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Upregulation of Homeobox Gene Is Correlated with Poor Survival Outcomes in Cervical Cancer

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Upregulation of Homeobox Gene Is Correlated with Poor Survival Outcomes in Cervical Cancer www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 48), pp: 84396-84402 Research Paper Upregulation of homeobox gene is correlated with poor survival outcomes in cervical cancer Kyung Jin Eoh1, Hee Jung Kim1, Jung-Yun Lee1, Eun Ji Nam1, Sunghoon Kim1, Sang Wun Kim1 and Young Tae Kim1 1Institute of Women’s Medical Life Science, Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Korea Correspondence to: Young Tae Kim, email: [email protected] Keywords: cervical cancer, homeobox genes, survival, TCGA, biomarker Received: July 20, 2017 Accepted: August 09, 2017 Published: September 16, 2017 Copyright: Eoh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT HOX family members encode transcription factors crucial for embryogenesis and may be associated with carcinogenesis. Here, we evaluated the expression of 39 HOX genes in cervical cancer by using clinicopathological information and gene expression data of 308 patients from The Cancer Genome Atlas (TCGA) database. Correlations between mRNA expression of HOX family members and clinicopathological variables were explored. Seventy-three (23.7%) patients died during the follow-up period (median, 22.0 months). Overall mortality was significantly associated with advanced FIGO stage, lymph node metastasis, lymphovascular invasion, and increased HOXA1, HOXA5, HOXA6, and HOXC11 mRNA expression. Kaplan–Meier survival analysis revealed that overall survival was significantly shorter in patients with high HOXA rather than low HOXA expression (HOXA1, P = 0.012; HOXA5, P = 0.008; and HOXA6, P = 0.006). Upregulated HOXA1, HOXA5, and HOXA6 expression are significantly correlated with unfavorable overall survival and increased mortality in cervical cancer patients. Therefore, HOXA expression is a potential cervical cancer prognostic indicator. INTRODUCTION commonly share a 120-base pair DNA sequence called the homeobox, which codes a 61-amino acid peptide termed Cervical cancer is a multifactorial disease caused as the homeodomain. This domain has been characterized due to genetic, environmental, and epigenetic factors, as previously using nuclear magnetic resonance spectroscopy well as infection by human papillomavirus [1]. Recently, [6, 7]. HOX genes and their protein structures have also alterations in the expression of transcription factors have been found in humans [8, 9]. In the human genome, there been focused upon for its importance in the development are 39 HOX genes located on four different chromosomes, of this malignancy. and these genes are the structural and functional homologs A large amount of scientific evidence indicates that of the homeotic complex of Drosophila [10]. the expression levels of many genes involved in normal Previous studies have reported that upregulation of embryo development are aberrant in and contribute to the HOX gene is related to adverse prognostic factors in carcinogenesis [2]. Homeobox (HOX) genes encode cervical cancer, but the majority of these studies have been homeoproteins, which function as transcription factors limited by small sample sizes and have been performed in the differentiation and proliferation processes at the only in vitro. Aberrant expression of HOXD9, HOXC5, time of development of embryonic structures, and their HOXC8, and HOXB2, HOXB4, HOXC10, and HOXD13 aberrant expression has been found to be associated with has been found in cervical cancer cell lines [11–13]. A carcinogenesis and aggressiveness [3, 4]. HOX genes recent study focused on the mechanism of HPV16 E7- were first described as factors involved in embryogenesis mediated epigenetic regulation of HOX genes showed in the fruit fly, Drosophila melanogaster [5]. HOX genes the master regulatory role of HPV16 E7 in modulating www.impactjournals.com/oncotarget 84396 Oncotarget the expression of HOX cluster genes [14]. Several studies expression levels had significantly unfavorable overall have also revealed the potential roles of HOX antisense survival than those with a lower level of expression long non-coding RNAs in cervical cancer aggressiveness of these genes (P = 0.012, P = 0.008, and P = 0.006, [15–17]. These results suggest that aberrant expression respectively) (Figure 1). of HOX-related genes is associated with the process of cervical carcinogenesis. DISCUSSION Therefore, in this study, we aimed to analyze the mRNA expression levels of all the 39 HOX genes using In this study, we showed that the increased mRNA data from The Cancer Genome Atlas (TCGA) database expression of four HOX genes—HOXA1, HOXA5, [18]. We then went on to explore their correlations with HOXA6, and HOXC11—is independently associated with clinical data including survival outcomes in cervical mortality in cervical cancer based on data from TCGA cancer and evaluated the prognostic value of HOX gene [18]. Several HOX genes were shown to be correlated expression analysis. To the best of our knowledge, this is with risk factors for poor prognoses including advanced the first study to analyze the expression of all HOX genes FIGO stage, high grade, lymph node metastasis, and using data from the TCGA database. Our findings indicate lymphovascular invasion. Interestingly, high expression that measurement of HOX gene expression can help of most of the HOX genes was found to be strongly predict prognosis and overall survival in cervical cancer. associated with squamous cell type histology. In particular, the upregulation of the HOXA1, HOXA5, and HOXA6 RESULTS genes were found to be significantly associated with unfavorable overall survival in patients with cervical A total of 308 cervical cancer cases were included cancer. in this study; of these, 253 were squamous cell carcinoma, Cancers have been revealed as aberrations in 28 adenocarcinomas, 17 mucinous carcinomas, three the growth, differentiation, and organization of cell endometrioid carcinomas, and seven adenosquamous populations [19]. These basic processes are supposed to be carcinoma cases. The median follow-up period was tightly coordinated and controlled during embryogenesis 22.0 months (range: 0.1–213.6 months). Among the as well as in adult tissues [20]. The oncogerminative clinicopathological features, overall mortality was found theory of cancer development suggests that malignant to be associated with FIGO stage III/IV, lymph node transformation occurs due to the aberrant expression of metastasis, and lymphovascular invasion (Table 1). development-related genes [21]. According to this concept, Table 2 shows the correlations between the carcinogenesis is a dynamic self-organizing process that clinicopathological features and the mRNA expression resembles the process of early embryo development. The levels of HOX family genes. When the cases were malignant transformation that arises from gene mutations categorized into low and high mRNA expression groups in combination with epigenetic dysregulation eventually based on cut-off values determined as medians for each results in reprogramming of somatic cells into immortal gene, higher HOXA1, HOXA5, HOXA6, and HOXC11 cells that simulate germline cells, which is consistent with expression was found to be associated with increased the characteristics of cancer stem cells or, in other words, overall mortality (odds ratio (OR): 1.858, 95% confidence oncogerminative cells. interval (CI): 1.086–3.178; OR: 2.003, 95% CI: 1.167– As a developing malignant transformation, the 3.438; OR: 2.162, 95% CI: 1.256–3.724; and OR: 1.724, oncogerminative cell is considered to follow the same 95% CI: 1.011–2.942, respectively). High FIGO stage biological principles as those in play in a germline cell also highly correlated with high HOXB7 expression, as it develops into a blastocyst-stage embryo [21]. and lymph node metastasis was found to be associated The oncogerminative theory of cancer development with high HOXD12 and HOXD13 expression (P < 0.01). hypothesizes that to have a cancer is the same as Moreover, squamous cell histologic type was found to gestating a damaging embryo. This oncogerminative be highly correlated with high expression of HOXA1, hypothesis of tumor growth includes five stages of tumor HOXA4, HOXA7, HOXA9, HOXB2, HOXB3, HOXB5–9, development: (i) malignant transformation of normal cells HOXC4, HOXC5, HOXC13, HOXD1, HOXD9, HOXD10, into oncogerminative cells, i.e. cancer stem cells; (ii) HOXD11, and HOXD13 (P < 0.001). reproduction of the oncogerminative cells; (iii) formation Linear regression analysis indicated that overall of a multicellular spheroid (a parody of blastocyst mortality was significantly associated with high mRNA formation) characterized by a heterogeneous population expression levels of HOXA1 (t = 3.033, P = 0.003) (Table of cells in addition to the oncogerminative cells; (iv) 3). High expression of the HOXA1 gene was also found to vascularization of the oncospheroid and its growth; and (v) be positively correlated with squamous cell histologic type development of the majority of malignant tumors together and lymph node metastasis. with disaggregation of the oncogerminative cells, their In Kaplan–Meier survival analyses, we found that migration into the organism’s tissues, and development of groups with higher HOXA1, HOXA5, and HOXA6 mRNA metastatic foci of tumor growth [22]. www.impactjournals.com/oncotarget 84397 Oncotarget
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