Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2017 | Research

LncRNA AK023391 promotes tumorigenesis and invasion of gastric cancer through activation of the PI3K/Akt signaling pathway

Authors: Yanxia Huang, Jing Zhang, Lidan Hou, Ge Wang, Hui Liu, Rui Zhang, Xiaoyu Chen, Jinshui Zhu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

Abstract

Background

Patients with gastric cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Recent studies have confirmed the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including gastric cancer. However, little is known about the molecular mechanism by which lncRNA AK023391 contributes to gastric cancer.

Methods

A lncRNA microarray was used to identify the differentially expressed lncRNA AK023391 in gastric cancer and adjacent normal tissues. In addition, RNA fluorescence in situ hybridization (FISH) was used to investigate the association between AK023391 expression and the clinicopathological characteristics and prognosis of patients with gastric cancer. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of lncRNA AK023391 in gastric cancer cells. A cancer pathway microarray, bioinformatic analysis, western blotting, and immunochemistry were carried out to verify the regulation of AK023391 and its downstream PI3K/Akt signaling pathway.

Results

Expression of lncRNA AK023391 was significantly upregulated in gastric cancer samples and cell lines in comparison to adjacent normal tissues, and was positively correlated with poor survival in patients with gastric cancer. The multivariate Cox regression model revealed that AK023391 expression acted as an independent prognostic factor for survival in patients with gastric cancer. Knockdown of AK023391 inhibited cell growth and invasion both in vitro and in vivo, and induced apoptosis and cell cycle arrest in gastric cancer cells, whereas its overexpression reversed these effects. Mechanistically, PI3K/Akt signaling mediated the NF-κB, FOXO3a, and p53 pathways. Moreover, downstream transcription factors, such as c-myb, cyclinB1/G2, and BCL-6 might be involved in AK023391-induced tumorigenesis in gastric cancer.

Conclusions

The novel oncogenic lncRNA AK023391 in gastric cancer exerts its effects through activation of the PI3K/Akt signaling pathway, and may act as a potential biomarker for survival in patients with gastric cancer.

Available only for authorised users

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMed

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, XQ Y, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRefPubMed

Leung WK, M-s W, Kakugawa Y, Kim JJ, Yeoh K-g, Goh KL, Wu K-c, D-c W, Sollano J, Kachintorn U, et al. Asia Pacific working group on gastric cancer: screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol. 2008;9(3):279–87.CrossRefPubMed

Rona KA, Schwameis K, Zehetner J, Samakar K, Green K, Samaan J, Sandhu K, Bildzukewicz N, Katkhouda N, Lipham JC. Gastric cancer in the young: an advanced disease with poor prognostic features. J Surg Oncol. 2017;115(4):371–5.CrossRefPubMed

Zeng H, Zheng R, Guo Y, Zhang S, Zou X, Wang N, Zhang L, Tang J, Chen J, Wei K, et al. Cancer survival in China, 2003-2005: a population-based study. Int J Cancer. 2015;136(8):1921–30.CrossRefPubMed

Li R, Liu B, Gao J. The application of nanoparticles in diagnosis and theranostics of gastric cancer. Cancer Lett. 2017;386:123–30.CrossRefPubMed

Zhang JX, Xu Y, Gao Y, Chen C, Zheng ZS, Yun M, Weng HW, Xie D, Ye S. Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway. Mol Cancer. 2017;16(1):18.CrossRefPubMedPubMedCentral

Chandra Gupta S, Nandan TY. Potential of long non-coding RNAs in cancer patients: from biomarkers to therapeutic targets. Int J Cancer. 2017;140(9):1955–67.CrossRefPubMed

Volders PJ, Helsens K, Wang X, Menten B, Martens L, Gevaert K, Vandesompele J, Mestdagh P. LNCipedia: a database for annotated human lncRNA transcript sequences and structures. Nucleic Acids Res. 2013;41(Database issue):D246–51.CrossRefPubMed

10.

Volders PJ, Verheggen K, Menschaert G, Vandepoele K, Martens L, Vandesompele J, Mestdagh P. An update on LNCipedia: a database for annotated human lncRNA sequences. Nucleic Acids Rese. 2015;43(Database issue):D174–80.CrossRef

11.

Latos PA, Pauler FM, Koerner MV, Senergin HB, Hudson QJ, Stocsits RR, Allhoff W, Stricker SH, Klement RM, Warczok KE, et al. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science. 2012;338(6113):1469–72.CrossRefPubMed

12.

Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011;472(7341):120–4.CrossRefPubMedPubMedCentral

13.

Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, Khalil AM, Zuk O, Amit I, Rabani M, et al. A large Intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 2010;142(3):409–19.CrossRefPubMedPubMedCentral

14.

Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011;10:38.CrossRefPubMedPubMedCentral

15.

Chen QN, Chen X, Chen ZY, Nie FQ, Wei CC, Ma HW, Wan L, Yan S, Ren SN, Wang ZX. Long intergenic non-coding RNA 00152 promotes lung adenocarcinoma proliferation via interacting with EZH2 and repressing IL24 expression. Mol Cancer. 2017;16(1):17.CrossRefPubMedPubMedCentral

16.

Lu Z, Li Y, Wang J, Che Y, Sun S, Huang J, Chen Z, He J. Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-κB/snail pathway. J Exp Clin Cancer Res. 2017;36(1):54.CrossRefPubMedPubMedCentral

17.

Shou-Hua Wang W-JZ, Wu X-C, Zhang M-D, Ming-ZheWeng DZ, Wang J-D, Quan Z-W. Long non-coding RNA Malat1 promotes gallbladder cancer development by acting as a molecular sponge to regulate miR-206. Oncotarget. 2016;7(25):37857–67.CrossRefPubMedPubMedCentral

18.

Sun Y, S-DJin QZ, Liang H, Feng J, Lu X-Y, Wang W, Wang F, Guo R-H. Long non-coding RNA LUCAT1 is associated with poor prognosis in human non-small cell lung cancer and regulates cell proliferation via epigenetically repressing p21 and p57 expression. Oncotarget. 2017;8(17):28297–311.PubMedPubMedCentral

19.

Wang S-H, Zhang W-J, Wu X-C, Zhang M-D, Weng M-Z, Zhou D, Wang J-D, Quan Z-W. Long non-coding RNA Malat1 promotes gallbladder cancer development by acting as a molecular sponge to regulate miR-206. Oncotarget. 2016;7(25):37857–67.CrossRefPubMedPubMedCentral

20.

Li Y, Wu Z, Yuan J, Sun L, Lin L, Huang N, Bin J, Liao Y, Liao W. Long non-coding RNA MALAT1 promotes gastric cancer tumorigenicity and metastasis by regulating vasculogenic mimicry and angiogenesis. Cancer Lett. 2017;395:31–44.CrossRefPubMed

21.

Pushkar Malakar AS, Mogilevsky A, Stein I, Pikarsky E, Nevo Y, Benyamini H, Elgavish S, Zong X, Prasanth KV, Karni R. Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 up-regulation and mTOR activation. Cancer Res. 2017;77(5):1155–67.CrossRefPubMed

22.

Lan T, Ma W, Hong Z, Wu L, Chen X, Yuan Y. Long non-coding RNA small nucleolar RNA host gene 12 (SNHG12) promotes tumorigenesis and metastasis by targeting miR-199a/b-5p in hepatocellular carcinoma. J Exp Clin Cancer Res. 2017;36(1):11.CrossRefPubMedPubMedCentral

23.

Dong L, Li Y, Luo G, Xiao X, Tao D, Wu X, Wang M, Huang C, Wang L, Zeng F, et al. LncRNA SPRY4-IT1 sponges miR-101-3p to promote proliferation and metastasis of bladder cancer cells through up-regulating EZH2. Cancer Lett. 2016;388:281–91.

24.

Zhang P, Cao P, Zhu X, Pan M, Zhong K, He R, Yang L, Jiao X, Gao Y. Upregulation of long non-coding RNA HOXA-AS2 promotes proliferation and induces epithelial-mesenchymal transition in gallbladder carcinoma. Oncotarget. 2017;8(20):33137–43.PubMedPubMedCentral

25.

Huang M, Hou J, Wang Y, Xie M, Wei C, Nie F, Wang Z, Sun M. Long noncoding RNA LINC00673 is activated by SP1 and exerts Oncogenic properties by interacting with LSD1 and EZH2 in gastric cancer. Mol Ther. 2017;25(4):1014–26.CrossRefPubMed

26.

Chen DL, Ju HQ, Lu YX, Chen LZ, Zeng ZL, Zhang DS, Luo HY, Wang F, Qiu MZ, Wang DS, et al. Long non-coding RNA XIST regulates gastric cancer progression by acting as a molecular sponge of miR-101 to modulate EZH2 expression. J Exp Clin Cancer Res. 2016;35(1):142.CrossRefPubMedPubMedCentral

27.

Yu Y, Li L, Zheng Z, Chen S, Chen E, Hu Y. Long non-coding RNA linc00261 suppresses gastric cancer progression via promoting slug degradation. J Cell Mol Med. 2017;21(5):955–67.CrossRefPubMed

28.

Zhang J, Wang G, Chu S-J, Zhu J-S, Zhang R, Lu W-W, Xia L-Q, Lu Y-M, Da W, Sun Q. Loss of large tumor suppressor 1 promotes growth and metastasis of gastric cancer cells through upregulation of the YAP signaling. Oncotarget. 2016;7(13):16180–93.CrossRefPubMedPubMedCentral

29.

Lu X, Huang C, He X, Liu X, Ji J, Zhang E, Wang W, Guo R. A novel long non-coding RNA, SOX21-AS1, indicates a poor prognosis and promotes lung Adenocarcinoma proliferation. Cell Physiol Biochem. 2017;42(5):1857–69.CrossRefPubMed

30.

Xiong Y, Wang L, Li Y, Chen M, He W, Qi L. The long non-coding RNA XIST interacted with MiR-124 to modulate bladder cancer growth, invasion and migration by targeting androgen receptor (AR). Cell Physiol Biochem. 2017;43(1):405–18.CrossRefPubMed

31.

Pan C, Yao G, Liu B, Ma T, Xia Y, Wei K, Wang J, Xu J, Chen L, Chen Y. Long noncoding RNA FAL1 promotes cell proliferation, invasion and epithelial-Mesenchymal transition through the PTEN/AKT signaling Axis in non-small cell lung cancer. Cell Physiol Biochem. 2017;43(1):339–52.CrossRefPubMed

32.

Yan J, Zhang Y, She Q, Li X, Peng L, Wang X, Liu S, Shen X, Zhang W, Dong Y, et al. Long noncoding RNA H19/miR-675 Axis promotes gastric cancer via FADD/Caspase 8/Caspase 3 signaling pathway. Cell Physiol Biochem. 2017;42(6):2364–76.CrossRefPubMed

33.

Ding J, Xie M, Lian Y, Zhu Y, Peng P, Wang J, Wang L, Wang K. Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2, LSD1 in colorectal cancer. Oncogene. 2017;6(1):e288.CrossRef

34.

Zhao J, Liu Y, Zhang W, Zhou Z, Wu J, Cui P, Zhang Y, Huang G. Long non-coding RNA Linc00152 is involved in cell cycle arrest, apoptosis, epithelial to mesenchymal transition, cell migration and invasion in gastric cancer. Cell Cycle. 2015;14(19):3112–23.CrossRefPubMedPubMedCentral

35.

Kelley K, Berberich SJ. FHIT gene expression is repressed by mitogenic signaling through the PI3K/AKT/FOXO pathway. Am J Cancer Res. 2011;1(1):62–70.PubMed

36.

Shukla S, Bhaskaran N, Babcook MA, Fu P, Maclennan GT, Gupta S. Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway. Carcinogenesis. 2014;35(2):452–60.CrossRefPubMed

37.

Smit L, Berns K, Spence K, Ryder WD, Zeps N, Madiredjo M, Beijersbergen R, Bernards R, Clarke RB. An integrated genomic approach identifies that the PI3K/AKT/FOXO pathway is involved in breast cancer tumor initiation. Oncotarget. 2016;7(3):2596–610.CrossRefPubMed

38.

Hao NB, Tang B, Wang GZ, Xie R, CJ H, Wang SM, YY W, Liu E, Xie X, Yang SM. Hepatocyte growth factor (HGF) upregulates heparanase expression via the PI3K/Akt/NF-κB signaling pathway for gastric cancer metastasis. Cancer Lett. 2015;361(1):57–66.CrossRefPubMed

39.

Amin H, Wani NA, Farooq S, Nayak D, Chakraborty S, Shankar S, Rasool RU, Koul S, Goswami A, Rai R. Inhibition of invasion in pancreatic cancer cells by conjugate of EPA with β(3,3)-pip-OH via PI3K/Akt/NF-kB pathway. ACS Med Chem Lett. 2015;6(10):1071–4.CrossRefPubMedPubMedCentral

40.

Zhou J, Zhi X, Wang L, Wang W, Li Z, Tang J, Wang J, Zhang Q, Xu Z. Linc00152 promotes proliferation in gastric cancer through the EGFR-dependent pathway. J Exp Clin Cancer Res. 2015;34:135.CrossRefPubMedPubMedCentral

41.

Pan H, Jiang T, Cheng N, Wang Q, Ren S, Li X, Zhao C, Zhang L, Cai W, Zhou C. Long non-coding RNA BC087858 induces non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT in non-small-cell lung cancer. Oncotarget. 2016;7(31):49948–60.CrossRefPubMedPubMedCentral

42.

Wang C, Mao ZP, Wang L, GH W, Zhang FH, Wang DY, Shi JL. Long non-coding RNA MALAT1 promotes cholangiocarcinoma cell proliferation and invasion by activating PI3K/Akt pathway. Neoplasma. 2017;64(5):725–31.CrossRefPubMed

43.

Bartholomeusz C, Gonzalez-Angulo AM. Targeting the PI3K signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:121–30.CrossRefPubMed

44.

Li Y, Jin K, van Pelt GW, van Dam H, Yu X, Mesker WE, Ten Dijke P, Zhou F, Zhang L. C-Myb enhances breast cancer invasion and metastasis through the Wnt/beta-catenin/Axin2 pathway. Cancer Res. 2016;76(11):3364–75.CrossRefPubMed

45.

Liu J, Cui ZS, Luo Y, Jiang L, Man XH, Zhang X. Effect of cyclin G2 on proliferative ability of SGC-7901 cell. World J Gastroenterol. 2004;10(9):1357–60.CrossRefPubMedPubMedCentral

46.

Shi Q, Wang W, Jia Z, Chen P, Ma K, Zhou C. ISL1, a novel regulator of CCNB1, CCNB2 and c-MYC genes,promotes gastric cancer cell proliferation and tumor growth. Oncotarget. 2016;7(24):36489–500.CrossRefPubMedPubMedCentral

47.

Li Y, Qu X, Qu J, Zhang Y, Liu J, Teng Y, Hu X, Hou K, Liu Y. Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation. Cancer Lett. 2009;284(2):208–15.CrossRefPubMed

48.

Wu X, Chen Y, Li G, Xia L, Gu R, Wen X, Ming X, Chen H. Her3 is associated with poor survival of gastric adenocarcinoma: Her3 promotes proliferation, survival and migration of human gastric cancer mediated by PI3K/AKT signaling pathway. Med Oncol. 2014;31(4):903.CrossRefPubMed

Title: LncRNA AK023391 promotes tumorigenesis and invasion of gastric cancer through activation of the PI3K/Akt signaling pathway
Authors: Yanxia Huang
Jing Zhang
Lidan Hou
Ge Wang
Hui Liu
Rui Zhang
Xiaoyu Chen
Jinshui Zhu
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-017-0666-2

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

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

Intake of Boron, Cadmium, and Molybdenum enhances rat thyroid cell transformation

Oleuropein enhances radiation sensitivity of nasopharyngeal carcinoma by downregulating PDRG1 through HIF1α-repressed microRNA-519d

Involvement of aberrantly activated HOTAIR/EZH2/miR-193a feedback loop in progression of prostate cancer

MiR-361-5p inhibits glycolytic metabolism, proliferation and invasion of breast cancer by targeting FGFR1 and MMP-1

Stathmin is overexpressed and regulated by mutant p53 in oral squamous cell carcinoma

CAPZA1 modulates EMT by regulating actin cytoskeleton remodelling in hepatocellular carcinoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer