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Lost miR-141 and upregulated TM4SF1 expressions associate with poor prognosis of pancreatic cancer: regulation of EMT and angiogenesis by miR-141 and TM4SF1 via AKT.

ABSTRACT: Background: Transmembrane-4-L-six-family-1 (TM4SF1) functions to regulate cell growth and mobility and TM4SF1 expression was upregulated in pancreatic cancer. This study further investigated the role of TM4SF1 in regulating pancreatic cancer epithelial-mesenchymal transition (EMT) and angiogenesis and the underlying molecular events.Methods: Tissue specimens were collected from 90 pancreatic cancer patients for immunohistochemical and qRT-PCR analysis of miR-141 and TM4SF1 levels, respectively. Pancreatic cancer cell lines were used for in vitro assays, while nude mice were used for the in vivo assay.Results: TM4SF1 expression was upregulated, whereas miR-141 expression was lost in pancreatic cancer tissues, both of which was associated with advanced clinicopathological features and poor survival of pancreatic cancer patients. Furthermore, miR-141 was able to target and reduce TM4SF1 expression in pancreatic cancer cells and miR-141 expression inhibited pancreatic cancer cell EMT in vitro and Matrigel plug angiogenesis and lung metastasis in nude mice. At the gene level, miR-141 directly targeted and reduced TM4SF1 expression and in turn induced E-cadherin expression and reduced VEGF-A expression by suppressing activation of the AKT signaling pathway.Conclusions: This study demonstrated that upregulated TM4SF1 and lost miR-141 expression were associated with advanced clinicopathological features and poor survival of pancreatic cancer patients. Lost miR-141 expression but induced TM4SF1 expression altered expression of VEGF-A and E-cadherin and promoted pancreatic cancer cell EMT and angiogenesis via the AKT signaling pathway, suggesting that targeting of miR-141 and TM4SF1 may be a potential therapeutic strategy to control pancreatic cancer.

SUBMITTER: Xu D

PROVIDER: S-EPMC7515451 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAngiogenesis, a basic requirement for tumor cell survival, is considered to be a malignant characteristic of small cell lung cancer (SCLC) and is closely related to the poor outcomes of SCLC patients. miR-141 has been found to play pro- and antiangiogenic roles in different cancers, but its role in SCLC angiogenesis has never been explored.MethodsTotal RNA was isolated from plasm exosomes and serum of SCLC patients to examine the expression of miR-141 by qRT-PCR. Cell proliferation, invasion, migration, tube formation assay, aortic ring assay and mouse tumor model were used to investigate the effect of exosomal miR-141 in angiogenesis in vitro and in vivo. Dual-luciferase assay was conducted to explore the target gene of miR-141.ResultsCirculating miR-141 was upregulated in samples from 122 SCLC patients compared with those from normal volunteers and that the increase in miR-141 was significantly associated with advanced TNM stages, implying the potential oncogenic role of miR-141 in SCLC malignancy. In vitro, miR-141 that was packaged into SCLC cell-secreted exosomes and delivered to human umbilical vein vascular endothelial cells (HUVECs) via exosomes facilitated HUVEC proliferation, invasion, migration and tube formation and promoted microvessel sprouting from mouse aortic rings. Matrigel plug assays demonstrated that SCLC cell-derived exosomal miR-141 induced neoangiogenesis in vivo. Furthermore, mouse subcutaneous tumor nodules that were developed from miR-141-overexpressing SCLC cells had a higher microvessel density (MVD) and grew faster than those developed from negative control cells. KLF12 was found to be the direct target gene of miR-141 and that the proangiogenic effect of miR-141 on HUVECs was abrogated by KLF12 overexpression.ConclusionsOur results demonstrate the specific function of the exosomal miR-141/KLF12 pathway in SCLC angiogenesis for the first time and provide potential novel targets for antiangiogenic therapies for SCLC patients.

Project description:PURPOSE:Novel biomarkers for the diagnosis of prostate cancer (PCa) are urgently required. Increasing evidence suggests that exosomal microRNAs (miRNAs or miRs) in serum may be potential noninvasive biomarkers for certain diseases. The objective of the present study was to investigate and assess whether exosomal miR-141 is an effective biomarker for human PCa. METHODS:In the present study, exosomes were isolated from the serum of patients with PCa, patients with benign prostate hyperplasia (BPH), and healthy volunteers. The total RNA was extracted from the exosomes and the level of miR-141 was analyzed by quantitative reverse transcription-polymerase chain reaction. The expression levels of miR-141 were compared between the whole serum and the serum exosomes of the three groups. Subsequently, the relevance of the exosomal expression of miR-141 to the clinicopathological factors in PCa was investigated. RESULTS:The expression of miR-141 was higher in exosomes compared with whole serum (control group, P=0.0003; BPH group, P=0.0016; PCa group, P<0.0001). The level of serum exosomal miR-141 was significantly higher in the patients with PCa compared with the patients with BPH and the healthy controls (3.85-fold, P=0.0007 and 4.06-fold, P=0.0005, respectively). In addition, the expression levels were significantly higher in metastatic PCa compared with localized PCa (P<0.0001). Receiver-operating characteristic curve revealed that the serum exosomal miR-141 yielded an area under the curve of 0.8694, with 80% sensitivity and 87.1% specificity in discriminating patients with metastatic PCa from the patients with localized PCa. CONCLUSION:Serum exosomes may serve as a more suitable material compared with the whole serum for measuring circulating miR-141 levels in patients with PCa. Exosomal miR-141 is upregulated in the serum from patients with PCa compared with patients with BPH or the healthy volunteers, and it may be a useful potential biomarker for the diagnosis of metastatic PCa.

Project description:BackgroundTransmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive.MethodsWe investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC.ResultsTM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model.ConclusionOur study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.

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Lost miR-141 and upregulated TM4SF1 expressions associate with poor prognosis of pancreatic cancer: regulation of EMT and angiogenesis by miR-141 and TM4SF1 via AKT.

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