LAMC2 modulates the acidity of microenvironments to promote invasion and migration of pancreatic cancer cells via regulating AKT-dependent NHE1 activity

Wang, Hui; Cai, Jin; Du, Shaoxia; Wei, Wei; Shen, Xiaohong

doi:10.1016/j.yexcr.2020.111984

Cited by 33 publications

(30 citation statements)

References 36 publications

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“…Moreover, some subsequent studies indicated that miR-652 participated in the acidity-induced metastasis of PC by directly regulating the expression of zinc finger E-box binding homeobox 1, which was the key transcription factor for EMT 14 . Another study showed that laminin subunit gamma 2 promoted the expression and activity of Na + /H + exchanger 1, which exaggerated extracellular acidification to induce dynamic actin-dependent EMT and invasion in PC cells 15 . Although preliminary investigations on the acidity-induced metastasis of PC were performed, more precise studies are still needed to explore novel targets for the therapeutic treatment of PC.…”

Section: Introductionmentioning

confidence: 99%

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer

Wang

et al. 2020

Theranostics

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Rationale: Previous studies have reported on the role of extracellular acidity in the metastasis of numerous cancers. However, the involvement of long noncoding RNA (lncRNA) in the extracellular acidity-induced cancer metastasis of pancreatic cancer (PC) remains unclear. Methods: Different expression levels of lncRNAs in PC cells under normal and acidic conditions were compared by RNA sequencing (RNA-seq). The effects of antisense lncRNA of metastasis suppressor 1 (MTSS1-AS) on acidic PC cells were assessed by gain- and loss-of-function experiments. Fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, Western blot, luciferase reporter, and Chromatin immunoprecipitation assays were employed to determine the regulatory mechanisms of MTSS1-AS in the acidity-induced metastasis of PC cells. The expression of MTSS1-AS and associated pathways were compared in PC samples and peritumoral normal tissues. Results: RNA-seq demonstrated that MTSS1-AS was significantly downregulated in pancreatic cells cultured with the acidic medium. The overexpression of MTSS1-AS remarkably inhibited the acidity-promoted metastasis of PC cells by upregulating the expression of its sense gene metastasis suppressor 1 (MTSS1). Mechanistically, MTSS1-AS scaffolded the interaction between E3 ubiquitin-protein ligase STIP1 homology and U-box containing protein 1 (STUB1) and transcription regulator myeloid zinc finger 1 (MZF1), leading to ubiquitination-mediated degradation of MZF1. Further, MZF1 inhibited the expression of MTSS1 by binding to the MTSS1 promoter. Thus, the acidity-reduced MTSS1-AS facilitated the stability of MZF1 and its inhibitory effect on MTSS1 transcription, thereby promoting the metastasis of PC cells under acidic conditions. Moreover, MTSS1-AS was transcriptionally repressed by the binding of MYC proto-oncogene (Myc) with initiator (Inr) elements of the MTSS1-AS promoter. Meanwhile, MTSS1-AS mutually repressed the expression of Myc by impairing the MZF1-mediated transcription activation of Myc, thereby forming a negative feedback loop between MTSS1-AS and Myc in acidic PC cells. In accordance with the experimental results, MTSS1-AS and MTSS1 were downregulated in PC and correlated with poor overall survival. Conclusions: The results implicated that a reciprocal feedback loop between Myc and MTSS1-AS contributed to the extracellular acidity-promoted metastasis of PC, and indicated that MTSS1-AS was a valuable biomarker and therapeutic target for PC.

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Section: Introductionmentioning

confidence: 99%

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer

Wang

et al. 2020

Theranostics

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“…Furthermore, LAMC2 and TGM2 have been found to promote the migration of pancreatic cancer cells. TGM2 knockdown has been reported to inhibit the proliferation and invasion of pancreatic cancer cells (Sagini et al, 2018;Wang et al, 2020). Finally, HLF was the only down-regulated gene in the TCGA pancreatic cancer metastasis group.…”

Section: Discussionmentioning

confidence: 91%

Identification of Key mRNAs as Prediction Models for Early Metastasis of Pancreatic Cancer Based on LASSO

Xue

Zheng

Qian

et al. 2021

Front. Bioeng. Biotechnol.

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Pancreatic cancer is a highly malignant and metastatic tumor of the digestive system. Even after surgical removal of the tumor, most patients are still at risk of metastasis. Therefore, screening for metastatic biomarkers can identify precise therapeutic intervention targets. In this study, we analyzed 96 pancreatic cancer samples from The Cancer Genome Atlas (TCGA) without metastasis or with metastasis after R0 resection. We also retrieved data from metastatic pancreatic cancer cell lines from Gene Expression Omnibus (GEO), as well as collected sequencing data from our own cell lines, BxPC-3 and BxPC-3-M8. Finally, we analyzed the expression of metastasis-related genes in different datasets by the Limma and edgeR packages in R software, and enrichment analysis of differential gene expression was used to gain insight into the mechanism of pancreatic cancer metastasis. Our analysis identified six genes as risk factors for predicting metastatic status by LASSO regression, including zinc finger BED-Type Containing 2 (ZBED2), S100 calcium-binding protein A2 (S100A2), Jagged canonical Notch ligand 1 (JAG1), laminin subunit gamma 2 (LAMC2), transglutaminase 2 (TGM2), and the transcription factor hepatic leukemia factor (HLF). We used these six EMT-related genes to construct a risk-scoring model. The receiver operating characteristic (ROC) curve showed that the risk score could better predict the risk of metastasis. Univariate and multivariate Cox regression analyses revealed that the risk score was also an important predictor of pancreatic cancer. In conclusion, 6-mRNA expression is a potentially valuable method for predicting pancreatic cancer metastasis, assessing clinical outcomes, and facilitating future personalized treatment for patients with ductal adenocarcinoma of the pancreas (PDAC).

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“…There was speculated that a similar mechanism may exist in cancer cells with BRAF V600E mutation. Moreover, the transport activity of NHE1 regulated by multiple intracellular signaling molecules, including MAPK/ERK 23 and PI3K/AKT kinases [24][25] , those interact with different site of serine residues of the cytosolic C-terminus and phosphorylate NHE1. Additionally, we found that both the phosphorylation and activity of NHE1 were positively regulated by ERK activator and inhibitor in GBM cells, but not NHE1 expression.…”

Section: Discussionmentioning

confidence: 99%

The positive feedback loop of NHE1-ERK phosphorylation mediated by BRAFV600E mutation contributes to tumorigenesis and development of glioblastoma

Liu

et al. 2022

Biochemical and Biophysical Research Communications

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The occurrence rate of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation V600E (BRAF V600E ) in glioblastoma multiforme (GBM) is more than 50%. Na/H exchanger 1 (NHE1), a main pH regulator affecting cell microenvironment, is hyper-expressed in GBM. However, the relationship between BRAF V600E signal pathway and NHE1 in GMB cells remains unclear. This study found that NHE1 was a downstream target of BRAF V600E and an upstream factor of extracellular signal-regulated kinase (ERK). In addition, there was a positive feedback loop between NHE1-ERK phosphorylation under regulation of BRAF V600E mutation contributing to the proliferation and invasion of GBM cells. Moreover, the proliferation and invasion abilities of BRAF V600E -mutant and BRAF wild type GBM cells were all suppressed by the NHE1 inhibitor, BRAF V600E inhibitor and combination of them. The inhibitory effect of combination of the two inhibitors was better than each single drug both in vitro and in vivo. Combination of BRAF V600E and NHE1 inhibitors could be considered as a new therapeutic regimen for GBM, especially for GBM with BRAF V600E .

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LAMC2 modulates the acidity of microenvironments to promote invasion and migration of pancreatic cancer cells via regulating AKT-dependent NHE1 activity

Cited by 33 publications

References 36 publications

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer

Identification of Key mRNAs as Prediction Models for Early Metastasis of Pancreatic Cancer Based on LASSO

The positive feedback loop of NHE1-ERK phosphorylation mediated by BRAFV600E mutation contributes to tumorigenesis and development of glioblastoma

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