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Long noncoding RNA ARHGAP27P1 inhibits gastric cancer cell proliferation and cell cycle progression through epigenetically regulating p15 and p16.

ABSTRACT: Long noncoding RNAs (lncRNAs) have emerged as important regulators in the development and progression of gastric cancer (GC). ARHGAP27P1 is a pseudogene-derived lncRNA, and it has been found to be associated with GC in our preliminary study, but this association has not been studied further. Herein, we confirmed that ARHGAP27P1 was significantly downregulated in GC tissues, plasma and cells. Low expression of ARHGAP27P1 was closely associated with advanced TNM stage, increased invasion depth and lymphatic metastasis. Low ARHGAP27P1 expression also predicted a poor prognosis in GC patients. Functionally, overexpression of ARHGAP27P1 inhibited proliferation, invasion, and migration in GC cells, while silencing of ARHGAP27P1 showed the opposite effects. Mechanistic investigations showed that ARHGAP27P1 had a key role in G0/G1 arrest. We further demonstrated that ARHGAP27P1 was associated with Jumonji-domain containing 3 (JMJD3) and that this association was required for the demethylation of H3K27me3, thereby epigenetically activating expression of p15, p16 and p57. Moreover, knockdown of JMJD3, p15, or p16 consistently reversed the inhibitory effects of ARHGAP27P1 in cell proliferation and cell cycle progression. Taken together, these results suggest that lncRNA ARHGAP27P1, as a novel cell cycle regulator, may serve as a potential target for GC prevention and treatment in human GC.

SUBMITTER: Zhang G

PROVIDER: S-EPMC6834409 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Long noncoding RNA ARHGAP27P1 inhibits gastric cancer cell proliferation and cell cycle progression through epigenetically regulating p15 and p16.

Zhang Guohua G Xu Ying Y Zou Chen C Tang Yinbing Y Lu Jiawei J Gong Zhigang Z Ma Gui G Zhang Wenbo W Jiang Pengcheng P

Aging 20191030 20

Long noncoding RNAs (lncRNAs) have emerged as important regulators in the development and progression of gastric cancer (GC). ARHGAP27P1 is a pseudogene-derived lncRNA, and it has been found to be associated with GC in our preliminary study, but this association has not been studied further. Herein, we confirmed that ARHGAP27P1 was significantly downregulated in GC tissues, plasma and cells. Low expression of ARHGAP27P1 was closely associated with advanced TNM stage, increased invasion depth and ...[more]

PMID: 31665700

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Project description:BackgroundGastric carcinoma (GC) is a digestive system disease with high morbidity and mortality. However, early clinical detection is difficult, and the therapeutic effect for advanced disease is not satisfactory. Thus, finding new tumor markers and therapeutic targets conducive to the treatment of GC is imperative. MRPL35 is a member of the large subunit family of mitochondrial ribosomal protein. MRPL35 shows the characteristic of oncogene in colorectal cancer and esophageal cancer, which promotes the exploration of the correlation between MRPL35 and GC. We proposed that the expression of MRPL35 might be critical in GC.AimTo study the effect of MRPL35 knockdown on GC cell proliferation.MethodsThe expression of MRPL35 in GC was evaluated based on data from the public tumor database UALCAN (www.ualcan.path.uab.edu). The effect of the expression of MRPL35 on the prognosis was evaluated with KMplot (www.kmplot.com). The expression of MRPL35 was assessed on the tissue microarray by immunohistochemistry and the level of MRPL35 mRNA in 25 pairs of clinical GC tissues and matched adjacent tissues was detected by quantitative reverse transcription-polymerase chain reaction. Celigo cell count assay, colony formation assay, and flow cytometry were used to assess the role of MRPL35 in GC cell proliferation and apoptosis in vitro. Additionally, tumor formation experiment in BALB/c nude mice was utilized to determine the effect of MRPL35 on GC cell proliferation. After knockdown of MRPL35, related proteins were identified by isobaric tags for relative and absolute quantification analysis, and the expression of related proteins was detected by Western blot.ResultsThe expression of MRPL35 was up-regulated in GC (P = 1.77 × 10-4). The Kaplan-Meier plots of the overall survival indicated that high expression of MRPL35 was associated with a poor survival in GC. Compared with adjacent tissues, the expression of MRPL35 in GC tissues was increased, which was related to age (P = 0.03), lymph node metastasis (P = 0.007), and pathological tumor-node-metastasis stage (P = 0.024). Knockdown of MRPL35 inhibited GC cell proliferation and colony formation and induced apoptosis. Animal experiment results showed that knockdown of MRPL35 inhibited tumor formation in BALB/c nude mice. Western blotting analysis showed that after knockdown of MRPL35, the expression of PICK1 and BCL-XL proteins decreased, and that of AGR2 protein increased.ConclusionCollectively, our findings demonstrate that knockdown of MRPL35 inhibits GC cell proliferation through related proteins including PICK1, BCL-XL, and AGR2.

Dataset Information

Long noncoding RNA ARHGAP27P1 inhibits gastric cancer cell proliferation and cell cycle progression through epigenetically regulating p15 and p16.

Publications

Long noncoding RNA ARHGAP27P1 inhibits gastric cancer cell proliferation and cell cycle progression through epigenetically regulating p15 and p16.

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