Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma

Natsuizaka, Mitsuteru; Whelan, Kelly A.; Kagawa, Shingo; Tanaka, Koji; Giroux, Véronique; Chandramouleeswaran, Prasanna M.; Long, Apple; Sahu, Varun; Darling, Douglas S.; Que, Jianwen; Yang, Yizeng; Katz, Jonathan P.; Wileyto, E. Paul; Basu, Devraj; Kita, Yoshiaki; Natsugoe, Shoji; Naganuma, Seiji; Klein‐Szanto, Andres J.; Diehl, J. Alan; Bass, Adam J.; Wong, Kwok-Kin; Rustgi, Anil K.; Nakagawa, Hiroshi

doi:10.1038/s41467-017-01500-9

Cited by 158 publications

(157 citation statements)

References 84 publications

(157 reference statements)

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“…The important role that EMT plays in tumor invasion and metastasis has been well verified [29,30]. To further investigate the influence of ALDH3A1 on OSCC cell EMT, the expression of EMT markers (E-cadherin, vimentin, snail, MMP3) on SCC15 and SCC25 cells were detected using western blot analysis.…”

Section: Aldh3a1 Suppresses Epithelial-mesenchymal Transition By Targmentioning

confidence: 99%

ALDH3A1 acts as a prognostic biomarker and inhibits the epithelial mesenchymal transition of oral squamous cell carcinoma through IL-6/STAT3 signaling pathway

Yang

et al. 2020

J. Cancer

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Objectives: Aldehyde dehydrogenase 3A1 (ALDH3A1) is a member of the ALDH superfamily and its relationship with oral squamous cell carcinoma (OSCC) still unknown. In our subject, we aimed to reveal the expression pattern and clinical value of ALDH3A1 in OSCC and its biological function in OSCC cell lines. Materials and methods: The expression level of ALDH3A1 in paired OSCC tissues and adjacent noncancerous tissues were detected by quantitative real-time PCR, Western blot and immunohistochemistry. The relationship between ALDH3A1 expression and clinical characteristics was analyzed. Besides, cell-counting kit 8, colony formation, wound healing, transwell invasion, apoptosis and cell cycle assays were employed to assess the role of ALDH3A1 in OSCC cells. To explore the influence of ALDH3A1 on OSCC epithelial-to-mesenchymal transition (EMT), the expression of EMT markers (E-cadherin, vimentin, snail, MMP3) on OSCC cells were detected, and possible mechanisms were analyzed. Results: In OSCC tissues, ALDH3A1 was significantly decreased compared to the adjacent normal tissues. Lower ALDH3A1 expression in OSCC tissues was associated with a higher incidence of lymph node metastasis (LNM). Moreover, the overall survival of OSCC with low ALDH3A1 expression was significantly worse compared to that of OSCC with high ALDH3A1 expression. Restored expression of ALDH3A1 suppressed cell proliferation, migration and invasion in OSCC cells. Further experiments showed that ALDH3A1 might inhibit EMT in OSCC via a regulation of the IL-6/STAT3 signal pathway. Conclusion: These data indicate that ALDH3A1 may serve as a biomarker and may be developed into a novel treatment for OSCC.

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Section: Aldh3a1 Suppresses Epithelial-mesenchymal Transition By Targmentioning

confidence: 99%

ALDH3A1 acts as a prognostic biomarker and inhibits the epithelial mesenchymal transition of oral squamous cell carcinoma through IL-6/STAT3 signaling pathway

Yang

et al. 2020

J. Cancer

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“…Notch1 was reported to be overexpressed in OSCC, which was correlated with the T-stage, clinical stage, differentiation, lymph node metastasis, depth of invasion and locoregional recurrence (27)(28)(29). Notch1 activation has been reported to promote OSCC cell proliferation, apoptosis, migration, invasion and EMT (29)(30)(31). These data suggested that targeting Notch1 may be a useful approach for treating OSCC.…”

Section: Discussionmentioning

confidence: 90%

“…3A). Notch1 was previously reported to be involved in the onset and progression of OSCC (27)(28)(29)(30)(31) and was therefore selected as a candidate for further confirmation in the present study. A luciferase reporter assay was performed to determine whether the 3'-UTR of Notch1 may be directly targeted by miR-495.…”

Section: Overexpression Of Mir-495 Prohibits the Proliferation And Inmentioning

confidence: 99%

MicroRNA‑495 targets Notch1 to prohibit cell proliferation and invasion in oral squamous cell carcinoma

Wang

Yang

et al. 2018

Mol Med Report

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MicroRNAs (miRNAs) are associated with the initiation and progression of oral squamous cell carcinoma (OSCC) by regulating a variety of cancer-associated behaviors. Fully understanding the regulatory mechanism of miRNAs in the pathogenesis of OSCC may provide novel promising approaches for the identification of prognostic biomarkers and therapeutic targets for this particular malignancy. In the present study, reverse transcription-quantitative polymerase chain reaction analysis was performed to detect miRNA (miR)-495 expression in OSCC tissues and cell lines. The effects of miR-495 on the proliferation and invasion of OSCC cells were determined using Cell Counting Kit-8 and Matrigel invasion assays, respectively. The mechanisms underlying the action of miR-495 in OSCC cells were also investigated. Results from the present study revealed that miR-495 expression was downregulated in OSCC tissues and cell lines compare with in adjacent normal tissues and human oral keratinocytes, respectively. Exogenous expression of miR-495 restricted cell proliferation and invasion of OSCC cells in vitro. Notch1 was identified as a direct functional target of miR-495 in OSCC. Furthermore, Notch1 knockdown exhibited inhibitory effects, similar to those induced by miR-495 overexpression in OSCC cells. Restoration of Notch1 expression rescued the suppressive effects of miR-495 on OSCC cell proliferation and invasion. These findings suggested an important role for miR-495 in the regulation of OSCC cell growth and metastasis, at least partly by directly targeting Notch1. In addition, the findings of the present study revealed the potential of miR-495 as a novel therapeutic target for the treatment of patients with OSCC.

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“…EMT is a key step toward cancer metastasis . Wnt, TGF‐β, Notch, NF‐κB, and MAPK/ERK have been implicated as the key pathways involved in EMT process. Several lncRNAs participate in EMT process .…”

Section: Discussionmentioning

confidence: 99%

“…21,22 In this study, a novel lncRNA, lncRNA DRHC, was shown to be EMT is a key step toward cancer metastasis. 26 Wnt, 27 TGF-β, 28,29 Notch, 30,31 NF-κB, 32,33 and MAPK/ERK 34 have been implicated as the key pathways involved in EMT process. Several lncRNAs participate in EMT process.…”

Section: Discussionmentioning

confidence: 99%

lncRNA DRHC inhibits proliferation and invasion in hepatocellular carcinoma via c‐Myb‐regulated MEK/ERK signaling

Zhuang

Zhang

et al. 2018

Molecular Carcinogenesis

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Accumulating evidence indicates that long non‐coding RNAs (lncRNAs) play a crucial role in hepatocellular carcinoma (HCC). Here, we reported a novel lncRNA, CTC‐505O3 (lncRNA DRHC), that was downregulated in HCC and its low expression was associated with dismal survival. Gain‐of‐function studies indicated that it inhibited proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) in HCC cell lines in vitro. lncRNA DRHC also inhibited tumorigenicity in vivo. In mechanistic experiments, GO analysis based on NGS indicated that MAPK signaling was most affected. The result was confirmed by Western blot and this effect was abolished either by MEK1/2 specific inhibitor Trametinib or ERK1/2 inhibitor SCH772984. In addition, differences in proliferation and invasion were abrogated by Trametinib. Moreover, we found that lncRNA DRHC interacted with MYBBP1A and modulated MEK/ERK signaling via c‐Myb. Taken together, our findings indicate that the lncRNA DRHC play a key role in HCC progression and may serve as a novel therapeutic target.

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Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma

Cited by 158 publications

References 84 publications

ALDH3A1 acts as a prognostic biomarker and inhibits the epithelial mesenchymal transition of oral squamous cell carcinoma through IL-6/STAT3 signaling pathway

ALDH3A1 acts as a prognostic biomarker and inhibits the epithelial mesenchymal transition of oral squamous cell carcinoma through IL-6/STAT3 signaling pathway

MicroRNA‑495 targets Notch1 to prohibit cell proliferation and invasion in oral squamous cell carcinoma

lncRNA DRHC inhibits proliferation and invasion in hepatocellular carcinoma via c‐Myb‐regulated MEK/ERK signaling

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