Long noncoding RNA HOTTIP overexpression: A potential prognostic biomarker in prostate cancer

https://doi.org/10.1016/j.prp.2019.152649Get rights and content

Abstract

HOXA transcript at the distal tip (HOTTIP) is a long noncoding RNA (lncRNA), which is >200 nucleotides in length. HOTTIP expression has been demonstrated to play a crucial oncogenic role in cancer pathogenesis, and is said to be associated with poor human cancer prognosis. In prostate cancer, HOTTIP has been identified as an oncogene, but its clinicopathologic significance remains unclear. Array-based qRT-PCR was used to investigate lncRNA levels in 10 pairs of prostate cancer tissues and non-neoplastic parenchyma. Tissue microarray (TMA) was constructed using a total of 70 surgically resected prostatic adenocarcinoma tissues obtained from the Korea University Anam Hospital from 2009 to 2013. HOTTIP expression was determined by RNA in situ hybridization(ISH) and was correlated with clinicopathologic features. Increased HOTTIP expression was observed in all available prostate cancer tissue specimens compared with that in paired normal tissue. High HOTTIP expression was positively associated with bad clinicopathologic features, including higher pathologic T stage (p < 0.001), presence of extraprostatic extension (p < 0.001), seminal vesicle invasion (p < 0.001), perineural invasion (p < 0.001), and the tumor involvement of resection margin (p = 0.044). In particular, significantly increased HOTTIP expression was observed in specimens from patients in the high or very high-risk group, according to the 2018 National Comprehensive Cancer Network (NCCN) guidelines (p < 0.001). Also, patients with high HOTTIP expression showed poorer overall survival than those with low expression. In conclusion, we analytically validated the poor prognostic significance of HOTTIP overexpression and its association with bad clinicopathologic features, and present HOTTIP as a potential prognostic biomarker in prostate cancer.

Introduction

Due to recent technological advances with respect to researching human genomes, including next-generation sequencing, it has been evidenced that the human genome is much more complex than previously expected. Long noncoding RNA (lncRNA) is a group of non-protein-coding RNA molecules, >200 nucleotides in length [1]. An increasing number of cancer-related lncRNAs are being recognized as significant contributors to human carcinogenesis and malignancy and as potential oncogenes or tumor suppressors [2]. However, few studies have functionally characterized and clinically validated the importance of dysregulated lncRNAs in vitro [[3], [4], [5], [6]].

The lncRNA, ‘HOXA transcript at the distal tip’ (HOTTIP), has been identified to be associated with the human homeobox loci [4], and coordinates the activation of multiple 5’ homeobox A genes in vivo [7]. HOTTIP expression has been demonstrated to regulate genes by various mechanisms and to be significantly upregulated in many human cancers; so it seems that it plays a crucial role in cancer pathogenesis [[7], [8], [9]]. Many articles have suggested that HOTTIP expression is associated with poor prognosis of human cancers, and implied its important oncogenic role in cancer pathogenesis [8,10,11]. Recently, more studies have revealed HOTTIP as a potential prognostic biomarker for various human cancers [2,[12], [13], [14], [15], [16], [17]].

Prostate cancer is one of the common causes of cancer morbidity and mortality among the male population worldwide [18]. The initiation and aggravation of prostate cancer include complex and dynamic biological processes, involving various genomic and epigenetic changes. Some studies have demonstrated that aberrant expression of individual lncRNAs in prostate cancer is related to disease progression, and have attempted to investigate lncRNAs specific to prostate cancer [3,19].

The functional role of HOTTIP, as an oncogene, has been identified [4], but its clinicopathologic significance remains unclear. This study was aimed to investigate HOTTIP expression in human prostate cancer tissues, and clarify the association between HOTTIP expression and clinicopathologic features.

Section snippets

Sample collection and tissue microarray construction

Tissue microarray (TMA) was constructed with prostate cancer tissue specimens from 70 patients. These samples had been collected by radical prostatectomy at the Korea University Anam hospital from 2009 to 2013. Patients who were diagnosed with other cancers or who received other treatment before operation were excluded. Total 70 cases were selected, which had enough formalin-fixed paraffin embedded tissue block to make tissue microarray. Patients classified as pathologically acinar

Clinicopathologic characteristics of the cases

Clinicopathologic data were collected retrospectively, and the findings are shown in Table 1. The median age was 64 years (range: 49–76). The average serum PSA level was 11.35 ng/mL (range: 3.34–45.91 ng/mL). 34 cases (48.6%) were classified as high-risk or very high-risk according to the 2018 NCCN guidelines, while 36 cases (51.4%) were low-risk. A total of eighteen cases (25.7%) had a Gleason score 6 or less, 46 cases (65.7%) had a Gleason score 7, and 6 cases (8.6%) had a Gleason score 8 or

Discussion

Protein-encoding genes account for only 1.5% of the total genome, while the rest, called noncoding regions, do not encode proteins. As many biological processes at the transcriptional and posttranscriptional level cannot be explained only by protein-coding genes, it has been suggested that lncRNAs participate in various cellular processes and their dysregulation contributes to the development of various diseases, especially tumor development [8,22].

HOTTIP is a lncRNA found to have significant

Conclusions

In conclusion, we analytically validated the poor prognostic significance and association with bad clinicopathologic features of HOTTIP overexpression, and present it as a potential prognostic biomarker in prostate cancer.

Funding

This work was supported by Korea University R&D research fund, Seoul, Republic of Korea (grant number K1325501).

Declaration of Competing Interest

None.

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