Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway

Peng, Wen; Li, Jie; Chen, Ranran; Gu, Qiou; Yang, Peng; Qian, Wenwei; Ji, Dongjian; Wang, Hongtao; Zhang, Zhiyuan; Tang, Junwei; Sun, Yueming

doi:10.1186/s13046-019-1408-4

Cited by 300 publications

(279 citation statements)

References 38 publications

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“…However, METTL3 has recently been reported to play crucial roles through m6A epitranscriptional modification in several common cancers. 43,44 Whether METTL3 affects the progression of HB through a m6A modification pattern remains a subject for further study.…”

Section: Mettl3mentioning

confidence: 99%

Cross talk between RNA N6‐methyladenosine methyltransferase‐like 3 and miR‐186 regulates hepatoblastoma progression through Wnt/β‐catenin signalling pathway

Cui

Wang

et al. 2020

Cell Proliferation

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Objectives N6‐methyladenosine (m6A) is a ubiquitous epigenetic RNA modification that plays a pivotal role in tumour development and metastasis. In this study, we aimed to investigate the expression profiling, clinical significance, biological function and the regulation of m6A‐related genes in hepatoblastoma (HB). Materials and Methods The mRNA and protein expression levels of m6A‐related genes were analysed using Gene Expression Omnibus (GEO) and tissue microarray (TMA) cohort. Kaplan‐Meier analysis was performed to evaluate the prognostic value of m6A‐related genes in HB. Knockdown of m6A‐related genes was conducted to analyse its function on cell proliferation, migration and invasion. Furthermore, bioinformatics analysis and experimental verification were used to explore the potential molecular mechanism and signalling pathway. Results We found that most m6A‐related genes were significantly upregulated in HB tumour tissues. High levels of methyltransferase‐like 3 (METTL3, P = .013), YTHDF2 (P = .037) and FTO (P = .032) indicated poor clinical outcomes, and the upregulation of METTL3 was an independent prognostic factor in HB patients. Functional assays showed that knockdown of METTL3 could dramatically suppress the proliferation, migration and invasion of HB cells. In addition, METTL3 was identified to be a direct target of microRNA‐186 (miR‐186). Consistently, miR‐186 was low expressed in HB tumour tissues. Moreover, overexpression of miR‐186 significantly inhibited cell aggressive phenotype both in vitro and in vivo, while the inhibitory effect could be reversed by METTL3 overexpression. Mechanism study indicated that miR‐186/METTL3 axis contributed to the progression of HB via the Wnt/β‐catenin signalling pathway. Conclusions M6A‐related genes were frequently dysregulated in HB. miR‐186/METTL3/Wnt/β‐catenin axis might serve as novel therapeutic targets and prognostic biomarkers in HB.

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Section: Mettl3mentioning

confidence: 99%

Cross talk between RNA N6‐methyladenosine methyltransferase‐like 3 and miR‐186 regulates hepatoblastoma progression through Wnt/β‐catenin signalling pathway

Cui

Wang

et al. 2020

Cell Proliferation

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“…It has been widely established that migration and invasion are key factors affecting the treatment of various cancers, and are also leading cause of high mortality associated with CRC. 26 Typically, MMP2 and MMP9 mediate degradation of tumor extracellular matrix, and overexpression of these crucial regulators has been reported to facilitate metastasis of malignant tumors. 27 In our present study, transwell migration assay and wound healing assay revealed that DHM remarkably suppresses the invasion and migration of CRC cell lines.…”

Section: Discussionmentioning

confidence: 99%

Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway

Pan

Liu

Wang

et al. 2020

Molecular Carcinogenesis

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Dihydromethysticin (DHM), a natural compound derived from Kava, has been reported to be effective against mental disorders and some malignant tu mors. However, little is known about the inhibitory effect of DHM on colorectal cancer (CRC). First, we examined the impact of DHM on human colon cancer cell lines, which demonstrated that DHM inhibits proliferation, migration, and invasion and promotes apoptosis and cell cycle arrest in colon cancer cells in vitro. Using small hairpin RNA, we inhibited nucleotide-oligomerization domain-like receptor subfamily C3 (NLRC3)/phosphoinositide 3-kinase (PI3K) pathway to elucidate the partial signaling of DHM-mediated tumor suppression. Additionally, using an ectopic human CRC model, we verified whether DHM inhibits tumor growth and angiogenesis via the NLRC3/PI3K pathway in vivo. Overall, DHM showed an inhibitory effect on CRC by altering cell proliferation, migration, invasion, apoptosis, cell cycle, and angiogenesis, possibly via the NLRC3/PI3K pathway. Thus, DHM may be a promising candidate for CRC therapy. K E Y W O R D S colorectal cancer, dihydromethysticin, NLRC3 1 | INTRODUCTION Colorectal cancer (CRC) is third most prevailing malignant tumor in the world. In 2016, approximately 134 490 individuals were diagnosed with CRC in the United States, and it was responsible for mortality of more than one-third. 1 In the past few decades, remarkable progress has been made in the treatment of CRC with variety of chemotherapy drugs and immunotherapies constantly emerging. However, due to drug resistance and dose-limiting toxicity, limited success has been achieved in treating advanced CRC. 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CDK4, cyclin-dependent kinase 4; CK, creatine kinase.; CRC, colorectal cancer; DAPI, 4′, 6-diamidino-2-phenylindole; DHM, dihydromethysticin; H&E staining, hematoxylin and eosin staining; JNK, c-Jun NH2 terminal kinase; LDH, lactate dehydrogenase; MMP2, matrix metallopeptidase 2; MMP9, matrix metallopeptidase 9; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; NLRC3, nucleotide-oligomerization domain-like receptor subfamily C3; PBS, phosphate-buffered saline; PI3K, phosphoinositide 3-kinase; RIPA, radio immunoprecipitation assay; TUNEL, terminal dUTP nick-end labeling; VEGF, vascular endothelial growth factor. Huayang Pan, Fukai Liu, and Jinge Wang contributed equally to this work. Terminal dUTP nick-end labeling (TUNEL) assay was performed according to the manufacturer's instructions (Roche, Shanghai, China). CRC cells were washed once with PBS, fixed with formalin for 30 minutes, and washed again with PBS. Cells were then suspended 576 | PAN ET AL.

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“…Moreover, some specific exosomal microRNAs (miRNAs), including miR-1246, were identified as a biomarker for metastatic colorectal cancer [26][27][28] . In addition, Peng et al demonstrated that miR-1246/SPRED2/MAPK axis played an important role in the progression of CRC 29 . Consistently, our present study showed that miR-1246 was involved in the downregulation of DUSP9 in CRC.…”

Section: Dusp9 Expression Is Silenced Via Promoter Hypermethylation Inmentioning

confidence: 99%

Downregulation of Dual-specificity phosphatase 9 promotes tumor progression and contributes to poor prognosis in colorectal cancer

Qiu¹,

Liang²,

Sun³

et al. 2020

Preprint

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Background Dual-specificity phosphatase 9 (DUSP9) belongs to the dual-specificity protein phosphatase subfamily. Recently, increasing attention has been paid on the role of DUSP9 in a variety of cancers. However, its functional role in tumor development is still unclear, especially in colorectal cancer (CRC). Methods The functional role of DUSP9 in inhibiting the progression of CRC was verified both in vivo and in vitro using colony formation assay, EdU incorporation assay, wound healing assay, nude mice xenograft model, and et al. RNA-seq was performed to assess the gene expression profiling in SW480 cells with DUSP9 stable knockdown and shControl cells. Bisulfite sequencing (BSE) was performed to reveal methylation status of CpG island in promoter of DUSP9. Results DUSP9 was significantly down regulated in tumor tissues compared with peritumor tissues. Moreover, low DUSP9 expression in CRC was closely associated with tumor size, depth of invasion and advanced TNM stage, indicating that DUSP9 may be involved in the progression of CRC. Kaplan–Meier survival analysis showed that the overall survival (OS) and recurrence-free survival (RFS) of patients with low expression of DUSP9 were significantly shorter than that of patients with high expression of DUSP9. Functional study revealed that DUSP9 inhibited tumor migration, invasion and metastasis both in vitro and in vivo . Mechanistically, low expression of DUSP9 in CRC was caused by the upregulation of miR-1246 and hypermethylation status of CpG island in promoter of DUSP9. Conclusion Our findings demonstrate that DUSP9 plays a critical role in the progression of CRC and therapeutic intervention to increase the expression or activity of DUSP9 may be a potential target for CRC treatment in the future.

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Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway

Cited by 300 publications

References 38 publications

Cross talk between RNA N6‐methyladenosine methyltransferase‐like 3 and miR‐186 regulates hepatoblastoma progression through Wnt/β‐catenin signalling pathway

Cross talk between RNA N6‐methyladenosine methyltransferase‐like 3 and miR‐186 regulates hepatoblastoma progression through Wnt/β‐catenin signalling pathway

Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway

Downregulation of Dual-specificity phosphatase 9 promotes tumor progression and contributes to poor prognosis in colorectal cancer

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