Expression of HIF‑1α is a predictive marker of the efficacy of neoadjuvant chemotherapy for locally advanced cervical cancer

Yan,Bin; Ma,Quan‑Fu; Tan,Wen‑Fu; Cai,Hong‑Ning; Li,Yan‑Li; Zhou,Zhi‑Gang; Dai,Xuan; Zhu,Fa‑Xia; Xiong,Yu‑Jing; Xu,Meng; Guo,Yu‑Lin; Gao,Han; Hu,Jun‑Bo; Wu,Xu‑Feng

doi:10.3892/ol.2020.11596

Expression of HIF‑1α is a predictive marker of the efficacy of neoadjuvant chemotherapy for locally advanced cervical cancer

Authors:
- Bin Yan
- Quan‑Fu Ma
- Wen‑Fu Tan
- Hong‑Ning Cai
- Yan‑Li Li
- Zhi‑Gang Zhou
- Xuan Dai
- Fa‑Xia Zhu
- Yu‑Jing Xiong
- Meng Xu
- Yu‑Lin Guo
- Han Gao
- Jun‑Bo Hu
- Xu‑Feng Wu
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Affiliations: Department of Gynecologic Oncology, Maternal and Child Health Hospital of Hubei Province, Huazhong University of Science and Technology, Wuhan, Hubei 430070, P.R. China, Department of Pathology, Maternal and Child Health Hospital of Hubei Province, Huazhong University of Science and Technology, Wuhan, Hubei 430070, P.R. China
Published online on: May 7, 2020 https://doi.org/10.3892/ol.2020.11596
Pages: 841-849
Copyright: © Yan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Platinum-based, arterial infusion chemotherapy as a neoadjuvant chemotherapy (NACT) followed by hysterectomy may be efficient for the treatment of locally advanced cervical cancer and improve prognosis. It is important to predict whether the NACT would be effective before it is launched. Hypoxia inducible factor‑1α (HIF‑1α) is the master transcriptional regulator of the cellular response to altered oxygen concentration. HIF‑1α protein expression is elevated in numerous human malignancies, contributes to poor disease outcome, and has been reported to induce tumorigenesis and chemoresistance. In the present study, patients with International Federation of Gynecology and Obstetrics stage IIB‑IIIB cervical cancer (n=59) between 2008 and 2014 were assessed for HIF‑1α expression by immunohistochemistry. Tumor samples were obtained by biopsy before any treatment. A double‑path chemotherapy regimen, paclitaxel (intravenous) plus cisplatin (intra‑arterial injection into the uterine region), was used as NACT. The patients were then separated into two groups according to NACT response: One group comprised patients with NACT, for whom the response to treatment was efficient resulting in complete/partial remission of the tumor (CR + PR group; n=52), the other group contained patients with NACT, for whom the result of the treatment was a stable/progressive disease (SD + PD group; n=7). HIF‑1α expression was tested in paraffin‑embedded sections using immunohistochemistry. HIF‑1α expression was significantly higher in the SD + PD group compared with the CR + PR group (P=0.029). The overall survival time was significantly longer in the CR + PR group compared with the SD + PD group (P<0.001). When the patients were divided into two groups based on HIF‑1α expression levels. Low (weighted score ≤4, n=39) and high (weighted score ≥6, n=20) expression level groups; the low HIF‑1α expression group was significantly more susceptible to NACT treatment (P=0.025). Cox hazard analysis revealed that a high level of HIF‑1α expression and lymph node metastases were significant independent predictors of poor overall survival (P=0.025, HR=6.354; P=0.020, HR=6.909, respectively). These results indicated that the expression of HIF‑1α may be able to predict the efficiency of NACT and may be considered an independent prognostic factor for stage IIB‑IIIB cervical cancer.

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1	Gupta S, Maheshwari A, Parab P, Mahantshetty U, Hawaldar R, Sastri Chopra S, Kerkar R, Engineer R, Tongaonkar H, Ghosh J, et al: Neoadjuvant chemotherapy followed by radical surgery versus concomitant chemotherapy and radiotherapy in patients with stage IB2, IIA, or IIB squamous cervical cancer: A randomized controlled trial. J Clin Oncol. 36:1548–1555. 2018. View Article : Google Scholar : PubMed/NCBI
2	Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM and Mutch DG: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 340:1137–1143. 1999. View Article : Google Scholar : PubMed/NCBI
3	Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL III, Walker JL and Gersell D: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 340:1154–1161. 1999. View Article : Google Scholar : PubMed/NCBI
4	Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL and Insalaco S: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 340:1144–1153. 1999. View Article : Google Scholar : PubMed/NCBI
5	Ishiko O, Sumi T, Yasui T, Matsumoto Y, Kawamura N, Ogita S, Kamino T, Nakamura K and Yamada R: Balloon-occluded arterial infusion chemotherapy, simple total hysterectomy, and radiotherapy as a useful combination-therapy for advanced cancer of the uterine cervix. Oncol Rep. 7:141–144. 2000.PubMed/NCBI
6	Kawaguchi R, Nakamura H, Morioka S, Ito H, Tanase Y, Haruta S, Kanayama S, Yosida S, Furukawa N, Oi H and Kobayashi H: Comparison of neoadjuvant intraarterial chemotherapy versus concurrent chemoradiotherapy in patients with stage IIIB uterine cervical cancer. World J Oncol. 4:221–229. 2013.PubMed/NCBI
7	Chen H, Liang C, Zhang L, Huang S and Wu X: Clinical efficacy of modified preoperative neoadjuvant chemotherapy in the treatment of locally advanced (stage IB2 to IIB) cervical cancer: Randomized study. Gynecol Oncol. 110:308–315. 2008. View Article : Google Scholar : PubMed/NCBI
8	Souhami L, Gil RA, Allan SE, Canary PC, Araújo CM, Pinto LH and Silveira TR: A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix. J Clin Oncol. 9:970–977. 1991. View Article : Google Scholar : PubMed/NCBI
9	Tattersall MH, Lorvidhaya V, Vootiprux V, Cheirsilpa A, Wong F, Azhar T, Lee HP, Kang SB, Manalo A, Yen MS, et al: Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer. Cervical cancer study group of the Asian Oceanian clinical oncology association. J Clin Oncol. 13:444–451. 1995. View Article : Google Scholar : PubMed/NCBI
10	de la Torre M: Neoadjuvant chemotherapy in woman with early or locally advanced cervical cancer. Rep Pract Oncol Radiother. 23:528–532. 2018. View Article : Google Scholar : PubMed/NCBI
11	Yamauchi M, Fukuda T, Wada T, Kawanishi M, Imai K, Tasaka R, Yasui T and Sumi T: Expression of epidermal growth factor-like domain 7 may be a predictive marker of the effect of neoadjuvant chemotherapy for locally advanced uterine cervical cancer. Oncol Lett. 12:5183–5189. 2016. View Article : Google Scholar : PubMed/NCBI
12	Imai K, Fukuda T, Wada T, Kawanishi M, Tasaka R, Yasui T and Sumi T: UCP2 expression may represent a predictive marker of neoadjuvant chemotherapy effectiveness for locally advanced uterine cervical cancer. Oncol Lett. 14:951–957. 2017. View Article : Google Scholar : PubMed/NCBI
13	Okamoto E, Sumi T, Misugi F, Nobeyama H, Hattori K, Yoshida H, Matsumoto Y, Yasui T, Honda K and Ishiko O: Expression of apoptosis-related proteins in advanced uterine cervical cancer after balloon-occluded arterial infusion chemotherapy as an indicator of the efficiency of this therapy. Int J Mol Med. 15:41–47. 2005.PubMed/NCBI
14	Nobeyama H, Sumi T, Misugi F, Okamoto E, Hattori K, Matsumoto Y, Yasui T, Honda K, Iwai K and Ishiko O: Association of HPV infection with prognosis after neoadjuvant chemotherapy in advanced uterine cervical cancer. Int J Mol Med. 14:101–105. 2004.PubMed/NCBI
15	Benedetti Panici P, Bellati F, Manci N, Pernice M, Plotti F, Di Donato V, Calcagno M, Zullo MA, Muzii L and Angioli R: Neoadjuvant chemotherapy followed by radical surgery in patients affected by FIGO stage IVA cervical cancer. Ann Surg Oncol. 14:2643–2648. 2007. View Article : Google Scholar : PubMed/NCBI
16	Karakashev SV and Reginato MJ: Progress toward overcoming hypoxia-induced resistance to solid tumor therapy. Cancer Manag Res 7: 253-264, 2015. Graham K and Unger E: Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment. Int J Nanomedicine. 13:6049–6058. 2018. View Article : Google Scholar : PubMed/NCBI
17	Balamurugan K: HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer. 138:1058–1066. 2016. View Article : Google Scholar : PubMed/NCBI
18	Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, et al: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 292:468–472. 2001. View Article : Google Scholar : PubMed/NCBI
19	Lin SC, Chien CW, Lee JC, Yeh YC, Hsu KF, Lai YY, Lin SC and Tsai SJ: Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells. J Clin Invest. 121:1905–1916. 2011. View Article : Google Scholar : PubMed/NCBI
20	Chen Q, Tian WJ, Huang ML, Liu CH, Yao TT and Guan MM: Association between HIF-1 alpha gene polymorphisms and response in patients undergoing neoadjuvant chemotherapy for locally advanced cervical cancer. Med Sci Monit. 22:3140–3146. 2016. View Article : Google Scholar : PubMed/NCBI
21	Semenza GL: Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 29:625–634. 2010. View Article : Google Scholar : PubMed/NCBI
22	Brown JM and Wilson WR: Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 4:437–447. 2004. View Article : Google Scholar : PubMed/NCBI
23	Iwasaki K, Yabushita H, Ueno T and Wakatsuki A: Role of hypoxia-inducible factor-1α, carbonic anhydrase-IX, glucose transporter-1 and vascular endothelial growth factor associated with lymph node metastasis and recurrence in patients with locally advanced cervical cancer. Oncol Lett. 10:1970–1978. 2015. View Article : Google Scholar : PubMed/NCBI
24	Kim BW, Cho H, Chung JY, Conway C, Ylaya K, Kim JH and Hewitt SM: Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry. J Transl Med. 11:1852013. View Article : Google Scholar : PubMed/NCBI
25	Huang M, Chen Q, Xiao J, Yao T, Bian L, Liu C and Lin Z: Overexpression of hypoxia-inducible factor-1α is a predictor of poor prognosis in cervical cancer: A clinicopathologic study and a meta-analysis. Int J Gynecol Cancer. 24:1054–1064. 2014. View Article : Google Scholar : PubMed/NCBI
26	Matsui Y, Kanoh H, Okudaira Y, Hashimoto T and Nakamura H: Superselective transcatheter-arterial-chemo-embolization in uterine cervical cancer. Gan To Kagaku Ryoho. 16:2801–2804. 1989.(In Japanese). PubMed/NCBI
27	Tsuji K, Yamada R, Kawabata M, Mitsuzane K, Sato M, Iwahashi M, Kitayama S and Nakano R: Effect of balloon occluded arterial infusion of anticancer drugs on the prognosis of cervical cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys. 32:1337–1345. 1995. View Article : Google Scholar : PubMed/NCBI
28	World Health Handbook for reporting results of cancer treatment. World Health Organization. (Geneva, Offset Publication, No. 48). 1989.
29	Yan B, Wei JJ, Yuan Y, Sun R, Li D, Luo J, Liao SJ, Zhou YH, Shu Y, Wang Q, et al: IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation. J Immunol. 190:5882–5893. 2013. View Article : Google Scholar : PubMed/NCBI
30	Sinicrope FA, Ruan SB, Cleary KR, Stephens LC, Lee JJ and Levin B: bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res. 55:237–241. 1995.PubMed/NCBI
31	National Comprehensive Cancer Network, . NCCN Clinical Practice Guidelines in Oncology-Cervical Cancer-Version II. 2013.
32	Angioli R, Luvero D, Aloisi A, Capriglione S, Gennari P, Linciano F, Li Destri M, Scaletta G, Montera R and Plotti F: Adjuvant chemotherapy after primary treatments for cervical cancer: A critical point of view and review of the literature. Expert Rev Anticancer Ther. 14:431–439. 2014. View Article : Google Scholar : PubMed/NCBI
33	Wada T, Fukuda T, Shimomura M, Inoue Y, Kawanishi M, Tasaka R, Yasui T, Ikeda K and Sumi T: XPA expression is a predictive marker of the effectiveness of neoadjuvant chemotherapy for locally advanced uterine cervical cancer. Oncol Lett. 15:3766–3771. 2018.PubMed/NCBI
34	Ditto A, Martinelli F, Borreani C, Kusamura S, Hanozet F, Brunelli C, Rossi G, Solima E, Fontanelli R, Zanaboni F, et al: Quality of life and sexual, bladder, and intestinal dysfunctions after class III nerve-sparing and class II radical hysterectomies: A questionnaire-based study. Int J Gynecol Cancer. 19:953–957. 2009. View Article : Google Scholar : PubMed/NCBI
35	Robova H, Halaska M, Pluta M, Skapa P, Strnad P, Lisy J and Rob L: The role of neoadjuvant chemotherapy and surgery in cervical cancer. Int J Gynecol Cancer. 20 (11 Suppl 2):S42–S46. 2010. View Article : Google Scholar : PubMed/NCBI
36	Iwata T, Miyauchi A, Suga Y, Nishio H, Nakamura M, Ohno A, Hirao N, Morisada T, Tanaka K, Ueyama H, et al: Neoadjuvant chemotherapy for locally advanced cervical cancer. Chin J Cancer Res. 28:235–240. 2016. View Article : Google Scholar : PubMed/NCBI
37	Landoni F, Sartori E, Maggino T, Zola P, Zanagnolo V, Cosio S, Ferrari F, Piovano E and Gadducci A: Is there a role for postoperative treatment in patients with stage Ib2-IIb cervical cancer treated with neo-adjuvant chemotherapy and radical surgery? An Italian multicenter retrospective study. Gynecol Oncol. 132:611–617. 2014. View Article : Google Scholar : PubMed/NCBI
38	Minig L, Colombo N, Zanagnolo V, Landoni F, Bocciolone L, Cárdenas-Rebollo JM, Iodice S and Maggioni A: Platinum-based neoadjuvant chemotherapy followed by radical surgery for cervical carcinoma international federation of gynecology and obstetrics stage IB2-IIB. Int J Gynecol Cancer. 23:1647–1654. 2013. View Article : Google Scholar : PubMed/NCBI
39	Semenza GL: HIF-1: Upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 20:51–56. 2010. View Article : Google Scholar : PubMed/NCBI
40	Wang GL, Jiang BH, Rue EA and Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 92:5510–5514. 1995. View Article : Google Scholar : PubMed/NCBI
41	Seeber LM, Horrée N, Vooijs MA, Heintz AP, van der Wall E, Verheijen RH and van Diest PJ: The role of hypoxia inducible factor-1alpha in gynecological cancer. Crit Rev Oncol Hematol. 78:173–184. 2011. View Article : Google Scholar : PubMed/NCBI
42	Łuczak MW, Roszak A, Pawlik P, Kędzia H, Lianeri M and Jagodziński PP: Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced cervical carcinoma. Oncol Rep. 26:1259–1264. 2011.PubMed/NCBI
43	Masoud GN and Li W: HIF-1α pathway: Role, regulation and intervention for cancer therapy. Acta Pharm Sin B. 5:378–389. 2015. View Article : Google Scholar : PubMed/NCBI