Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis

Abstract

The prognosis of gastric cancer (GC) patients with peritoneal dissemination remains poor, and a better understanding of the underlying mechanisms is critical for the development of new treatments that will improve survival in these patients. This study aimed to clarify the clinical and biological role of two key metastasis-associated long non-coding RNAs (lncRNAs) in GC. We analyzed the expression levels of two lncRNAs-Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX-Antisense Intergenic RNA (HOTAIR)-by real-time reverse transcription PCR in 300 gastric tissues (150 GC and 150 adjacent normal mucosa), and in seven GC cell lines. Functional characterization for the role of HOTAIR in GC was performed by small interfering RNA (siRNA) knockdown, followed by series of in-vitro and in-vivo experiments. Expression of both lncRNAs was significantly higher in cancerous tissues than in corresponding normal mucosa, and higher expression of these lncRNAs significantly correlated with peritoneal metastasis in GC patients. In addition, elevated HOTAIR expression emerged both as an independent prognostic and risk factor for peritoneal dissemination. SiRNA knockdown of HOTAIR in GC cells significantly inhibited cell proliferation, migration and invasion, but concurrently enhanced the anoikis rate in transfected cells. In an in vivo assay, HOTAIR siRNA-transfected MKN45 cells injected into nude mice inhibited the growth of xenograft tumors and peritoneal metastasis compared with controls. Our data provide novel evidence for the biological and clinical significance of HOTAIR expression as a potential biomarker for identifying patients with peritoneal metastasis, and as a novel therapeutic target in patients with gastric neoplasia.

Functional annotation of noncoding variants and prioritization of cancer-associated lncRNAs in lung cancer

“…Based on these findings, the present study combined the fraction of high-scoring regions and average score of each lncRNA to filter out a subset of functional lncRNA candidates, which contained a number of well-characterized cancer lncRNAs, for example, HOTAIR, the expression of which is elevated in lung cancer and correlated with metastasis and poor prognosis (54). MALAT1 has been implicated in tumorigenesis and progression in a variety of cancer types (55)(56)(57). A total of 104 functional lncRNA candidates were are differentially expressed in lung cancer and normal samples.…”

Novel insight into MALAT-1 in cancer: Therapeutic targets and clinical applications

“…A study conducted by Okugawa et al illustrated that the expression levels of both MALAT-1 and HOX transcript antisense RNA were significantly increased in GC tissues compared with matching adjacent normal mucosa (82). Elevated MALAT-1 expression significantly correlated with peritoneal dissemination.…”

Epigenetic modulation associated with carcinogenesis and prognosis of human gastric cancer

“…Previously, lncRNA was thought to be 'junk nucleotides', but recent evidence indicates that lncRNA is as important in epigenetic modulation as miRNA (74). Aberrant expression of certain types of lncRNA has been associated with poorer prognosis in breast cancer (75), hepatocellular carcinoma (76) and lung carcinoma (77); and it has recently been demonstrated to possess clinical significance in GC (78)(79)(80)(81)(82)(83)(84)(85) (Table III). lncRNA in plasma is reportedly detectable in patients with GC, as with miRNA (86).…”