Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2018

Open Access 01-12-2018 | Research

The long non-coding RNA PTTG3P promotes cell growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in hepatocellular carcinoma

Authors: Jin-lan Huang, Shun-wang Cao, Qi-shui Ou, Bin Yang, Shi-hao Zheng, Jing Tang, Jing Chen, Yan-wei Hu, Lei Zheng, Qian Wang

Published in: Molecular Cancer | Issue 1/2018

Login to get access

Abstract

Background

Dysfunctions of long non-coding RNA (lncRNAs) have been associated with the initiation and progression of hepatocellular carcinoma (HCC), but the clinicopathologic significance and potential role of lncRNA PTTG3P (pituitary tumor-transforming 3, pseudogene) in HCC remains largely unknown.

Methods

We compared the expression profiles of lncRNAs in 3 HCC tumor tissues and adjacent non-tumor tissues by microarrays. In situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to assess the level of PTTG3P and prognostic values of PTTG3P were assayed in two HCC cohorts (n = 46 and 90). Artificial modulation of PTTG3P (down- and over-expression) was performed to explore the role of PTTG3P in tumor growth and metastasis in vitro and in vivo. Involvement of PTTG1 (pituitary tumor-transforming 1), PI3K/AKT signaling and its downstream signals were validated by qRT-PCR and western blot.

Results

We found that PTTG3P was frequently up-regulated in HCC and its level was positively correlated to tumor size, TNM stage and poor survival of patients with HCC. Enforced expression of PTTG3P significantly promoted cell proliferation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, PTTG3P knockdown had opposite effects. Mechanistically, over-expression of PTTG3P up-regulated PTTG1, activated PI3K/AKT signaling and its downstream signals including cell cycle progression, cell apoptosis and epithelial-mesenchymal transition (EMT)-associated genes.

Conclusions

Our findings suggest that PTTG3P, a valuable marker of HCC prognosis, promotes tumor growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in HCC and might represent a potential target for gene-based therapy.
Appendix
Available only for authorised users
Literature
1.
Torre LA, Siegel RL, Ward EM, Jemal A. Global Cancer Incidence and Mortality Rates and Trends--An Update. Cancer Epidemiol Biomark Prev. 2016;25:16–27.CrossRef
2.
3.
4.
Yang X, Xie X, Xiao Y-F, Xie R, Hu C-J, Tang B, et al. The emergence of long non-coding RNAs in the tumorigenesis of hepatocellular carcinoma. Cancer Lett. 2015;360:119–24.CrossRefPubMed
5.
6.
Huang JL, Zheng L, Hu YW, Wang Q. Characteristics of long non-coding RNA and its relation to hepatocellular carcinoma. Carcinogenesis. 2014;35:507–14.CrossRefPubMed
7.
Jain S, Thakkar N, Chhatai J, Pal Bhadra M, Bhadra U. Long non-coding RNA: Functional agent for disease traits. RNA Biol. 2017;14:522–35.CrossRefPubMed
8.
Chandra Gupta S, Nandan TY. Potential of long non-coding RNAs in cancer patients: From biomarkers to therapeutic targets. Int J Cancer. 2017;140:1955–67.CrossRefPubMed
9.
10.
11.
Yao J, Wu L, Meng X, Yang H, Ni S, Wang Q, et al. Profiling, clinicopathological correlation and functional validation of specific long non-coding RNAs for hepatocellular carcinoma. Mol Cancer. 2017;16:164.CrossRefPubMedPubMedCentral
12.
Yuan SX, Wang J, Yang F, Tao QF, Zhang J, Wang LL, et al. Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1. Hepatology. 2016;63:499–511.CrossRefPubMed
13.
Zhang JY, Weng MZ, Song FB, Xu YG, Liu Q, Wu JY, et al. Long noncoding RNA AFAP1-AS1 indicates a poor prognosis of hepatocellular carcinoma and promotes cell proliferation and invasion via upregulation of the RhoA/Rac2 signaling. Int J Oncol. 2016;48:1590–8.CrossRefPubMed
14.
Xiao JN, Yan TH, Yu RM, Gao Y, Zeng WL, Lu SW, et al. Long non-coding RNA UCA1 regulates the expression of Snail2 by miR-203 to promote hepatocellular carcinoma progression. J Cancer Res Clin Oncol. 2017;143:981–90.CrossRefPubMed
15.
Li T, Xie J, Shen C, Cheng D, Shi Y, Wu Z, et al. Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma. Oncogene. 2016;35:1575–84.CrossRefPubMed
16.
Huang JL, Ren TY, Cao SW, Zheng SH, Hu XM, Hu YW, et al. HBx-related long non-coding RNA DBH-AS1 promotes cell proliferation and survival by activating MAPK signaling in hepatocellular carcinoma. Oncotarget. 2015;6:33791–804.PubMedPubMedCentral
17.
Cao SW, Huang JL, Chen J, Hu YW, Hu XM, Ren TY, et al. Long non-coding RNA UBE2CP3 promotes tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. Oncotarget. 2017;8:65370–85.PubMedPubMedCentral
18.
19.
20.
21.
Grander D, Johnsson P. Pseudogene-Expressed RNAs: Emerging Roles in Gene Regulation and Disease. Curr Top Microbiol Immunol. 2016;394:111–26.PubMed
22.
Chen L, Puri R, Lefkowitz EJ, Kakar SS. Identification of the human pituitary tumor transforming gene (hPTTG) family: molecular structure, expression, and chromosomal localization. Gene. 2000;248:41–50.CrossRefPubMed
23.
Chen CL, Tseng YW, Wu JC, Chen GY, Lin KC, Hwang SM, et al. Suppression of hepatocellular carcinoma by baculovirus-mediated expression of long non-coding RNA PTENP1 and MicroRNA regulation. Biomaterials. 2015;44:71–81.CrossRefPubMed
24.
Chan JJ, Kwok ZH, Chew XH, Zhang B, Liu C, Soong TW, et al. A FTH1 gene:pseudogene:microRNA network regulates tumorigenesis in prostate cancer. Nucleic Acids Res. 2018;46:1998–2011.
25.
Kong Y, Zhang L, Huang Y, He T, Zhang L, Zhao X, et al. Pseudogene PDIA3P1 promotes cell proliferation, migration and invasion, and suppresses apoptosis in hepatocellular carcinoma by regulating the p53 pathway. Cancer Lett. 2017;407:76–83.CrossRefPubMed
26.
Karreth FA, Reschke M, Ruocco A, Ng C, Chapuy B, Leopold V, et al. The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. Cell. 2015;161:319–32.CrossRefPubMed
27.
Jennen DG, Magkoufopoulou C, Ketelslegers HB, van Herwijnen MH, Kleinjans JC, van Delft JH. Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010;115:66–79.CrossRefPubMed
28.
Rieswijk L, Claessen SM, Bekers O, van Herwijnen M, Theunissen DH, Jennen DG, et al. Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma. Toxicology. 2016;350-352:31–9.CrossRefPubMed
29.
Anestopoulos I, Voulgaridou GP, Georgakilas AG, Franco R, Pappa A, Panayiotidis MI. Epigenetic therapy as a novel approach in hepatocellular carcinoma. Pharmacol Ther. 2015;145:103–19.CrossRefPubMed
30.
Weng W, Ni S, Wang Y, Xu M, Zhang Q, Yang Y, et al. PTTG3P promotes gastric tumour cell proliferation and invasion and is an indicator of poor prognosis. J Cell Mol Med. 2017;21:3360–71.CrossRefPubMedPubMedCentral
31.
Kittler R, Pelletier L, Heninger AK, Slabicki M, Theis M, Miroslaw L, et al. Genome-scale RNAi profiling of cell division in human tissue culture cells. Nat Cell Biol. 2007;9:1401–12.CrossRefPubMed
32.
Kho PS, Wang Z, Zhuang L, Li Y, Chew JL, Ng HH, et al. p53-regulated transcriptional program associated with genotoxic stress-induced apoptosis. J Biol Chem. 2004;279:21183–92.CrossRefPubMed
33.
Bonelli P, Tuccillo FM, Borrelli A, Schiattarella A, Buonaguro FM. CDK/CCN and CDKI alterations for cancer prognosis and therapeutic predictivity. Biomed Res Int. 2014;2014:361020.CrossRefPubMedPubMedCentral
34.
Matsuda Y, Wakai T, Kubota M, Takamura M, Yamagiwa S, Aoyagi Y, et al. Clinical significance of cell cycle inhibitors in hepatocellular carcinoma. Med Mol Morphol. 2013;46:185–92.CrossRefPubMed
35.
Bretones G, Delgado MD, Leon J. Myc and cell cycle control. Biochim Biophys Acta. 1849;2015:506–16.
36.
37.
Smith BN, Bhowmick NA. Role of EMT in Metastasis and Therapy Resistance. J Clin Med. 2016;5
38.
39.
Wang H, Wu Q, Liu Z, Luo X, Fan Y, Liu Y, et al. Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma. Cell Death Dis. 2014;5:e1155.CrossRefPubMedPubMedCentral
40.
Wang M, Wu H, Li S, Xu Z, Li X, Yang Y, et al. SYNJ2BP promotes the degradation of PTEN through the lysosome-pathway and enhances breast tumor metastasis via PI3K/AKT/SNAI1 signaling. Oncotarget. 2017;8:89692–706.PubMedPubMedCentral
41.
Li HB, You QS, Xu LX, Sun LX, Abdul Majid AS, Xia XB, et al. Long Non-Coding RNA-MALAT1 Mediates Retinal Ganglion Cell Apoptosis Through the PI3K/Akt Signaling Pathway in Rats with Glaucoma. Cell Physiol Biochem. 2017;43:2117–32.CrossRefPubMed
42.
An Y, Furber KL, Ji S. Pseudogenes regulate parental gene expression via ceRNA network. J Cell Mol Med. 2017;21:185–92.CrossRefPubMed
43.
Romero Arenas MA, Whitsett TG, Aronova A, Henderson SA, LoBello J, Habra MA, et al. Protein Expression of PTTG1 as a Diagnostic Biomarker in Adrenocortical Carcinoma. Ann Surg Oncol. 2018;25:801–7.CrossRefPubMed
44.
Liang M, Chen X, Liu W, Li S, Li C, Jiang L, et al. Role of the pituitary tumor transforming gene 1 in the progression of hepatocellular carcinoma. Cancer Biol Ther. 2011;11:337–45.CrossRefPubMed
45.
Xiang W, Wu X, Huang C, Wang M, Zhao X, Luo G, et al. PTTG1 regulated by miR-146-3p promotes bladder cancer migration, invasion, metastasis and growth. Oncotarget. 2017;8:664–78.PubMed
46.
Liang M, Liu J, Ji H, Chen M, Zhao Y, Li S, et al. A Aconitum coreanum polysaccharide fraction induces apoptosis of hepatocellular carcinoma (HCC) cells via pituitary tumor transforming gene 1 (PTTG1)-mediated suppression of the P13K/Akt and activation of p38 MAPK signaling pathway and displays antitumor activity in vivo. Tumour Biol. 2015;36:7085–91.CrossRefPubMed
Metadata
Title
The long non-coding RNA PTTG3P promotes cell growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in hepatocellular carcinoma
Authors
Jin-lan Huang
Shun-wang Cao
Qi-shui Ou
Bin Yang
Shi-hao Zheng
Jing Tang
Jing Chen
Yan-wei Hu
Lei Zheng
Qian Wang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2018
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-018-0841-x

Other articles of this Issue 1/2018

Molecular Cancer 1/2018 Go to the issue

Letter to the Editor

High expression of Tob1 indicates poor survival outcome and promotes tumour progression via a Wnt positive feedback loop in colon cancer

Research

The long noncoding RNA SNHG1 regulates colorectal cancer cell growth through interactions with EZH2 and miR-154-5p

Review

Thyroid cancers of follicular origin in a genomic light: in-depth overview of common and unique molecular marker candidates

Letter to the Editor

Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer

Review

Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges

Letter to the Editor

Structure-based assessment and network analysis of targeting 14-3-3 proteins in prostate cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits