Open Access

STC1 regulates glioblastoma migration and invasion via the TGF‑β/SMAD4 signaling pathway

  • Authors:
    • Yan Xiong
    • Qibai Wang
  • View Affiliations

  • Published online on: August 9, 2019     https://doi.org/10.3892/mmr.2019.10579
  • Pages: 3055-3064
  • Copyright: © Xiong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Stanniocalcin‑1 (STC1) is involved in cancer progression; however, the function of STC1 in glioblastoma remains unknown. In the present study, the expression levels of STC1 protein in glioblastoma were detected using immunohistochemistry. The expression levels of STC1, SMAD2/3 and SMAD4 proteins, following silencing of STC1, were assessed via western blotting. EdU and Transwell assays were performed to determine the proliferation and migration ability of the cells. The mRNA expression levels of STC1, SMAD4 and microRNA (miR)‑34a were determined using quantitative PCR. The expression levels of STC1 were increased in glioblastoma tissues. STC1 revealed a significant association with poor outcome in patients with glioblastoma (P<0.05). The proliferation and invasion abilities were repressed in LN229 cells infected with LV3‑shSTC1‑1 and LV3‑shSTC1‑2 compared with LV3‑NC. By contrast, the proliferation and invasion abilities were increased in T98G cells infected with LV5‑STC1 compared with LV5‑NC (P<0.05). The expression levels of STC1, SMAD2/3 and SMAD4 were decreased in LN229 cells infected with LV3‑shSTC1‑1 and LV3‑shSTC1‑2 compared with LV3‑NC. However, the expression levels of STC1, SMAD2/3 and SMAD4 were elevated in T98G cells infected with LV5‑STC1 compared with LV5‑NC. The expression levels of miR‑34a were decreased following silencing of STC1 (P<0.05). The expression levels of SMAD4 were decreased when transfected with miR‑34a mimics (P<0.05). The luciferase activity of the wild‑type 3'untranslated region of SMAD4 was decreased following transfection with miR‑34a mimics (P<0.05). Silencing of STC1 inhibited the growth of LN229 in vivo. In conclusion, STC1 expression levels were increased in the present study, and it was revealed that STC1 regulated glioblastoma malignancy. This phenotype was observed in the SMAD2/3 and SMAD4 pathways.

References

1 

Millauer B, Shawver LK, Plate KH, Risaui W and Ullrich A: Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature. 367:576–579. 1994. View Article : Google Scholar : PubMed/NCBI

2 

Ohgaki H and Kleihues P: Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 170:1445–1453. 2007. View Article : Google Scholar : PubMed/NCBI

3 

Vredenburgh JJ, Desjardins A, Herndon JE II, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, et al: Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 25:4722–4729. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Wang J, Cazzato E, Ladewig E, Frattini V, Rosenbloom DI, Zairis S, Abate F, Liu Z, Elliott O, Shin YJ, et al: Clonal evolution of glioblastoma under therapy. Nat Genet. 48:768–776. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, et al: Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 375:2561–2569. 2016. View Article : Google Scholar : PubMed/NCBI

6 

Iwadate Y: Epithelial-mesenchymal transition in glioblastoma progression. Oncol Lett. 11:1615–1620. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Ozeki S, Baba I, Takaya N and Shoun H: A novel C1-using denitrifier alcaligenes sp. STC1 and its genes for copper-containing nitrite reductase and azurin. Biosci Biotechnol Biochem. 65:1206–1210. 2001. View Article : Google Scholar : PubMed/NCBI

8 

Wagner GF, Hampong M, Park CM and Copp DH: Purification, characterization, and bioassay of teleocalcin, a glycoprotein from salmon corpuscles of Stannius. Gen Comp Endocrinol. 63:481–491. 1986. View Article : Google Scholar : PubMed/NCBI

9 

Schein V, Cardoso JC, Pinto PI, Anjos L, Silva N, Power DM and Canário AV: Four stanniocalcin genes in teleost fish: Structure, phylogenetic analysis, tissue distribution and expression during hypercalcemic challenge. Gen Comp Endocrinol. 175:344–356. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Kawabata M, Umemoto N, Shimada Y, Nishimura Y, Zhang B, Kuroyanagi J, Miyabe M and Tanaka T: Downregulation of stanniocalcin 1 is responsible for sorafenib-induced cardiotoxicity. Toxicol Sci. 143:374–384. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Ma X, Gu L, Li H, Gao Y, Li X, Shen D, Gong H, Li S, Niu S, Zhang Y, et al: Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma. J Transl Med. 13:562015. View Article : Google Scholar : PubMed/NCBI

12 

Su J, Guo B, Zhang T, Wang K, Li X and Liang G: Stanniocalcin-1, a new biomarker of glioma progression, is associated with prognosis of patients. Tumour Biol. 36:6333–6339. 2015. View Article : Google Scholar : PubMed/NCBI

13 

Du YZ, Gu XH, Cheng SF, Li L, Liu H, Hu LP and Gao F: The oncogenetic role of stanniocalcin 1 in lung adenocarcinoma: A promising serum candidate biomarker for tracking lung adenocarcinoma progression. Tumour Biol. 37:5633–5644. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Jepsen MR, Kløverpris S, Bøtkjær JA, Wissing ML, Andersen CY and Oxvig C: The proteolytic activity of pregnancy-associated plasma protein-A is potentially regulated by stanniocalcin-1 and −2 during human ovarian follicle development. Hum Reprod. 31:866–874. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Law AY and Wong CK: Stanniocalcin-1 and −2 promote angiogenic sprouting in HUVECs via VEGF/VEGFR2 and angiopoietin signaling pathways. Mol Cell Endocrinol. 374:73–81. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Tang SE, Wu CP, Wu SY, Peng CK, Perng WC, Kang BH, Chu SJ and Huang KL: Stanniocalcin-1 ameliorates lipopolysaccharide-induced pulmonary oxidative stress, inflammation, and apoptosis in mice. Free Radic Biol Med. 71:321–331. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Cornmark L, Lønne GK, Jögi A and Larsson C: Protein kinase Cα suppresses the expression of STC1 in MDA-MB-231 breast cancer cells. Tumour Biol. 32:1023–1030. 2011. View Article : Google Scholar : PubMed/NCBI

18 

Tamura S, Oshima T, Yoshihara K, Kanazawa A, Yamada T, Inagaki D, Sato T, Yamamoto N, Shiozawa M, Morinaga S, et al: Clinical significance of STC1 gene expression in patients with colorectal cancer. Anticancer Res. 31:325–329. 2011.PubMed/NCBI

19 

Yeung BH, Shek FH, Lee NP and Wong CK: Stanniocalcin-1 reduces tumor size in human hepatocellular carcinoma. PLoS One. 10:e01399772015. View Article : Google Scholar : PubMed/NCBI

20 

Leung CC and Wong CK: Effects of STC1 overexpression on tumorigenicity and metabolism of hepatocellular carcinoma. Oncotarget. 9:6852–6861. 2018. View Article : Google Scholar : PubMed/NCBI

21 

Pan X, Jiang B, Liu J, Ding J, Li Y, Sun R, Peng L, Qin C, Fang S and Li G: STC1 promotes cell apoptosis via NF-κB phospho-P65 Ser536 in cervical cancer cells. Oncotarget. 8:46249–46261. 2017.PubMed/NCBI

22 

Han J, Jeon M, Shin I and Kim S: Elevated STC-1 augments the invasiveness of triple-negative breast cancer cells through activation of the JNK/c-Jun signaling pathway. Oncol Rep. 36:1764–1771. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Hu J, Meng Y, Zhang Z, Yan Q, Jiang X, Lv Z and Hu L: MARCH5 RNA promotes autophagy, migration, and invasion of ovarian cancer cells. Autophagy. 13:333–344. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Kurio N, Saunders C, Bechtold TE, Salhab I, Nah HD, Sinha S, Billings PC, Pacifici M and Koyama E: Roles of Ihh signaling in chondroprogenitor function in postnatal condylar cartilage. Matrix Biol. 67:15–31. 2018. View Article : Google Scholar : PubMed/NCBI

25 

Tao L, Bei Y, Li Y and Xiao J: Neonatal rat cardiomyocytes isolation, culture, and determination of microRNAs' effects in proliferation. Methods Mol Biol. 1733:203–213. 2018. View Article : Google Scholar : PubMed/NCBI

26 

Min X, Liu K, Zhu H and Zhang J: Long noncoding RNA LINC003121 inhibits proliferation and invasion of thyroid cancer cells by suppression of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. Med Sci Monit. 24:4592–4601. 2018. View Article : Google Scholar : PubMed/NCBI

27 

Yang Z, Li K, Liang Q, Zheng G, Zhang S, Lao X, Liang Y and Liao G: Elevated hydrostatic pressure promotes ameloblastoma cell invasion through up-regulation of MMP-2 and MMP-9 expression via Wnt/β-catenin signalling. J Oral Pathol Med. 47:836–846. 2018. View Article : Google Scholar : PubMed/NCBI

28 

Pan Y, Yuan F, Li Y, Wang G, Lin Z and Chen L: Bromodomain PHD-finger transcription factor promotes glioma progression and indicates poor prognosis. Oncol Rep. 41:246–256. 2019.PubMed/NCBI

29 

Yeung HY, Lai KP, Chan HY, Mak NK, Wagner GF and Wong CK: Hypoxia-inducible factor-1-mediated activation of stanniocalcin-1 in human cancer cells. Endocrinology. 146:4951–4960. 2005. View Article : Google Scholar : PubMed/NCBI

30 

Peña C, Céspedes MV, Lindh MB, Kiflemariam S, Mezheyeuski A, Edqvist PH, Hägglöf C, Birgisson H, Bojmar L, Jirström K, et al: STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res. 73:1287–1297. 2013. View Article : Google Scholar : PubMed/NCBI

31 

Chang AC, Doherty J, Huschtscha LI, Redvers R, Restall C, Reddel RR and Anderson RL: STC1 expression is associated with tumor growth and metastasis in breast cancer. Clin Exp Metastasis. 32:15–27. 2015. View Article : Google Scholar : PubMed/NCBI

32 

Karthikeyan A, Gupta N, Tang C, Mallilankaraman K, Silambarasan M, Shi M, Lu L, Ang BT, Ling EA and Dheen ST: Microglial SMAD4 regulated by microRNA-146a promotes migration of microglia which support tumor progression in a glioma environment. Oncotarget. 9:24950–24969. 2018. View Article : Google Scholar : PubMed/NCBI

33 

Zhang Z, Gong Q, Li M, Xu J, Zheng Y, Ge P and Chi G: MicroRNA-124 inhibits the proliferation of C6 glioma cells by targeting Smad4. Int J Mol Med. 40:1226–1234. 2017. View Article : Google Scholar : PubMed/NCBI

34 

Liu H, Xu D, Zhong X, Xu D, Chen G, Ge J and Li H: LncRNA-mRNA competing endogenous RNA network depicts transcriptional regulation in ischaemia reperfusion injury. J Cell Mol Med. 23:2272–2276. 2019. View Article : Google Scholar : PubMed/NCBI

35 

Chen HH, Zong J and Wang SJ: LncRNA GAPLINC promotes the growth and metastasis of glioblastoma by sponging miR-331-3p. Eur Rev Med Pharmacol Sci. 23:262–270. 2019.PubMed/NCBI

36 

Chen J, Du G, Chang Y, Wang Y, Shi L, Mi J and Tang G: Downregulated miR-27b promotes keratinocyte proliferation by targeting PLK2 in oral lichen planus. J Oral Pathol Med. 48:326–334. 2019. View Article : Google Scholar : PubMed/NCBI

37 

Werner TV, Hart M, Nickels R, Kim YJ, Menger MD, Bohle RM, Keller A, Ludwig N and Meese E: MiR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro and is directly targeting SMAD4, FRAT1 and BCL2. Aging (Albany NY). 9:932–954. 2017. View Article : Google Scholar : PubMed/NCBI

38 

Dong P, Xiong Y, Yue J, Hanley SJB and Watari H: miR-34a, miR-424 and miR-513 inhibit MMSET expression to repress endometrial cancer cell invasion and sphere formation. Oncotarget. 9:23253–23263. 2018. View Article : Google Scholar : PubMed/NCBI

39 

Li ZH, Weng X, Xiong QY, Tu JH, Xiao A, Qiu W, Gong Y, Hu EW, Huang S and Cao YL: miR-34a expression in human breast cancer is associated with drug resistance. Oncotarget. 8:106270–106282. 2017.PubMed/NCBI

40 

Zhang D, Qiu X, Li J, Zheng S, Li L and Zhao H: TGF-β secreted by tumor-associated macrophages promotes proliferation and invasion of colorectal cancer via miR-34a-VEGF axis. Cell Cycle. 17:2766–2778. 2018. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2019
Volume 20 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Xiong, Y., & Xiong, Y. (2019). STC1 regulates glioblastoma migration and invasion via the TGF‑β/SMAD4 signaling pathway. Molecular Medicine Reports, 20, 3055-3064. https://doi.org/10.3892/mmr.2019.10579
MLA
Xiong, Y., Wang, Q."STC1 regulates glioblastoma migration and invasion via the TGF‑β/SMAD4 signaling pathway". Molecular Medicine Reports 20.4 (2019): 3055-3064.
Chicago
Xiong, Y., Wang, Q."STC1 regulates glioblastoma migration and invasion via the TGF‑β/SMAD4 signaling pathway". Molecular Medicine Reports 20, no. 4 (2019): 3055-3064. https://doi.org/10.3892/mmr.2019.10579