164641 PMC: 11334498. DOI: 10.1186/s11658-024-00630-5.

The role of RNA-modifying proteins in renal cell carcinoma.

Alhammadi M, Bajbouj K, Talaat I, Hamoudi R Cell Death Dis. 2024; 15(3):227.

PMID: 38503745 PMC: 10951318. DOI: 10.1038/s41419-024-06479-y.

Y-Box Binding Protein 1: Unraveling the Multifaceted Role in Cancer Development and Therapeutic Potential.

Dinh N, Nguyen T, Park M, Lee C Int J Mol Sci. 2024; 25(2).

PMID: 38255791 PMC: 10815159. DOI: 10.3390/ijms25020717.

Deciphering the vital roles and mechanism of m5C modification on RNA in cancers.

Zheng L, Duan Y, Li M, Wei J, Xue C, Chen S Am J Cancer Res. 2024; 13(12):6125-6146.

PMID: 38187052 PMC: 10767349.

References

Chen X, Li A, Sun B, Yang Y, Han Y, Yuan X . 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nat Cell Biol. 2019; 21(8):978-990. DOI: 10.1038/s41556-019-0361-y. View

Hitti E, Bakheet T, Al-Souhibani N, Moghrabi W, Al-Yahya S, Al-Ghamdi M . Systematic Analysis of AU-Rich Element Expression in Cancer Reveals Common Functional Clusters Regulated by Key RNA-Binding Proteins. Cancer Res. 2016; 76(14):4068-80. DOI: 10.1158/0008-5472.CAN-15-3110. View

Chen Y, Pan C, Wang X, Xu D, Ma Y, Hu J . Silencing of METTL3 effectively hinders invasion and metastasis of prostate cancer cells. Theranostics. 2021; 11(16):7640-7657. PMC: 8315076. DOI: 10.7150/thno.61178. View

Xi S, Cai H, Lu J, Zhang Y, Yu Y, Chen F . The pseudogene PRELID1P6 promotes glioma progression via the hnHNPH1-Akt/mTOR axis. Oncogene. 2021; 40(26):4453-4467. PMC: 8249232. DOI: 10.1038/s41388-021-01854-x. View

Shen H, Ontiveros R, Owens M, Liu M, Ghanty U, Kohli R . TET-mediated 5-methylcytosine oxidation in tRNA promotes translation. J Biol Chem. 2020; 296:100087. PMC: 7949041. DOI: 10.1074/jbc.RA120.014226. View

Chang S, Elemento O, Zhang J, Zhuang Z, Simons M, Hla T . ELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis. Proc Natl Acad Sci U S A. 2014; 111(51):18309-14. PMC: 4280608. DOI: 10.1073/pnas.1412172111. View

Zhu A, Sahani D, Duda D, Tomaso E, Ancukiewicz M, Catalano O . Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol. 2009; 27(18):3027-35. PMC: 2702235. DOI: 10.1200/JCO.2008.20.9908. View

Bai X, Yi M, Dong B, Zheng X, Wu K . The global, regional, and national burden of kidney cancer and attributable risk factor analysis from 1990 to 2017. Exp Hematol Oncol. 2020; 9:27. PMC: 7525971. DOI: 10.1186/s40164-020-00181-3. View

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

10.

Lam H, Khurana E, Fang G, Cayting P, Carriero N, Cheung K . Pseudofam: the pseudogene families database. Nucleic Acids Res. 2008; 37(Database issue):D738-43. PMC: 2686518. DOI: 10.1093/nar/gkn758. View

11.

Su J, Wu G, Ye Y, Zhang J, Zeng L, Huang X . NSUN2-mediated RNA 5-methylcytosine promotes esophageal squamous cell carcinoma progression via LIN28B-dependent GRB2 mRNA stabilization. Oncogene. 2021; 40(39):5814-5828. PMC: 8484015. DOI: 10.1038/s41388-021-01978-0. View

12.

Gu Y, Cohn S, Christie A, McKenzie T, Wolff N, Do Q . Modeling Renal Cell Carcinoma in Mice: and Inactivation Drive Tumor Grade. Cancer Discov. 2017; 7(8):900-917. PMC: 5540776. DOI: 10.1158/2159-8290.CD-17-0292. View

13.

Fang Z, Mei W, Qu C, Lu J, Shang L, Cao F . Role of m6A writers, erasers and readers in cancer. Exp Hematol Oncol. 2022; 11(1):45. PMC: 9361621. DOI: 10.1186/s40164-022-00298-7. View

14.

Han L, Yuan Y, Zheng S, Yang Y, Li J, Edgerton M . The Pan-Cancer analysis of pseudogene expression reveals biologically and clinically relevant tumour subtypes. Nat Commun. 2014; 5:3963. PMC: 4339277. DOI: 10.1038/ncomms4963. View

15.

He X, Lian Z, Yang Y, Wang Z, Fu X, Liu Y . Long Non-coding RNA PEBP1P2 Suppresses Proliferative VSMCs Phenotypic Switching and Proliferation in Atherosclerosis. Mol Ther Nucleic Acids. 2020; 22:84-98. PMC: 7490454. DOI: 10.1016/j.omtn.2020.08.013. View

16.

Oliveira-Mateos C, Sanchez-Castillo A, Soler M, Obiols-Guardia A, Pineyro D, Boque-Sastre R . The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition. Nat Commun. 2019; 10(1):3979. PMC: 6726650. DOI: 10.1038/s41467-019-11910-6. View

17.

Raineri I, Wegmueller D, Gross B, Certa U, Moroni C . Roles of AUF1 isoforms, HuR and BRF1 in ARE-dependent mRNA turnover studied by RNA interference. Nucleic Acids Res. 2004; 32(4):1279-88. PMC: 390274. DOI: 10.1093/nar/gkh282. View

18.

Wang J, Zhu W, Han J, Yang X, Zhou R, Lu H . The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. Cancer Commun (Lond). 2021; 41(7):560-575. PMC: 8286140. DOI: 10.1002/cac2.12158. View

19.

Huang J, Shao Y, Gu W . Function and clinical significance of N6-methyladenosine in digestive system tumours. Exp Hematol Oncol. 2021; 10(1):40. PMC: 8272376. DOI: 10.1186/s40164-021-00234-1. View

20.

Courtney K, Infante J, Lam E, Figlin R, Rini B, Brugarolas J . Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2017; 36(9):867-874. PMC: 5946714. DOI: 10.1200/JCO.2017.74.2627. View