Identification of MST1 as a potential early detection biomarker for colorectal cancer through a proteomic approach

Yu, Jian; Zhai, Xiaoqiang; Li, Xiaofen; Zhong, Chenhan; Guo, Cheng; Yang, Fuquan; Yuan, Ying; Zheng, Shu

doi:10.1038/s41598-017-14539-x

Cited by 48 publications

(32 citation statements)

References 48 publications

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“…A previous study concluded that MST1 and cyclophilin D expressions were notably reduced in gemcitabine-resistant pancreatic cancer tissues and cell lines (24). MST1 was also found to be elevated in control patients compared with patients with stage I colorectal cancer during early colorectal cancer examinations (26). MST1 could also be activated by gemcitabine, making it capable of facilitating cancer cell death by means of complexation with mitochondrial protein cyclophilin D (24).…”

Section: Discussionmentioning

confidence: 99%

Poor expression of microRNA‐135b results in the inhibition of cisplatin resistance and proliferation and induces the apoptosis of gastric cancer cells through MST1‐mediated MAPK signaling pathway

Zhou

Chen

2018

FASEB j.

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Gastric cancer (GC) has been classified as the fourth leading cause of cancer‐related deaths worldwide. Due to their ability to suppress the expression of target genes, microRNAs (miRNAs) are listed as one of the key elements involved in the formation and development of tumors. This study was therefore conducted to investigate the effects of microRNA‐135b (miR‐135b) on cisplatin [ds‐diamminedichloroplatinum (CDDP)] resistance of GC cells through the MAPK signaling pathway by targeting mammalian ste20‐like kinase 1 (MST1). A microarray‐based gene expression analysis was performed to screen the GC‐related differentially expressed genes. The 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide assay was performed to determine the sensitivity of GC cells to CDDP. The bioinformatics database and dual lucif erase reporter gene assay were used to check whether MST1 was a direct target gene of miR‐135b. GC cell lines were prepared with high CDDP resistance, after which they were cultured and transfected respectively, followed by the administration of transfected cells into nude mice and subsequent treatment with CDDP in an attempt to identify the underlying mechanisms and functions of miR‐135b in relation to MST1 in GC progression. The results were highly indicative of the crucial role played by MST1 in the development of GC and the sensitivity of GC to CDDP. miR‐135b was found to regulate MST1, which in turn had an impact on the development of GC. MKN28 was observed to be most sensitive to CDDP, whereas MKN45 presented with the poorest sensitivity to CDDP. Furthermore, the down‐regulation of miR‐135b resulted in inactivation of the MAPK signaling pathway; increased the expression of MST1 and Bax; and decreased expression of p‐p38MAPK, p‐ERKl/2, P‐glycoprotein, p38MAPK, ERK1/2, multidrug resistance protein 1, multidrug resistance‐associated protein 1, lung resistance‐related protein, and Bcl‐2, thus inhibiting CDDP resistance of GC cells. The down‐regulation of miR‐135b also restrained cell proliferation and induced the apoptosis rate of GC cells. In summary, the results of this study showed that the down‐regulation of miR‐135b induced apoptosis, and it inhibited proliferation and CDDP resistance of GC cells by inactivating the MAPK signaling pathway and increasing the expression of MST1.—Zhou, J., Chen, Q. Poor expression of microRNA‐135b results in the inhibition of cisplatin resistance and proliferation and induces the apoptosis of gastric cancer cells through MST1‐mediated MAPK signaling pathway. FASEB J. 33, 3420–3436 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Poor expression of microRNA‐135b results in the inhibition of cisplatin resistance and proliferation and induces the apoptosis of gastric cancer cells through MST1‐mediated MAPK signaling pathway

Zhou

Chen

2018

FASEB j.

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“…Our findings are consistent with those already reported in the literature for other cancers, such as breast cancer, 29 hepatocellular carcinoma, 30 and colorectal cancer. 31 …”

Section: Discussionmentioning

confidence: 99%

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial

et al. 2019

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BACKGROUND: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation. METHODS: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines. RESULTS: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines. CONCLUSIONS: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.

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“…Mst1 is a downstream factor of the Hippo pathway, which has been implicated in several pathological processes, including diabetic cardiomyopathy, osteoblast differentiation ( 45 ) and milk fat metabolism disorder ( 46 ). Furthermore, Mst1 downregulation has been identified as a potential early detection biomarker for numerous types of cancer, including colorectal cancer ( 47 ), breast cancer ( 48 ), pancreatic cancer ( 49 ), lung cancer ( 50 ) and liver cancer. At the molecular level, Mst1 has been reported to be associated with the ER stress response ( 51 ), cellular oxidative stress ( 52 ), epithelial-to-mesenchymal transition ( 53 ), transforming growth factor β-mediated tissue fibrosis ( 54 ) and mitophagy ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

Mst1 regulates non-small cell lung cancer A549 cell apoptosis by inducing mitochondrial damage via ROCK1/F‑actin pathways

et al. 2018

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Mammalian STE20-like kinase 1 (Mst1) is well recognized as a major tumor suppressor in cancer development, growth, metabolic reprogramming, metastasis, cell death and recurrence. However, the roles of Mst1 in non-small cell lung cancer (NSCLC) A549 cell phenotypic alterations remain to be elucidated. The present study aimed to explore the functional role and underlying mechanisms of Mst1 with regards to A549 cell proliferation, migration and apoptosis; this study focused on mitochondrial homeostasis and Rho-associated coiled-coil containing protein kinase 1 (ROCK1)/F-actin pathways. The results demonstrated that Mst1 was downregulated in A549 cells compared with in a normal pulmonary epithelial cell line. Subsequently, overexpression of Mst1 in A549 cells reduced cell viability and promoted cell apoptosis. Furthermore, overexpression of Mst1 suppressed A549 cell proliferation and migration. At the molecular level, the reintroduction of Mst1 in A549 cells led to activation of mitochondrial apoptosis, as evidenced by a reduction in mitochondrial potential, overproduction of ROS, cytochrome c release from the mitochondria into the nucleus, and upregulation of pro-apoptotic protein expression. In addition, Mst1 overexpression was closely associated with impaired mitochondrial respiratory function and suppressed cellular energy metabolism. Functional studies illustrated that Mst1 overexpression activated ROCK1/F-actin pathways, which highly regulate mitochondrial function. Inhibition of ROCK1/F-actin pathways in A549 cells sustained mitochondrial homeostasis, alleviated caspase-9-dependent mitochondrial apoptosis, enhanced cancer cell migration and increased cell proliferation. In conclusion, these data firmly established the regulatory role of Mst1 in NSCLC A549 cell survival via the modulation of ROCK1/F-actin pathways, which may provide opportunities for novel treatment modalities in clinical practice.

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Identification of MST1 as a potential early detection biomarker for colorectal cancer through a proteomic approach

Cited by 48 publications

References 48 publications

Poor expression of microRNA‐135b results in the inhibition of cisplatin resistance and proliferation and induces the apoptosis of gastric cancer cells through MST1‐mediated MAPK signaling pathway

Poor expression of microRNA‐135b results in the inhibition of cisplatin resistance and proliferation and induces the apoptosis of gastric cancer cells through MST1‐mediated MAPK signaling pathway

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial

Mst1 regulates non-small cell lung cancer A549 cell apoptosis by inducing mitochondrial damage via ROCK1/F‑actin pathways

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