KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome

Ma, Gaoxiang; Liu, Hanting; Hua, Qiuhan; Wang, Meilin; Du, Mulong; Lin, Yadi; Ge, Yuqiu; Gong, Weida; Zhao, Qinghong; Fu, Qiang; Tao, Guoquan; Chu, Haiyan

doi:10.1186/s12943-017-0613-z

Cited by 36 publications

(25 citation statements)

References 38 publications

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“…BKCa was revealed as an important molecule in regulating contraction/relaxation of muscle cells [ 8 ], neurotransmission in the brain, and metabolism, proliferation, migration, and gene expression [ 9 ]. Although it has been described in some types of cancer cell, such as osteosarcoma [ 10 ], breast cancer [ 11 ] and gastric cancer [ 12 ], little is known about the functions of BKCa in uterus. BKCa was studied in uterus smooth muscle and was reported that BKCa is over expressed in adenomyosis tissues, and it might cause abnormal muscle contractility that induces the inflammation effects, endometrium impairment and pain [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway

et al. 2018

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BackgroundThe large-conductance, voltage-gated, calcium (Ca (2+))-activated potassium channel (BKCa) plays an important role in regulating Ca (2+) signaling and cell physiological function, and is aberrantly expressed in some types of cancers. The present study focuses on identifying the oncogenic potential and clinical significance of BKCa in endometrial adenocarcinoma, as well as exploring the mechanistic relevance by 17β -estradiol (E2) inducing aberrant activation of MEK1/2 and ERK1/2 via BKCa.MethodsThe expression of BKCa, ERK1/2 and p-ERK1/2 were examined by immunohistochemical staining in 263 cases, including 185 primary types I endometrial cancer tissues, 38 atypical endometrial hyperplasia tissues and 40 normal endometrium tissues. Cell growth, cycle, apoptosis rate, migration and invasion was separately tested in Ishikawa cells using siRNA-BKCa and/or E2 treatment, as well as the expression of these interested proteins by western blot analysis.ResultsWe showed that expression of BKCa is significantly elevated in 185 types I endometrial adenocarcinoma tissues compared to those of the normal endometrium and atypical endometrial hyperplasia tissues. Furthermore, in vitro observations revealed that down-regulation of BKCa expression inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, suppressed cell migration and invasion in Ishakiwa cells, and decreased the expression of p-MEK1/2 and p-ERK1/2. Additionally, RNAi-mediated knockdown of BKCa attenuated the increased cellular growth and invasion, as well as the elevated expression of p-MEK1/2 and p-ERK1/2 proteins, induced by E2 stimulation. More importantly, the aberrant expression of BKCa and p-ERK1/2 were closely related with poor prognostic factors in type I endometrial cancer, and up-regulated expression of p-ERK1/2 was significantly associated with shorter disease-free survival (DFS) and overall survival (OS) and was an independent prognostic factor in type I endometrial cancer patients.ConclusionOur results demonstrated that BKCa and the key downstream effectors p-ERK1/2 could be involved in important signaling pathways in initiation and development of endometrial adenocarcinoma and may provide a new therapeutic approach for women with endometrial cancer.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5027-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway

et al. 2018

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“…The primer sequences of all genes are available in Supporting Table 1. The clinical characteristics of all tissue samples were presented in our previous study . The messenger RNA (mRNA) expression levels of GBAP1 and GBA in GC and adjacent normal tissues were also detected from the Gene Expression Omnibus database (GSE29272, GSE63089, GSE2685).…”

Section: Methodsmentioning

confidence: 99%

A genetic variation in the CpG island of pseudogene GBAP1 promoter is associated with gastric cancer susceptibility

Liu

et al. 2019

Cancer

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Background Previous genome‐wide association studies (GWASs) have identified that several single nucleotide polymorphisms (SNPs) are implicated in gastric cancer (GC) risk. However, the multiple statistical comparisons of GWASs may reject some true biological positives with subthreshold P values. Methods This study annotated the genomic locations of all CpG islands in the genome using the Encyclopedia of DNA Elements (ENCODE). The SNPs in the regions were then genotyped using the Illumina 660W Quad chip. The effects of the prominent variations on GC risk were further confirmed in the other independent cohorts. Results SNP rs2990245, which is located in the promoter of pseudogene GBAP1, was associated with GC risk using GWASs data. An additional cohort of 1275 GC patients and 1424 controls validated that individuals with the CC genotype had a 62% decreased risk of GC compared with those who carried the TT genotype (P = 2.01E‐04) in the codominant model. The significant association was observed in the additive, dominant, and recessive models. A meta‐analysis combining the results from the GWASs and replication studies revealed that rs2990245 was significantly associated with decreased GC risk (P = 5.59E‐12). Importantly, rs2990245 can regulate the expression of GBAP1 by influencing the methylation status of the GBAP1 promoter. GBAP1 can act as a competing endogenous RNA by binding competitively with micro‐RNA‐212‐3p and then promoting GBA expression. Conclusion rs2990245 is significantly associated with a decreased risk of GC. Pseudogene GBAP1 contributes to the development and progression of GC by sequestering the miR‐212‐3p from binding to GBA.

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“…DNA methylation plays an important role in regulation of gene expression. Hypermethylation inhibits gene expression while hypomethylation is associated with gene activation (Irizarry et al, 2009;Thienpont et al, 2016;Ma et al, 2017;Wang et al, 2018). Using TCGA transcriptome profiles (Supplementary Table S3), we explored the association between the four-DNA methylation prognostic signature and gene expression.…”

Section: Association Of the Prognostic Signature With Gene Expressionmentioning

confidence: 99%

“…DNA methylation is a key epigenetic regulatory factor that typically results in gene silencing, playing an important role in cancer initiation and progression (Hattori and Ushijima, 2016;Koch et al, 2018). Numerous studies have shown that promoter hypermethylation is responsible for silencing of cancer tumor suppressor genes (Thienpont et al, 2016;Ma et al, 2017). Hypomethylation of oncogene promoters has also been observed in multiple types of cancer (Irizarry et al, 2009;Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Construction and Validation of Novel Diagnostic and Prognostic DNA Methylation Signatures for Hepatocellular Carcinoma

Shui

Jia

et al. 2020

Front. Genet.

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Hepatocellular carcinoma (HCC) is one of the most prevalent life-threatening human cancers and the leading cause of cancer-related mortality, with increased global incidence within the last decade. Identification of effective diagnostic and prognostic biomarkers would enable reliable risk stratification and efficient screening of highrisk patients, thereby facilitating clinical decision-making. Herein, we performed a comprehensive, robust DNA methylation analysis based on genome-wide DNA methylation profiling. We constructed a diagnostic signature with five DNA methylation markers, which precisely distinguished HCC patients from normal controls. Cox regression and LASSO analysis were applied to construct a prognostic signature with four DNA methylation markers. A one-to-one correlation analysis was carried out between genes of the whole genome and our prognostic signature. Exploration of the biological function and the role of the underlying significantly correlated genes was conducted. A mixed dataset of 463 HCC patients and 253 normal controls, derived from six independent datasets, was used to valid the diagnostic signature. Results showed a specificity of 96.84% and sensitivity of 96.77%. Class scores for the diagnostic signature were significantly different between normal controls, individuals with liver diseases, and HCC patients. The present signature has the potential to serve as a biomarker to monitor health in normal controls. Additionally, HCC patients were successfully separated into low-risk and high-risk groups by the prognostic signature, with a better prognosis for patients in the low-risk group. Kaplan-Meier and ROC analysis confirmed that the prognostic signature performed well. We found eight of the top ten genes to positively correlate with risk scores of the prognostic signature, and to be involved in cell cycle regulation. This eight-gene panel also served as a prognostic signature. The robust evidence presented in this study therefore demonstrates the effectiveness of the prognostic signature. In summary, we constructed diagnostic and prognostic signatures,

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KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome

Cited by 36 publications

References 38 publications

BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway

BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway

A genetic variation in the CpG island of pseudogene GBAP1 promoter is associated with gastric cancer susceptibility

Construction and Validation of Novel Diagnostic and Prognostic DNA Methylation Signatures for Hepatocellular Carcinoma

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