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Long Non-Coding RNA HOXA11 Antisense Promotes Cell Proliferation and Invasion and Predicts Patient Prognosis in Serous Ovarian Cancer

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Long Non-Coding RNA HOXA11 Antisense Promotes Cell Proliferation and Invasion and Predicts Patient Prognosis in Serous Ovarian Cancer pISSN 1598-2998, eISSN 2005-9256 Cancer Res Treat. 2017;49(3):656-668 https://doi.org/10.4143/crt.2016.263 Original Article Open Access Long Non-coding RNA HOXA11 Antisense Promotes Cell Proliferation and Invasion and Predicts Patient Prognosis in Serous Ovarian Cancer Ga Won Yim, MD, PhD1,2 Purpose Hee Jung Kim, PhD3 The biological function of long non-coding RNAs (lncRNAs) is only partially understood; there- fore, in this study, we investigated the expression of the novel HOXA11 antisense Lee Kyung Kim, MS3 (HOXA11as) lncRNA and its oncogenic role in serous ovarian cancer (SOC). Sang Wun Kim, MD, PhD3 Sunghoon Kim, MD, PhD3 Materials and Methods Eun Ji Nam, MD, PhD3 HOXA11as expression was examined in 129 SOC tissue samples by real time reverse tran- Young Tae Kim, MD, PhD3 scription polymerase chain reaction. Clinicopathological factors and patient survival were compared between the high (n=27) and low HOXA11as expression group (n=102). To investigate the role of HOXA11as in cell proliferation, invasion, and migration, HOXA11as expression in ovarian cancer cells was knocked down using RNA interference. 1 Department of Obstetrics and Gynecology, Results National Medical Center, Seoul, HOXA11as expression in cancer tissue was 77-fold higher than that of noncancerous tissue 2Department of Obstetrics and Gynecology, Yonsei University Graduate School, Seoul, (p < 0.05). Higher HOXA11as expression was significantly correlated with histological grade 3Department of Obstetrics and Gynecology, (p=0.017) and preoperative cancer antigen 125 (p=0.048). HOXA11as overexpression in Institute of Women's Life Medical Science, SOC cells led to increased cell proliferation, invasion, and migration. Moreover, HOXA11as Yonsei University College of Medicine, was associated with the expression of genes involved in cell invasion, migration, and Seoul, Korea epithelial-mesenchymal transition (EMT), including vascular endothelial growth factor, matrix metalloproteinase 9 (MMP-9), B-catenin, E-cadherin, Snail, Twist, and vimentin. Multivariate analysis revealed that HOXA11as was a prognostic factor of progressive disease and mor- + C +o r +re s+p o +n d +e n +c e :+ Y o+u n+g +T a +e K+i m +, M+ D +, P+h D+ + + tality (hazard ratio [HR], 1.730; p=0.043 and HR, 2.170; p=0.033, respectively). Progres- + + + + + + + + + + + + + + + + + + + + + D +i v +is i o+n +o f +G y+n e+c o +lo g+ic +O n+c o +lo g+y ,+ + + + + + sion-free and overall survival were significantly shorter in patients with high HOXA11as + D +e p +a r +tm +en +t o +f O +b s +te t +ri c s+ a +nd + G y+n e+c o +lo g+y ,+ + + expression. + I n+s t+it u +te +o f +W o+m +e n +'s L+i f e+ M +e d+i c a+l S+c i e+n c+e , + + + + Y +o n +s e +i U +n i v+e r+si t+y C +o l+le g +e o+f M+ e +d i c+in +e, + + + + Conclusion + 5 +0 Y +o n+s e +i- r o+, S+e o +d a +e m +u n+- g +u , +S e o+u l+ 0 3+7 2 +2 , +K o +re a+ These findings highlight the clinical significance of HOXA11as to predicting the prognosis + T +e l :+ 8 2 +-2 -+2 2 +28 -+2 2 +40 + + + + + + + + + + + + of SOC patients and suggest its potential in promoting tumor aggressiveness via regulation Fax: 82-2-313-8357 + + + + + + + + + + + + + + + + + + + + of vascular endothelial growth factor (VEGF), MMP-9, and EMT-related mechanisms. + E +-m +a i l+: y +tk c+h o +i@ +y u +h s +.a c + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + R +e c +ei v +e d + J u+n e+ 2 3+, 2+0 1 +6 + + + + + + + + + + + A +c c +ep +te d + S +e p +te m+ b +er +17 ,+ 2 0 +1 6 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + P +u b +li s +h e d+ O +n l+in e+ O+c t+o b +er +11 ,+ 2 0+1 6 + + + + + + Key words + + + + + + + + + + + + + + + + + + + + Cell proliferation, Long noncoding RNA, Ovarian neoplasms, + * +G a + W +o n + Y i+m +a n +d H+ e +e J u+n g+ K +i m + c o+n t+ri b+u t+ed + + Prognosis + e +q u +al l+y t +o t h+i s + w +or k+. + + + + + + + + + + + Introduction vival rate of less than 30% [2]. Serous ovarian cancer (SOC), which often presents at advanced stages and is characterized by metastases in the pelvic and abdominal cavity, is the most Epithelial ovarian cancer has the highest mortality rate common histological type. The poor prognosis of SOC has among cancers of the reproductive organs and is the fifth been correlated with tumor metastasis and recurrence; there- leading cause of female cancer death in the United States [1]. fore, it is crucial to understand the underlying molecular Despite advances in surgery and chemotherapeutic agents, mechanisms involved in ovarian carcinogenesis and progres- the prognosis for ovarian cancer is poor, with a 5-year sur- sion. 656 Copyright ⓒ 2017 by the Korean Cancer Association │ http://www.e-crt.org │ This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Ga Won Yim, LncRNA HOXA11 Antisense in Serous Ovarian Cancer Long non-coding RNAs (lncRNAs) comprise a heteroge- study focused on the ‘antisense’ strand of the HOXA gene nous group of genomic transcripts longer than 200 cluster, which contains non-coding RNA genes. The 5' region nucleotides that have no protein coding functions [3]. Unlike of the HOXA locus includes three protein-coding genes short non-coding RNAs such as microRNAs, the functional (HOXA9, HOXA10, and HOXA11) and three lncRNAs, HOT- role of lncRNAs have been underestimated since they were TIP, HOXA10as (antisense), and HOXA11as. Since little is initially regarded as transcriptional noise in the genome [4]; known about the function of locally residing lncRNAs, this however, recent data have demonstrated their importance in study was conducted to investigate the role of HOXA11as in normal physiology, as well as in the modulation of various carcinogenesis. biological processes such as cell proliferation, apoptosis, In this study, the expression of HOXA11as in SOC was invasion, and reprogramming of stem cell pluripotency [4]. examined and its clinical significance and correlation to dis- Furthermore, emerging evidence indicates that lncRNA ease prognosis were analyzed. Functional assays were also expression is altered in diverse human cancers, and that its conducted to explore the impact of HOXA11as on cancer cell expression pattern may be associated with cancer progres- invasion and migration in vitro. Finally, since epithelial-mes- sion and metastasis [5-7]. enchymal transition (EMT) is regarded as one of the major Members of the homeobox (HOX) family of genes are mechanisms inducing cancer metastasis, we investigated known to contain transcription factors that contribute to whether HOXA11as was involved in EMT and metastasis in embryogenesis and carcinogenesis [8]. Several studies have SOC. shown dysregulated HOX gene expression in breast, lung, prostate, and colon cancer [9-13]. In humans, HOX genes are located in four different chromosomes, organized into four clusters (A, B, C, and D) [14]. During development of the Materials and Methods female reproductive tract, HOXA11 is expressed in the cervix and lower uterine segment; however, its inappropriate expression is believed to lead to epithelial ovarian neoplasia 1. Patients and tissue samples since it promotes aberrant epithelial differentiation [15,16]. Similarly, the HOXA cluster of protein-coding genes con- A total of 129 SOC tissue samples were obtained from tributes to ovarian embryogenesis and carcinogenesis. This patients who underwent surgery at the Department of Table 1. HOXA11as expression and clinicopathologic variables in serous ovarian cancer patients (n=129) HOXA11as expression Factor p-value Low High Age, median±SD (yr) 54.7±11.4 54.6±8.7 0.971 FIGO stage, n (%) I 6 (5.9) 0 ( 0.463 II 5 (4.9) 0 ( III 68 (66.7) 19 (70.4) IV 23 (22.5) 8 (29.6) Histologic grade, n (%) G1-2 55 (55.6) 8 (29.6) 0.017 G3 44 (44.4) 19 (70.4) Residual disease, n (%) Optimal (residual & 1.0 cm) 88 (56.3) 20 (74.1) 0.146 Suboptimal (residual > 1.0 cm) 14 (13.7) 7 (25.9) Lymph node metastasis, n (%) Absent 35 (34.3) 10 (37.0) 0.792 Present 67 (65.7) 17 (63.0) CA125 level (U/mL) 823.1 (4-30,000) 1,599.5 (15-12,000) 0.048 HOXA11as, HOXA11 antisense; SD, standard deviation; FIGO, International Federation of Gynecology and Obstetrics; CA125, cancer antigen 125. VOLUME 49 NUMBER 3 JULY 2017 657 Cancer Res Treat. 2017;49(3):656-668 Obstetrics and Gynecology, Severance Hospital between titative real time polymerase chain reaction (qRT-PCR), total April 2003 and December 2013. Patients with borderline RNA was reverse transcribed to cDNA using a Reverse Tran- ovarian tumor, concomitant gynecological or other primary scription Reagent Kit (Invitrogen) according to the manufac- cancer, as well as those who had received preoperative turer’s protocols. Real-time PCR analyses were conducted chemotherapy were excluded. Table 1 summarizes the clin- using a SYBR Green Real-time PCR Kit (TOYOBO Co. Ltd., ical information describing the patients. The median dura- Osaka, Japan). Conditions for the amplification of HOXA11as tion of follow-up was 39 months (range, 2 to 116 months) for lncRNA were as follows: initial denaturation at 95°C for 3 survivors. Progression-free survival (PFS) was defined as the minutes, followed by 40 cycles of denaturation at 95°C for 15 interval between the date of surgery and the date of progres- seconds, annealing at 60°C for 60 seconds, and elongation at sion confirmed by imaging studies.
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