Tacrolimus promotes hepatocellular carcinoma and enhances CXCR4/SDF‑1α expression in vivo

Zhu,Huaqi; Sun,Qiman; Tan,Changjun; Xu,Min; Dai,Zhi; Wang,Zheng; Fan,Jia; Zhou,Jian

doi:10.3892/mmr.2014.2302

Tacrolimus promotes hepatocellular carcinoma and enhances CXCR4/SDF‑1α expression in vivo

Authors:
- Huaqi Zhu
- Qiman Sun
- Changjun Tan
- Min Xu
- Zhi Dai
- Zheng Wang
- Jia Fan
- Jian Zhou
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Affiliations: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
Published online on: June 5, 2014 https://doi.org/10.3892/mmr.2014.2302
Pages: 585-592
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The aim of our study was to elucidate the effect of tacrolimus (FK506) and of C-X-C chemokine receptor type 4 (CXCR4), which is a receptor specific to the stromal cell-derived factor-1α (SDF‑1α), on growth and metastasis of hepatocellular carcinoma (HCC). Following treatment with different concentrations of FK506, AMD3100 or normal saline (NS), the proliferation of Morris rat hepatoma 3924A (MH3924A) cells was measured by the MTT assay, the expression of CXCR4 was analyzed with immunohistochemistry, and the morphological changes and the invasiveness of cells were studied with a transwell assay and under a scanning electron microscope, respectively. In addition, August Copenhagen Irish rat models implanted with tumor were used to examine the pathological changes and invasiveness of tumor in vivo, the expression of CXCR4 in tumor tissues and the expression of SDF‑1α in the adjacent tissues to the HCC ones, using immunohistochemistry. In vitro, FK506 (100‑1,000 µg/l) significantly promoted the proliferation of MH3924A cells (P<0.01), and increased the expression of CXCR4 in MH3924A cells, albeit with no significance (P>0.05). By contrast, AMD3100 had no effect on the proliferation of MH3924A cells, but significantly reduced the expression of CXCR4 (P<0.05). The invasiveness of MH3924A cells was significantly (P<0.01) enhanced following treatment with FK506, SDF‑1α, FK506 + AMD3100, FK506 + SDF‑1α or FK506 + AMD3100 + SDF‑1α. In vivo, tumor weight (P=0.041), lymph node metastasis (P=0.002), the number of pulmonary nodules (P=0.012), the expression of CXCR4 in tumor tissues (P=0.048) and that of SDF‑1α in adjacent tissues (P=0.026) were significantly different between the FK506-treated and the NS group. Our results suggest that FK506 promotes the proliferation of MH3924A cells and the expression of CXCR4 and SDF‑1α in vivo. Therefore, inhibiting the formation of the CXCR4/SDF‑1α complex may partly reduce the promoting effect of FK506 on HCC.

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1	Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar
2	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
3	Cheng AL, Kang YK, Chen Z, et al: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10:25–34. 2009. View Article : Google Scholar : PubMed/NCBI
4	Thorgeirsson SS and Grisham JW: Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 31:339–346. 2002. View Article : Google Scholar : PubMed/NCBI
5	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
6	Yao FY, Ferrell L, Bass NM, et al: Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 33:1394–1403. 2001. View Article : Google Scholar : PubMed/NCBI
7	Escartin A, Sapisochin G, Bilbao I, et al: Recurrence of hepatocellular carcinoma after liver transplantation. Transplant Proc. 39:2308–2310. 2007. View Article : Google Scholar : PubMed/NCBI
8	Vivarelli M, Cucchetti A, Piscaglia F, et al: Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl. 11:497–503. 2005. View Article : Google Scholar : PubMed/NCBI
9	Leung JY, Zhu AX, Gordon FD, et al: Liver transplantation outcomes for early-stage hepatocellular carcinoma: results of a multicenter study. Liver Transpl. 10:1343–1354. 2004. View Article : Google Scholar : PubMed/NCBI
10	Vivarelli M, Bellusci R, Cucchetti A, et al: Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression? Transplantation. 74:1746–1751. 2002. View Article : Google Scholar
11	Haufroid V, Mourad M, Van Kerckhove V, et al: The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 14:147–154. 2004. View Article : Google Scholar : PubMed/NCBI
12	McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K and MacDonald AS: Sirolimus-tacrolimus combination immunosuppression. Lancet. 355:376–377. 2000. View Article : Google Scholar : PubMed/NCBI
13	Dumont FJ: FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem. 7:731–748. 2000. View Article : Google Scholar : PubMed/NCBI
14	Paloyan EB, Swinnen LJ, Montoya A, Lonchyna V, Sullivan HJ and Garrity E: Lung transplantation for advanced bronchioloalveolar carcinoma confined to the lungs. Transplantation. 69:2446–2448. 2000. View Article : Google Scholar : PubMed/NCBI
15	Zhou ZJ, Dai Z, Zhou SL, et al: Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma. Int J Cancer. 132:1080–1089. 2013. View Article : Google Scholar
16	Ogawa T, Tashiro H, Miyata Y, et al: Rho-associated kinase inhibitor reduces tumor recurrence after liver transplantation in a rat hepatoma model. Am J Transplant. 7:347–355. 2007. View Article : Google Scholar : PubMed/NCBI
17	Hatse S, Princen K, Bridger G, De Clercq E and Schols D: Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS Lett. 527:255–262. 2002. View Article : Google Scholar : PubMed/NCBI
18	Schimanski CC, Bahre R, Gockel I, et al: Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4. Br J Cancer. 95:210–217. 2006. View Article : Google Scholar : PubMed/NCBI
19	Sehgal A, Ricks S, Boynton AL, Warrick J and Murphy GP: Molecular characterization of CXCR-4: a potential brain tumor-associated gene. J Surg Oncol. 69:239–248. 1998. View Article : Google Scholar : PubMed/NCBI
20	Muller A, Homey B, Soto H, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature. 410:50–56. 2001. View Article : Google Scholar : PubMed/NCBI
21	Kucia M, Jankowski K, Reca R, et al: CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol. 35:233–245. 2004. View Article : Google Scholar : PubMed/NCBI
22	Libura J, Drukala J, Majka M, et al: CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood. 100:2597–2606. 2002. View Article : Google Scholar : PubMed/NCBI
23	Gao Q, Wang XY, Qiu SJ, et al: Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 15:971–979. 2009. View Article : Google Scholar
24	Gao Q, Qiu SJ, Fan J, et al: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 25:2586–2593. 2007. View Article : Google Scholar : PubMed/NCBI
25	Semela D, Piguet AC, Kolev M, et al: Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol. 46:840–848. 2007. View Article : Google Scholar : PubMed/NCBI
26	Yang R, Rescorla FJ, Reilly CR, et al: A reproducible rat liver cancer model for experimental therapy: introducing a technique of intrahepatic tumor implantation. J Surg Res. 52:193–198. 1992. View Article : Google Scholar : PubMed/NCBI
27	Zhang GQ, Han F, Fang XZ and Ma XM: CD4+, IL17 and Foxp3 expression in different pTNM stages of operable non-small cell lung cancer and effects on disease prognosis. Asian Pac J Cancer Prev. 13:3955–3960. 2012.
28	Maluccio M, Sharma V, Lagman M, et al: Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression. Transplantation. 76:597–602. 2003. View Article : Google Scholar : PubMed/NCBI
29	Gutierrez-Dalmau A and Campistol JM: Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. Drugs. 67:1167–1198. 2007. View Article : Google Scholar : PubMed/NCBI
30	Zhang JP, Lu WG, Ye F, Chen HZ, Zhou CY and Xie X: Study on CXCR4/SDF-1alpha axis in lymph node metastasis of cervical squamous cell carcinoma. Int J Gynecol Cancer. 17:478–483. 2007. View Article : Google Scholar : PubMed/NCBI
31	Mitra P, De A, Ethier MF, et al: Loss of chemokine SDF-1alpha-mediated CXCR4 signalling and receptor internalization in human hepatoma cell line HepG2. Cell Signal. 13:311–319. 2001. View Article : Google Scholar : PubMed/NCBI
32	Kim SW, Kim HY, Song IC, et al: Cytoplasmic trapping of CXCR4 in hepatocellular carcinoma cell lines. Cancer Res Treat. 40:53–61. 2008. View Article : Google Scholar : PubMed/NCBI
33	Sutton A, Friand V, Brule-Donneger S, et al: Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol Cancer Res. 5:21–33. 2007. View Article : Google Scholar : PubMed/NCBI
34	Arakaki R, Tamamura H, Premanathan M, et al: T134, a small-molecule CXCR4 inhibitor, has no cross-drug resistance with AMD3100, a CXCR4 antagonist with a different structure. J Virol. 73:1719–1723. 1999.PubMed/NCBI