Enhanced Expression of Long Non-Coding RNA HOTAIR Is Associated with the Development of Gastric Cancer

Hiroyuki Endo,Hiroyuki Endo,Kazunori Yamaguchi,Ikuro Sato,Kazuo Sugamura,Katsunori Iijima,Takeharu Shiroki,Misa Yokoyama,Takeharu Shiroki,Tooru Shimosegawa,Takayuki Nakagawa,Kennichi Satoh,Hideaki Yamanami,Tsuneaki Fujiya,Nobuyuki Tanaka,Keiichi Tamai

doi:10.1371/journal.pone.0077070

Hiroyuki Endo, Hiroyuki Endo + Show 14 more

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https://doi.org/10.1371/journal.pone.0077070

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Abstract

The long non-coding RNA HOTAIR has been reported to be a poor prognostic biomarker in a variety of malignant tumors. However, little is known about the association of HOTAIR with gastric cancer. We examined the expression of HOTAIR in 68 gastric cancer samples using quantitative real-time RT-PCR and analyzed its correlation with the clinical parameters. The functional role of HOTAIR was examined by generating human gastric cancer cell lines with increased or suppressed HOTAIR expression. The anchorage -independent growth was assessed by soft agar assay. The increased or suppressed HOTAIR expressing gastric cancer cells were injected into the tail vein or peritoneal cavity of immunodeficient mice to examine the effect of this molecule on metastasis and peritoneal dissemination. The expression of HOTAIR was significantly higher in cancer lesions than in adjacent non-cancerous tissues in human gastric cancers. In the diffuse type of gastric cancer, the High-HOTAIR group (HOTAIR/GAPDH > 1) showed significantly more venous invasion, frequent lymph node metastases and a lower overall survival rate compared to the Low-HOTAIR group (HOTAIR/GAPDH < 1). Colony formation on the soft agar was enhanced in a HOTAIR-dependent manner. HOTAIR-expressing MKN74 formed more liver metastasis compared to control when they were injected into the tail vein of mice. In addition, reduced expression of HOTAIR in KATO III suppressed peritoneal dissemination. These results suggest that HOTAIR plays a pivotal role in the development of gastric cancer.

Highlights

The incidence and mortality of gastric cancer have decreased dramatically over the past 50 years in most areas of the world, but it still remains the second leading cause of cancer-related deaths worldwide [1]
We investigated the expression of HOTAIR in gastric cancer and examine its correlation with the clinicopathological features including patients’ prognosis
Our results clearly revealed enhanced expression of HOTAIR in cancer tissues compared to non-cancerous tissues of the stomach and that the high level expression of this molecule was associated with lymph node metastasis, venous invasion and poor survival in the diffuse type of gastric cancer

Summary

Introduction

The incidence and mortality of gastric cancer have decreased dramatically over the past 50 years in most areas of the world, but it still remains the second leading cause of cancer-related deaths worldwide [1]. The genome sequencing projects revealed that the human genome is comprised of less than 2% protein coding genes, and more than 90% of the genome is transcribed as noncoding RNAs (ncRNA) [5,6,7]. These ncRNAs are classified into two groups depending on the nucleotide size. We investigated the involvement of HOTAIR in human gastric cancer development and examined whether its expression would correlate with the aggressive behavior of gastric cancer

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Conclusion