Abstract
This study was aimed at understanding the functional and clinicopathological significance of MAPK15 alteration in gastric cancer. Genome-wide copy number alterations (CNAs) were first investigated in 40 gastric cancers using Agilent aCGH-244K or aCGH-400K, and copy number gains of MAPK15 found in aCGH were validated in another set of 48 gastric cancer tissues. The expression of MAPK15 was analyzed using immunohistochemistry in concurrent lesions of normal, adenoma, and carcinoma from additional 45 gastric cancer patients. The effects of MAPK15 on cell cycle, c-Jun phosphorylation, and mRNA stability were analyzed in gastric cancer cells. Copy number gains of MAPK15 were found in 15 (17%) of 88 tumor tissues. The mRNA levels of MAPK15 were relatively high in the gastric cancer tissues and gastric cancer cells with higher copy number gains than those without. Knockdown of MAPK15 using siRNA in gastric cancer cells significantly suppressed cell proliferation and resulted in cell cycle arrest at G1-S phase. Reduced c-Jun phosphorylation and c-Jun half-life were observed in MAPK15-knockdowned cells. In addition, transient transfection of MAPK15 into AGS gastric cancer cells with low copy number resulted in an increase of c-Jun phosphorylation and stability. The overexpression of MAPK15 occurred at a high frequency in carcinomas (37%) compared to concurrent normal tissues (2%) and adenomas (21%). In conclusion, the present study suggests that MAPK15 overexpression may contribute to the malignant transformation of gastric mucosa by prolonging the stability of c-Jun. And, patients with copy number gain of MAPK15 in normal or premalignant tissues of stomach may have a chance to progress to invasive cancer.
Highlights
Gastric cancer is the third leading cause of cancer deaths worldwide despite a rapid decline in its incidence over the recent few decades
We validated the copy number alterations (CNAs) of MAPK15 obtained from the array comparative genomic hybridization (aCGH)
DNA copy number of MAPK15 in six samples (268-1, 271-1, 272-2, 301-1, 685-1 and 685-2) with available tumor and matched normal tissues among the 40 samples was analyzed by multiplex ligation-dependent probe amplification (MLPA) (Figure 2)
Summary
Gastric cancer is the third leading cause of cancer deaths worldwide despite a rapid decline in its incidence over the recent few decades. The past few years have witnessed major advances in the early detection and multimodality therapeutic approach in patients with gastric cancer. Five-year survival rates of gastric cancer patients reach below 30% in most countries [1]. It is important to identify new biomarkers for the early detection and targeted therapy of patients with gastric www.impactjournals.com/oncotarget cancer. DNA copy number alteration (CNA) defined as DNA segments that are 1 kb or larger in size, is an important type of genetic alteration observed in cancer cells [2]. We investigated CNAs in 40 gastric cancers using array comparative genomic hybridization (aCGH) and identified frequent copy number gains at 8q24.3. Several other studies have revealed high-level copy number gains at 8q24 in gastric cancers [4,5,6,7]. A number of genes (PLEC1, GPAA1, SHARPIN, BOP1, HSF1, SLC39A4, RECQL4) in this region were reported to play an oncogenic role [8,9,10,11,12,13,14], whereas genes such as SCRIB, PUF60, and PARP10 were reported to play a suppressive role in the tumorigenesis of human cancers [15,16,17]
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