Negative expression of PTEN identifies high risk for lymphatic-related metastasis in human esophageal squamous cell carcinoma

Sun,Zhenguo; Ji,Na; Bi,Mingming; Zhang,Zhiping; Liu,Xiangyan; Wang,Zhou

doi:10.3892/or.2015.3928

Negative expression of PTEN identifies high risk for lymphatic-related metastasis in human esophageal squamous cell carcinoma

Authors:
- Zhenguo Sun
- Na Ji
- Mingming Bi
- Zhiping Zhang
- Xiangyan Liu
- Zhou Wang
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Affiliations: Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Faculty of Health Science, Southampton University, Highfield Campus, Southampton SO171BJ, UK
Published online on: April 27, 2015 https://doi.org/10.3892/or.2015.3928
Pages: 3024-3032

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Abstract

The poor prognosis of esophageal squamous cell carcinoma (ESCC) is mainly attributed to higher lymphatic-related metastatic ability. Whether the loss of expression of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is associated with lymphatic‑related metastasis needs elucidation. In the present study, we assessed the mRNA and protein level of PTEN in ESCC by qRT-PCR and immunohistochemistry. The results showed PTEN mRNA level in tumors was significantly lower than that in corresponding non-tumor esophageal epitheliums (p<0.001), while 38 (51.4%) tumor samples were negative for expression of PTEN in ESCC tumors. Then the association between negative expression of PTEN and lymphatic-related metastasis (lymph node metastasis/3‑year postoperative lymphatic metastatic recurrence) was evaluated. The proportion of PTEN-negative expression was significantly higher in positive lymph node metastasis (pN+) than that in negative lymph node metastasis (pN0) (p=0.021). The negative expression of PTEN was not an independent risk factor for the lymphatic recurrence rate in multivariate analysis (p=0.498), however, the lymphatic recurrence rate (60.5%) in PTEN-negative expression group was higher than that (36.1%) in PTEN-positive expression group (p=0.019). Furthermore, PTEN expression was stably silenced by lentiviral-vectored shRNA (Lenti-shRNA) in Eca109 (ESCC‑derived cell line) to study functional effect of PTEN in vitro and in vivo. The laboratory study indicated increased cell proliferation, migration and invasion in vitro and more rapid growth rate of xenograft tumors in vivo after stable silencing of PTEN expression. Moreover, we proved that FAK/pFAK were not the main factors mediating the mechanism of metastasis in ESCC. In conclusion, negative expression of PTEN could be a useful biomarker to predict high risk for lymphatic-related metastasis in ESCC.

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1	Kamangar F, Dores GM and Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 24:2137–2150. 2006. View Article : Google Scholar : PubMed/NCBI
2	Law S and Wong J: Two-field dissection is enough for esophageal cancer. Dis Esophagus. 14:98–103. 2001. View Article : Google Scholar : PubMed/NCBI
3	Song Y, Wang Z, Liu X, Jiang W and Shi M: CCR7 and VEGF-C: Molecular indicator of lymphatic metastatic recurrence in pN0 esophageal squamous cell carcinoma after Ivor-Lewis esophagectomy? Ann Surg Oncol. 19:3606–3612. 2012. View Article : Google Scholar : PubMed/NCBI
4	Chen G, Wang Z, Liu XY and Liu FY: Recurrence pattern of squamous cell carcinoma in the middle thoracic esophagus after modified Ivor-Lewis esophagectomy. World J Surg. 31:1107–1114. 2007. View Article : Google Scholar : PubMed/NCBI
5	Maehama T and Dixon JE: The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 273:13375–13378. 1998. View Article : Google Scholar : PubMed/NCBI
6	Shi Y, Paluch BE, Wang X and Jiang X: PTEN at a glance. J Cell Sci. 125:4687–4692. 2012. View Article : Google Scholar : PubMed/NCBI
7	Tamura M, Gu J, Takino T and Yamada KM: Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: Differential involvement of focal adhesion kinase and p130^Cas. Cancer Res. 59:442–449. 1999.PubMed/NCBI
8	Blanco-Aparicio C, Renner O, Leal JF and Carnero A: PTEN, more than the AKT pathway. Carcinogenesis. 28:1379–1386. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kondo Y, Hollingsworth EF and Kondo S: Molecular targeting for malignant gliomas (Review). Int J Oncol. 24:1101–1109. 2004.PubMed/NCBI
10	Tang JM, He QY, Guo RX and Chang XJ: Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer. 51:181–191. 2006. View Article : Google Scholar
11	Terakawa N, Kanamori Y and Yoshida S: Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer. Endocr Relat Cancer. 10:203–208. 2003. View Article : Google Scholar : PubMed/NCBI
12	Koksal IT, Dirice E, Yasar D, Sanlioglu AD, Ciftcioglu A, Gulkesen KH, Ozes NO, Baykara M, Luleci G and Sanlioglu S: The assessment of PTEN tumor suppressor gene in combination with Gleason scoring and serum PSA to evaluate progression of prostate carcinoma. Urol Oncol. 22:307–312. 2004. View Article : Google Scholar : PubMed/NCBI
13	Im SA, Lee KE, Nam E, Kim DY, Lee JH, Han HS, Seoh JY, Park HY, Cho MS, Han WS, et al: Potential prognostic significance of p185(HER2) overexpression with loss of PTEN expression in gastric carcinomas. Tumori. 91:513–521. 2005.
14	Ding Y, Shimada Y, Kano M, Itami A, Kawabe A, Maeda M, Li Z, Hong T, Sato F, Kaganoi J, et al: PTEN/MMAC1 expression in esophageal squamous cell carcinomas. Int J Oncol. 17:695–699. 2000.PubMed/NCBI
15	Tachibana M, Shibakita M, Ohno S, Kinugasa S, Yoshimura H, Ueda S, Fujii T, Rahman MA, Dhar DK and Nagasue N: Expression and prognostic significance of PTEN product protein in patients with esophageal squamous cell carcinoma. Cancer. 94:1955–1960. 2002. View Article : Google Scholar : PubMed/NCBI
16	Chang D, Wang TY, Li HC, Wei JC and Song JX: Prognostic significance of PTEN expression in esophageal squamous cell carcinoma from Linzhou City, a high incidence area of northern China. Dis Esophagus. 20:491–496. 2007. View Article : Google Scholar : PubMed/NCBI
17	Damiano V, Rosa R, Formisano L, Nappi L, Gelardi T, Marciano R, Cozzolino I, Troncone G, Agrawal S, Veneziani BM, et al: Toll-like receptor 9 agonist IMO cooperates with everolimus in renal cell carcinoma by interfering with tumour growth and angiogenesis. Br J Cancer. 108:1616–1623. 2013. View Article : Google Scholar : PubMed/NCBI
18	Altorki N, Kent M, Ferrara C and Port J: Three-field lymph node dissection for squamous cell and adenocarcinoma of the esophagus. Ann Surg. 236:177–183. 2002. View Article : Google Scholar : PubMed/NCBI
19	Dresner SM and Griffin SM: Pattern of recurrence following radical oesophagectomy with two-field lymphadenectomy. Br J Surg. 87:1426–1433. 2000. View Article : Google Scholar : PubMed/NCBI
20	Thomas M, Greil J and Heidenreich O: Targeting leukemic fusion proteins with small interfering RNAs: Recent advances and therapeutic potentials. Acta Pharmacol Sin. 27:273–281. 2006. View Article : Google Scholar : PubMed/NCBI
21	Abbas-Terki T, Blanco-Bose W, Déglon N, Pralong W and Aebischer P: Lentiviral-mediated RNA interference. Hum Gene Ther. 13:2197–2201. 2002. View Article : Google Scholar
22	Fish RJ and Kruithof EK: Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors. BMC Mol Biol. 5:92004. View Article : Google Scholar : PubMed/NCBI
23	Akhtar J, Wang Z, Zhang ZP and Bi MM: Lentiviral-mediated RNA interference targeting stathmin1 gene in human gastric cancer cells inhibits proliferation in vitro and tumor growth in vivo. J Transl Med. 11:2122013. View Article : Google Scholar : PubMed/NCBI
24	Zhang C, Chakravarty D, Sakabe I, Mewani RR, Boudreau HE, Kumar D, Ahmad I and Kasid UN: Role of SCC-S2 in experimental metastasis and modulation of VEGFR-2, MMP-1, and MMP-9 expression. Mol Ther. 13:947–955. 2006. View Article : Google Scholar : PubMed/NCBI
25	Sawai H, Yasuda A, Ochi N, Ma J, Matsuo Y, Wakasugi T, Takahashi H, Funahashi H, Sato M and Takeyama H: Loss of PTEN expression is associated with colorectal cancer liver metastasis and poor patient survival. BMC Gastroenterol. 8:562008. View Article : Google Scholar : PubMed/NCBI
26	Chowdhury S, Ongchin M, Wan G, Sharratt E, Brattain MG and Rajput A: Restoration of PTEN activity decreases metastases in an orthotopic model of colon cancer. J Surg Res. 184:755–760. 2013. View Article : Google Scholar : PubMed/NCBI
27	Wikman H, Lamszus K, Detels N, Uslar L, Wrage M, Benner C, Hohensee I, Ylstra B, Eylmann K, Zapatka M, et al: Relevance of PTEN loss in brain metastasis formation in breast cancer patients. Breast Cancer Res. 14:R492012. View Article : Google Scholar : PubMed/NCBI
28	Tamura M, Gu J, Matsumoto K, Aota S, Parsons R and Yamada KM: Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 280:1614–1617. 1998. View Article : Google Scholar : PubMed/NCBI
29	Zhang LL, Liu J, Lei S, Zhang J, Zhou W and Yu HG: PTEN inhibits the invasion and metastasis of gastric cancer via down-regulation of FAK expression. Cell Signal. 26:1011–1020. 2014. View Article : Google Scholar : PubMed/NCBI
30	Hu Y, Xu S, Jin W, Yi Q and Wei W: Effect of the PTEN gene on adhesion, invasion and metastasis of osteosarcoma cells. Oncol Rep. 32:1741–1747. 2014.PubMed/NCBI