Expression of hypoxia-inducible factor-1α affects tumor proliferation and antiapoptosis in surgically resected lung cancer

Takasaki,Chihiro; Kobayashi,Masashi; Ishibashi,Hironori; Akashi,Takumi; Okubo,Kenichi

doi:10.3892/mco.2016.937

Expression of hypoxia-inducible factor-1α affects tumor proliferation and antiapoptosis in surgically resected lung cancer

Authors:
- Chihiro Takasaki
- Masashi Kobayashi
- Hironori Ishibashi
- Takumi Akashi
- Kenichi Okubo
View Affiliations

Affiliations: Department of Thoracic Surgery, Tokyo Medical and Dental University, Tokyo 113‑0034, Japan, Department of Pathology, Tokyo Medical and Dental University, Tokyo 113‑0034, Japan
Published online on: June 17, 2016 https://doi.org/10.3892/mco.2016.937
Pages: 295-300
Copyright: © Takasaki 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: )

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

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hypoxia-inducible factor (HIF)‑1 is a transcription factor that allows cells to adapt to hypoxic situations. HIF-1 is known to control tissue proliferation, antiapoptosis, angiogenesis and glucose metabolism. Furthermore, HIF‑1 is involved in the growth of numerous cancer types. The present study aimed to examine the expression of HIF‑1α immunohistochemically in resected lung cancers. The present study included 216 consecutive patients with lung cancer who underwent resection between April 2013 and January 2015. The patients' clinicopathological data were summarized, including imaging findings, tumor pathological characteristics, and the patient's age, sex and smoking status. The intratumoral expression of HIF‑1α, survivin, c‑Myc and the Ki‑67 proliferation index were evaluated immunohistochemically. The patients were divided into two groups, according to the expression of HIF‑1α (low vs. high) and the clinicopathological characteristics of these groups were compared. It was revealed that HIF‑1α expression was significantly associated with ground glass opacity ratio, maximum standardized uptake value index, histological type (squamous cell carcinoma), differentiation and lymphatic invasion. Regarding the immunohistochemical findings, HIF‑1α expression was significantly correlated with the expression levels of c‑Myc (P<0.01) and survivin (P<0.01). Furthermore, the Ki‑67 proliferation index was significantly higher in high‑HIF‑1α tumors compared with in low‑HIF‑1α tumors (P=0.01). The multivariate analysis identified squamous cell carcinoma, high SUVmax and lymphatic invasion as significant and independent factors for high HIF‑1α expression. In conclusion, HIF‑1 was highly expressed in certain subgroups of lung cancer with specific histopathology and images. HIF‑1α expression was associated with tumor proliferation and antiapoptosis in lung cancer.

View Figures

View References

1	Semenza GL: Expression of hypoxia-inducible factor 1: Mechanisms and consequences. Biochem Pharmacol. 59:47–53. 2000. View Article : Google Scholar : PubMed/NCBI
2	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar : PubMed/NCBI
3	Thrash-Bingham CA and Tartof KD: aHIF: A natural antisense transcript overexpressed in human renal cancer and during hypoxia. J Natl Cancer Inst. 91:143–151. 1999. View Article : Google Scholar : PubMed/NCBI
4	Harada H, Itasaka S, Kizaka-Kondoh S, Shibuya K, Morinibu A, Shinomiya K and Hiraoka M: The Akt/mTOR pathway assures the synthesis of HIF-1alpha protein in a glucose- and reoxygenation-dependent manner in irradiated tumors. J Biol Chem. 284:5332–5342. 2009. View Article : Google Scholar : PubMed/NCBI
5	Kaelin WG Jr: The won Hippel-Lindau tumor suppressor protein: O2 sensing and cancer. Nat Rev Cancer. 8:865–873. 2008. View Article : Google Scholar : PubMed/NCBI
6	Simon F, Bockhorn M, Praha C, Baba HA, Broelsch CE, Frilling A and Weber F: Deregulation of HIF1-alpha and hypoxia-regulated pathways in hepatocellular carcinoma and corresponding non-malignant liver tissue-influence of a modulated host stroma on the prognosis of HCC. Langenbecks Arch Surg. 395:395–405. 2010. View Article : Google Scholar : PubMed/NCBI
7	Giles RH, Lolkema MP, Snijckers CM, Belderbos M, van der Groep P, Mans DA, van Beest M, van Noort M, Goldschmeding R, van Diest PJ, et al: Interplay between VHL/HIF1alpha and Wnt/beta-catenin pathways during colorectal tumorigenesis. Oncogene. 25:3065–3070. 2006. View Article : Google Scholar : PubMed/NCBI
8	Kim SJ, Rabbani ZN, Dewhirst MW, Vujaskovic Z, Vollmer RT, Schreiber EG, Oosterwijk E and Kelley MJ: Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer. Lung Cancer. 49:325–335. 2005. View Article : Google Scholar : PubMed/NCBI
9	Volm M and Koomägi R: Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res. 20:1527–1533. 2000.PubMed/NCBI
10	Mita AC, Mita MM, Nawrocki ST and Giles FJ: Survivin: Key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 14:5000–5005. 2008. View Article : Google Scholar : PubMed/NCBI
11	Liu N, Sun Y, Zhao N and Chen L: Role of hypoxia-inducible factor-1α and survivin in oxygen-induced retinopathy in mice. Int J Clin Exp Pathol. 7:6814–6819. 2014.PubMed/NCBI
12	Wu XY, Fu ZX and Wang XH: Effect of hypoxia-inducible factor 1-α on survivin in colorectal cancer. Mol Med Rep. 3:409–415. 2010.PubMed/NCBI
13	Chen XQ, Zhao CL and Li W: Effect of hypoxia-inducible factor-1alpha on transcription of survivin in non-small cell lung cancer. J Exp Clin Cancer Res. 28:292009. View Article : Google Scholar : PubMed/NCBI
14	Shinohara ET, Gonzalez A, Massion PP, Chen H, Li M, Freyer AS, Olson SJ, Andersen JJ, Shyr Y, Carbone DP, et al: Nuclear survivin predicts recurrence and poor survival in patients with resected nonsmall cell lung carcinoma. Cancer. 103:1685–1692. 2005. View Article : Google Scholar : PubMed/NCBI
15	Brennan DJ, Rexhepaj E, O'Brien SL, McSherry E, O'Connor DP, Fagan A, Culhane AC, Higgins DG, Jirstrom K, Millikan RC, et al: Altered cytoplasmic-to-nuclear ratio of surivin is a prognostic indicator in breast cancer. Clin Cancer Res. 14:2681–2689. 2008. View Article : Google Scholar : PubMed/NCBI
16	Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barret JC and Huang LE: HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J. 23:1949–1956. 2004. View Article : Google Scholar : PubMed/NCBI
17	Pelengaris S, Khan M and Evan G: c-Myc: More than just a matter of life and death. Nat Rev Cancer. 2:764–776. 2002. View Article : Google Scholar : PubMed/NCBI
18	Dang CV, Resar LM, Emison E, Kim S, Li Q, Prescott JE, Wonsey D and Zeller K: Function of the c-Myc oncogenec transcription factor. Exp Cell Res. 253:63–77. 1999. View Article : Google Scholar : PubMed/NCBI
19	Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V and Sobin L: International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions: The IASLC lung cancer staging project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumors. J Thorac Oncol. 2:706–714. 2007. View Article : Google Scholar : PubMed/NCBI
20	Karetsi E, Ioannou MG, Kerenidi T, Minas M, Molyvdas PA, Gourgoulianis KL and Paraskeva E: Differential expression of hypoxia-inducible factor-1α in non-small cell lung cancer and small cell lung cancer. Clinics (Sao Paulo). 67:1373–1378. 2012. View Article : Google Scholar : PubMed/NCBI
21	Kobayashi M, Hyang CL, Sonobe M, Kikuchi R, Ishikawa M, Kitamura J, Miyahara R, Menju T, Iwakiri S, Itoi K, et al: Intratumoral Wnt2B expression affects tumor proliferation and survival in malignant pleural mesothelioma patients. Exp Ther Med. 3:952–958. 2012.PubMed/NCBI
22	Dang CV, Kim JW, Gao P and Yustein J: The interplay between MYC and HIF in cancer. Nat Rev Cancer. 8:51–56. 2008. View Article : Google Scholar : PubMed/NCBI
23	Huang LE: Carrot and stick: HIF-alpha engages c-Myc in hypoxic adaptation. Cell Death Differ. 15:672–677. 2008. View Article : Google Scholar : PubMed/NCBI
24	Semenza GL: Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today. 12:853–859. 2007. View Article : Google Scholar : PubMed/NCBI
25	Fujita M, Yasuda M, Kitatani K, Miyazawa M, Hirabayashi K, Takekoshi S, Iida T, Hirasawa T, Murakami M, Mikami M, et al: An up-to-date anti-cancer treatment strategy focusing on HIF-1alpha suppression: Its application for refractory ovarian cancer. Acta Histochem Cytochem. 40:139–142. 2007. View Article : Google Scholar : PubMed/NCBI