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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

14-3-3σ induces heat shock protein 70 expression in hepatocellular carcinoma

Authors: Chia-Chia Liu, Yee-Jee Jan, Bor-Sheng Ko, Yao-Ming Wu, Shu-Man Liang, Shyh-Chang Chen, Yen-Ming Lee, Tzu-An Liu, Tzu-Ching Chang, John Wang, Song-Kun Shyue, Li-Ying Sung, Jun-Yang Liou

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

14-3-3σ is implicated in promoting tumor development of various malignancies. However, the clinical relevance of 14-3-3σ in hepatocellular carcinoma (HCC) tumor progression and modulation and pathway elucidation remain unclear.

Methods

We investigated 14-3-3σ expression in 109 HCC tissues by immunohistochemistry. Overexpression and knockdown experiments were performed by transfection with cDNA or siRNA. Protein expression and cell migration were determined by Western blot and Boyden chamber assay.

Results

In this study, we found that 14-3-3σ is abundantly expressed in HCC tumors. Stable or transient overexpression of 14-3-3σ induces the expression of heat shock factor-1α (HSF-1α) and heat shock protein 70 (HSP70) in HCC cells. Moreover, expression of 14-3-3σ significantly correlates with HSF-1α/HSP70 in HCC tumors and both 14-3-3σ and HSP70 overexpression are associated with micro-vascular thrombi in HCC patients, suggesting that 14-3-3σ/HSP70 expression is potentially involved in cell migration/invasion. Results of an in vitro migration assay indicate that 14-3-3σ promotes cell migration and that 14-3-3σ-induced cell migration is impaired by siRNA knockdown of HSP70. Finally, 14-3-3σ-induced HSF-1α/HSP70 expression is abolished by the knockdown of β-catenin or activation of GSK-3β.

Conclusions

Our findings indicate that 14-3-3σ participates in promoting HCC cell migration and tumor development via β-catenin/HSF-1α/HSP70 pathway regulation. Thus, 14-3-3σ alone or combined with HSP70 are potential prognostic biomarkers for HCC.
Appendix
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Literature
1.
Aitken A: Post-translational modification of 14-3-3 isoforms and regulation of cellular function. Semin Cell Dev Biol. 2011, 22 (7): 673-680.CrossRefPubMed
2.
Yang X, Lee WH, Sobott F, Papagrigoriou E, Robinson CV, Grossmann JG, Sundstrom M, Doyle DA, Elkins JM: Structural basis for protein-protein interactions in the 14-3-3 protein family. Proc Natl Acad Sci U S A. 2006, 103 (46): 17237-17242.CrossRefPubMedPubMedCentral
3.
Chan TA, Hermeking H, Lengauer C, Kinzler KW, Vogelstein B: 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. Nature. 1999, 401: 616-620.CrossRefPubMed
4.
Laronga C, Yang HY, Neal C, Lee MH: Association of the cyclin-dependent kinases and 14-3-3 sigma negatively regulates cell cycle progression. J Biol Chem. 2000, 275 (30): 23106-23112.CrossRefPubMed
5.
6.
Lodygin D, Hermeking HL: Epigenetic silencing of 14-3-3sigma in cancer. Semin Cancer Biol. 2006, 16 (3): 214-224.CrossRefPubMed
7.
8.
9.
Guweidhi A, Kleeff J, Giese N, El Fitori J, Ketterer K, Giese T, Büchler MW, Korc M, Friess H: Enhanced expression of 14-3-3sigma in pancreatic cancer and its role in cell cycle regulation and apoptosis. Carcinogenesis. 2004, 25 (9): 575-1585. 1CrossRef
10.
Perathoner A, Pirkebner D, Brandacher G, Spizzo G, Stadlmann S, Obrist P, Margreiter R, Amberger A: 14-3-3sigma expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Clin Cancer Res. 2005, 11 (9): 3274-3279.CrossRefPubMed
11.
Ide M, Saito K, Tsutsumi S, Tsuboi K, Yamaguchi S, Asao T, Kuwano H, Nakajima T: Over-expression of 14-3-3sigma in budding colorectal cancer cells modulates cell migration in the presence of tenascin-C. Oncol Rep. 2007, 18 (6): 1451-1456.PubMed
12.
Zhou WH, Tang F, Xu J, Wu X, Feng ZY, Li HG, Lin DJ, Shao CK, Liu Q: Aberrant upregulation of 14-3-3o expression serves as an inferior prognostic biomarker for gastric cancer. BMC Cancer. 2011, 11: 397-CrossRefPubMedPubMedCentral
13.
Shiba-Ishii A, Noguchi M: Aberrant stratifin overexpression is regulated by tumor-associated CpG demethylation in lung adenocarcinoma. Am J Pathol. 2012, 180 (4): 1653-1662.CrossRefPubMed
14.
Radhakrishnan VM, Jensen TJ, Cui H, Futscher BW, Martinez JD: Hypomethylation of the 14-3-3sigma promoter leads to increased expression in non-small cell lung cancer. Genes Chromosomes Cancer. 2011, 50 (10): 830-836.CrossRefPubMedPubMedCentral
15.
Shiba-Ishii A, Kano J, Morishita Y, Sato Y, Minami Y, Noguchi M: High expression of stratifin is a universal abnormality during the course of malignant progression of early-stage lung adenocarcinoma. Int J Cancer. 2011, 129 (10): 2445-2453.CrossRefPubMed
16.
Iwata N, Yamamoto H, Sasaki S, Itoh F, Suzuki H, Kikuchi T, Kaneto H, Iku S, Ozeki I, Karino Y, Satoh T, Toyota J, Satoh M, Endo T, Imai K: Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 sigma gene in human hepatocellular carcinoma. Oncogene. 2000, 19 (46): 5298-5302.CrossRefPubMed
17.
Chen XL, Zhou L, Yang J, Shen FK, Zhao SP, Wang YL: Hepatocellular carcinoma-associated protein markers investigated by MALDI-TOF MS. Mol Med Report. 2010, 3 (4): 589-596.
18.
Chuma M, Sakamoto M, Yamazaki K, Ohta T, Ohki M, Asaka M, Hirohashi S: Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma. Hepatology. 2003, 37 (1): 198-207.CrossRefPubMed
19.
Di Tommaso L, Destro A, Seok JY, Balladore E, Terracciano L, Sangiovanni A, Iavarone M, Colombo M, Jang JJ, Yu E, Jin SY, Morenghi E, Park YN, Roncalli M: The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma. J Hepatol. 2009, 50 (4): 746-754.CrossRefPubMed
20.
Shin E, Ryu HS, Kim SH, Jung H, Jang JJ, Lee K: The clinicopathological significance of heat shock protein 70 and glutamine synthetase expression in hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. 2011, 18: 544-550.CrossRefPubMed
21.
Di Tommaso L, Franchi G, Park YN, Fiamengo B, Destro A, Morenghi E, Montorsi M, Torzilli G, Tommasini M, Terracciano L, Tornillo L, Vecchione R, Roncalli M: Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology. 2007, 45 (3): 725-734.CrossRefPubMed
22.
Tremosini S, Forner A, Boix L, Vilana R, Bianchi L, Reig M, Rimola J, Rodríguez-Lope C, Ayuso C, Solé M, Bruix J: Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma. Gut. 2012, 61 (10): 1481-1487.CrossRefPubMed
23.
Sakamoto M: Early HCC: diagnosis and molecular markers. J Gastroenterol. 2009, 44 (Suppl 19): 108-111.CrossRefPubMed
24.
Li L, Jin R, Zhang X, Lv F, Liu L, Liu D, Liu K, Li N, Chen D: Oncogenic activation of glypican-3 by c-Myc in human hepatocellular carcinoma. Hepatology. 2012, 56 (4): 1380-1390.CrossRefPubMed
25.
Wang RE: Targeting heat shock proteins 70/90 and proteasome for cancer therapy. Curr Med Chem. 2011, 18 (27): 4250-4264.CrossRefPubMed
26.
27.
Jin X, Moskophidis D, Mivechi NF: Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome. Cell Metab. 2011, 14 (1): 91-103.CrossRefPubMedPubMedCentral
28.
Fang F, Chang R, Yang L: Heat shock factor 1 promotes invasion and metastasis of hepatocellular carcinoma in vitro and in vivo. Cancer. 2012, 118 (7): 1782-1794.CrossRefPubMed
29.
He B, Meng YH, Mivechi NF: Glycogen synthase kinase 3beta and extracellular signal-regulated kinase inactivate heat shock transcription factor 1 by facilitating the disappearance of transcriptionally active granules after heat shock. Mol Cell Biol. 1998, 18 (1): 6624-6633.CrossRefPubMedPubMedCentral
30.
Bijur GN, Jope RS: Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3beta in the regulation of HSF-1 activity. J Neurochem. 2000, 75 (6): 2401-2408.CrossRefPubMed
31.
Carmichael J, Sugars KL, Bao YP, Rubinsztein DC: Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington’s disease mutation. J Biol Chem. 2002, 277 (37): 33791-33798.CrossRefPubMed
32.
Desbois-Mouthon C, Blivet-Van Eggelpoel MJ, Beurel E, Boissan M, Delelo R, Cadoret A, Capeau J: Dysregulation of glycogen synthase kinase-3beta signaling in hepatocellular carcinoma cells. Hepatology. 2002, 36 (6): 1528-1536.CrossRefPubMed
33.
34.
Prange W, Breuhahn K, Fischer F, Zilkens C, Pietsch T, Eilers R, Dienes HP, Schirmacher P: Beta-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes. J Pathol. 2003, 201 (2): 250-259.CrossRefPubMed
35.
Inagawa S, Itabashi M, Adachi S, Kawamoto T, Hori M, Shimazaki J, Yoshimi F, Fukao K: Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival. Clin Cancer Res. 2002, 8 (2): 450-456.PubMed
36.
Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA: Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 1999, 155 (3): 703-710.CrossRefPubMedPubMedCentral
37.
Wong CM, Fan ST, Ng IO: Beta-catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer. 2001, 92 (1): 136-145.CrossRefPubMed
38.
Liu TA, Jan YJ, Ko BS, Chen SC, Liang SM, Hung YL, Hsu C, Shen TL, Lee YM, Chem PF, Wang J, Shyue SK, Liou J: Increased expression of 14-3-3beta promotes tumor progression and predicts extrahepatic metastasis and worse survival in hepatocellular carcinoma. Am J Pathol. 2011, 179 (6): 2698-2708.CrossRefPubMedPubMedCentral
39.
Ko BS, Chang TC, Hsu C, Chen YC, Shen TL, Chen SC, Wang J, Wu KK, Jan YJ, Liou Y: Overexpression of 14-3-3epsilon predicts tumour metastasis and poor survival in hepatocellular carcinoma. Histopathology. 2011, 58 (5): 705-711.CrossRefPubMed
40.
Ko BS, Lai IR, Chang TC, Liu TA, Chen SC, Wang J, Jan JY, Liou JY: Involvement of 14-3-3gamma overexpression in extrahepatic metastasis of hepatocellular carcinoma. Hum Pathol. 2011, 42 (1): 129-135.CrossRefPubMed
41.
Jan YJ, Ko BS, Hsu C, Chang TC, Chen SC, Chen SC, Wang J, Liou JY: Overexpressed focal adhesion kinase predicts a higher incidence of extrahepatic metastasis and worse survival in hepatocellular carcinoma. Hum Pathol. 2009, 40 (10): 1384-1390.CrossRefPubMed
42.
Barnes DM, Harris WH, Smith P, Millis RR, Rubens RD: Immunohistochemical determination of oestrogen receptor: comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer. 1996, 74 (9): 1445-1451.CrossRefPubMedPubMedCentral
43.
Chang GC, Liu KJ, Hsieh CL, Hu TS, Charoenfuprasert S, Liu HK, Luch KT, Hsu LH, Wu CW, Ting CC, Chen CY, Chen KC, Yang TY, Chou TY, Wang WH, Whang-Png J, Shih NY: Identification of alpha-enolase as an autoantigen in lung cancer: its overexpression is associated with clinical outcomes. Clin Cancer Res. 2006, 12 (19): 5746-5754.CrossRefPubMed
44.
Yatabe Y, Osada H, Tatematsu Y, Mitsudomi T, Takahashi T: Decreased expression of 14-3-3sigma in neuroendocrine tumors is independent of origin and malignant potential. Oncogene. 2002, 21 (54): 8310-8319.CrossRefPubMed
45.
Chang TC, Liu CC, Hsing EW, Liang SM, Chi YH, Sung LY, Lin SP, Shen TL, Ko BS, Yen BL, Yet SF, Wu KK, Liou JY: 14-3-3sigma regulates beta-catenin-mediated mouse embryonic stem cell proliferation by sequestering GSK-3beta. PLoS One. 2012, 7 (6): e40193-CrossRefPubMedPubMedCentral
46.
Zucman-Rossi J, Benhamouche S, Godard C, Boyault S, Grimber G, Balabaud C, Cunha AS, Bioulac-Sage P, Perret C: Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas. Oncogene. 2007, 26 (5): 774-780.CrossRefPubMed
47.
Cadoret A, Ovejero C, Terris B, Souil E, Levy L, Lamers WH, Kitajewski J, Kahn A, Perret C: New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002, 21 (54): 8293-8301.CrossRefPubMed
Metadata
Title
14-3-3σ induces heat shock protein 70 expression in hepatocellular carcinoma
Authors
Chia-Chia Liu
Yee-Jee Jan
Bor-Sheng Ko
Yao-Ming Wu
Shu-Man Liang
Shyh-Chang Chen
Yen-Ming Lee
Tzu-An Liu
Tzu-Ching Chang
John Wang
Song-Kun Shyue
Li-Ying Sung
Jun-Yang Liou
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-425

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