Abstract
Aim:
To study the effect of pSilencer 1.0-U6-siRNA-stat3 on the growth of human laryngeal tumors in nude mice.
Methods:
Hep2 cells were transplanted into nude mice, then at the time of tumor formation, growth rates were observed. After the tumor formed, pSilencer 1.0-U6-siRNA-stat3 was injected. Tumor volumes were calculated, and growth curves were plotted. Representative histological sections were taken from mice bearing transplantation tumors in both treated and control groups, and start3, pTyr-stat3, Bcl-2, cyclin D1, and survivin expression were detected by Western blotting. survivin mRNA levels were detected by Northern blotting, hematoxylin and eosin staining and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) assay to confirm the apoptosis of tumors.
Results:
In nude mice, pSilencer 1.0-U6-siRNA-stat3 significantly suppressed the growth of tumors compared with controls (P<0.01). In suppressed stat3 expression, and downregulated BcL2, cyclin D1, and survivin expression within the tumor. This significantly induced apoptosis of the tumors.
Conclusion:
pSilencer 1.0-U6-siRNA-stat3 was able to inhibit the growth of transplanted human laryngeal tumors in nude mice and induce apoptosis.
Similar content being viewed by others
Article PDF
References
Darnell JE Jr . STATs adn gene regulation. Science 1997; 277: 1630–35.
Bromberg J, Darnell JE Jr . The role STATs in transcriptional control and their impact on cellular function. Oncogene 2000; 19: 2468–73.
Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, et al. Constitutive activation of STAT3 in fibroblsts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ 1997; 8: 1267–76.
Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, et al. Constitutive activation fo STAT3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 2001; 20: 2499–513.
Grandis JR, Drenning SD, Chakraborty A, Zhou MY, Zeng Q, Pitt AS, et al. Requirement of STAT3 but not stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro. J Clin Invest 1998; 102: 1385–92.
Takemoto S, Mulloy JC, Cereseto A, Migone TS, Patel BK, Matsuoka M, et al. Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins. Proc Natl Acad Sci USA 1997; 94: 13897–902.
Gouilleux-Gruart V, Gouilleux F, Desanint C, Claisse JF, Capiod JC, Delobel J, et al. STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leute leukemia patients. Blood 1996; 87: 1692–7.
Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, et al. Inhibition of acute lymphoblastic leukaemia by a jak-2 inhibitor. Nature 1996; 379; 645–48.
Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM, et al. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potentantitumor activity against human and murine cancer cells in mice. Cancer Res 2003; 63: 1270–9.
Leong PL, Andrews GA, Johnson DE, Dyer KF, Xi S, Mai JC, et al. Targeted inhibition of STAT3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci USA 2003; 100: 4138–43.
Ni Z, Lou W, Leman ES, Gao AC . Inhibition of constitutively activated STAT3 signaling pathway suppresses growth of prostate cancer cells. Cancer Res 2000; 60: 1225–8.
Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, et al. A central role for STAT3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. Embo J 1996; 15: 3651–8.
Lee SO, Lou W, Qureshi KM, Mehraein-Ghomi F, Trump DL, Gao AC . RNA interference targeting STAT3 inhibits growth and induces apoptosis of human prostate cancer cells. Prostate 2004; 60: 303–9.
Konnikova L, Kotecki M, Kruger MM, Cochran BH . Knock-down of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer 2003; 3: 23.
Leong PL, Andrews GA, Johnson DE, Dyer KF, Xi SC, Mai JC, et al. Targeted inhibition of STAT3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci USA 2003; 100: 4138–43.
Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, Garcia R, et al. Constitutive activation of STAT3 in human prostate tumors and cell lines: direct inhibition of STAT3 signaling induces apoptosis of prostate cancer cells. Cancer Res 2002; 62: 6659–66.
Fuchs B, Zhang K, Schabel A, Bolander ME, Sarkar G . Identification of twenty-two candidate markers for human osteogenic sarcoma. Gene 2001; 278: 245–52.
Grandis JR, Zheng Q, Drenning SD . Epidermal growth factor receptor-mediated STAT3 signaling blocks apoptosis in head and neck cancer. Laryngoscope 2000; 110: 868–74.
Gao LF, Xu DQ, Wen LJ, Zhang XY, Shao YT, Zhao XJ . Inhibition of STAT3 expression by siRNA suppresses growth and induces apoptosis in laryngeal cancer cells. Acta Pharmacol Sin 2005; 26: 377–383.
Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res 2002; 62: 3351–5.
Sinibaldi D, Wharton W, Turkson J, Bowman T, Pledger WJ, Jove R . Induction of Survivin WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling. Oncogene 2000; 19: 5419–27.
Hannon GJ . RNA interference. Nature 2002; 418: 244–51.
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. STAT3 as an oncogene. Cell 1999; 98: 295–303.
Alas S, Bonavida B . Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res 2001; 61: 5137–44.
Puthier D, Bataille R, Amiot M . IL-6 up-regulates mcl-1 in human myeloma cells through JAK/STAT rather than ras/MAP kinase pathway. Eur J Immunol 1999; 29: 3945–50.
Aoki Y, Feldman GM, Tosato G . Inhibition of STAT3 signaling induces apoptosis and decreases surviving expression in primary effusion lymphoma. Blood 2003; 101: 1535–42.
Tsujimoto Y, Shimizu S . Bcl-2 family: life-or-death switch. FEBS Lett 2000; 466: 6–10.
Scott S, Higdon R, Beckett L, Shi XB, deVere White RW, Earle JD, et al. Bcl 2 antisense reduces prostate cancer cell survival following irradiation. Cancer Biother Radiopharm 2002; 17: 647–56.
Far KR, Sczakiel G . The activity of siRNA in mammalian cells is related to structural target accessibility: a comparison with antisense oligonucleotides. Nucleic Acids Res 2003; 31: 4417–24.
Elbashir SM, Harborth J, Weber K, Tuschl T, et al. Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods 2002; 26: 199–213.
Dechow TN, Pedranzini L, Leitch A, Leslie K, Gerald WL, Linkov I, et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by STAT3-C. Proc Natl Acad Sci USA 2004; 101: 10602–7.
Lou KQ, Chang DC . The gene-silencing efficiency of siRNA is strongly dependent on the local structure of mRNA at the targeted region. Biochem Biophys Res Commun 2004; 318: 303–10.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Gao, Lf., Wen, Lj., Yu, H. et al. Knockdown of Stat3 expression using RNAi inhibits growth of laryngeal tumors in vivo. Acta Pharmacol Sin 27, 347–352 (2006). https://doi.org/10.1111/j.1745-7254.2006.00277.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2006.00277.x
Keywords
This article is cited by
-
SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer
Oncogene (2016)
-
Celecoxib induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation
Acta Pharmacologica Sinica (2012)
-
Downregulation of STAT3 signaling induces apoptosis but also promotes anti-apoptotic gene expression in human pancreatic cancer cell lines
Tumor Biology (2011)
-
Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3
Cancer Gene Therapy (2010)
-
STAT3 silencing with lentivirus inhibits growth and induces apoptosis and differentiation of U251 cells
Journal of Neuro-Oncology (2009)