Hypoxia-Induced miR-378a-3p Inhibits Osteosarcoma Invasion and Epithelial-to-Mesenchymal Transition via BYSL Regulation

Zhang, Junlei; Tang, Haijun; Jiang, Xiaohong; Huang, Nenggan; Wei, Qingjun

doi:10.3389/fgene.2021.804952

Cited by 5 publications

(6 citation statements)

References 45 publications

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“…In addition, EMT is extensively involved in tumor initiation, invasion, and metastasis. Our results further showed that miR-378a-3p inhibited the EMT in GC, in agreement with Zhang’s results in osteosarcoma 54 . Mechanistically, the rescue experiments demonstrated that miR-378a-3p inhibited the progression of GC, partly through regulation of RAB31.…”

Section: Discussionsupporting

confidence: 93%

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MiR-378a-3p acts as a tumor suppressor in gastric cancer via directly targeting RAB31 and inhibiting the Hedgehog pathway proteins GLI1/2

Liu

et al. 2022

Cancer Biol Med

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Objective: To improve the prognosis of patients with gastric cancer (GC), more effective therapeutic targets are urgently needed. Increasing evidence indicates that miRNAs are involved in the progression of various tumors, and RAS-associated protein in the brain 31 (RAB31) is upregulated and promotes the progression of multiple malignant tumors. Here, we focused on identifying RAB31-targeted miRNAs and elucidating their potential mechanism in the progression of GC. Methods: RAB31 and miR-378a-3p expression levels were detected in paired fresh GC tissues and GC cell lines. Bioinformatics analysis was used to predict the miRNAs targeting RAB31 and the relationships between RAB31 and other genes. Dual-luciferase reporter assays were applied to verify the targeted interaction relationship. CCK-8, colony formation, flow cytometry, wound healing, and Transwell assays were performed to assess the proliferation, apoptosis, migration, and invasion of GC cells. Tumorsphere formation assays were performed to assess the stemness of gastric cancer stem cells. Related proteins were detected by Western blot. Xenograft assays in nude mice were performed to explore the effect of miR-378a-3p in vivo. Results: We report the first evidence that miR-378a-3p is downregulated in GC, whereas its overexpression inhibits proliferation, invasion, and migration as well as promotes apoptosis in GC cells. Mechanistically, miR-378a-3p inhibits the progression of GC by directly targeting RAB31. Restoring RAB31 expression partially offsets the inhibitory effect of miR-378a-3p. Further research revealed that miR-378a-3p inhibits GLI1/2 in the Hedgehog signaling pathway and attenuates the stemness of gastric cancer stem cells. Finally, xenograft assays showed that miR-378a-3p inhibits GC tumorigenesis in vivo. Conclusions: MiR-378a-3p inhibits GC progression by directly targeting RAB31 and inhibiting the Hedgehog signaling pathway proteins GLI1/2.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

MiR-378a-3p acts as a tumor suppressor in gastric cancer via directly targeting RAB31 and inhibiting the Hedgehog pathway proteins GLI1/2

Liu

et al. 2022

Cancer Biol Med

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“…To establish a more comprehensive view of non-canonical TGF-β1 effectors affecting miR-378a-3p, we cross-linked different database, performed bioinformatic analyses (Figure 5A), and uncovered distinct effectors linking TGF-β1 to miR-378a-3p regulation, including HIF-1α and TRIM25 (Figure 5C). Others reported that the hypoxic environment and associated molecular cascades triggered the up-regulation of miR-378a-3p in osteoblast lineage cells [15], supporting our observations. In addition, we showed that miR-378a-3p served as an upstream regulator of CTGF (Figure 4); similar findings have been reported in other cell types.…”

Section: Discussionsupporting

confidence: 92%

The context-dependent role of transforming growth factor-β/miR-378a-3p/connective tissue growth factor in vascular calcification: a translational study

Tsai

Yeh

Chao

et al. 2023

Aging

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Background: Vascular calcification (VC) constitutes an important vascular pathology with prognostic importance. The pathogenic role of transforming growth factor-β (TGF-β) in VC remains unclear, with heterogeneous findings that we aimed to evaluate using experimental models and clinical specimens. Methods: Two approaches, exogenous administration and endogenous expression upon osteogenic media (OM) exposure, were adopted. Aortic smooth muscle cells (ASMCs) were subjected to TGF-β1 alone, OM alone, or both, with calcification severity determined. We evaluated miR-378a-3p and TGF-β1 effectors (connective tissue growth factor; CTGF) at different periods of calcification. Results were validated in an ex vivo model and further in sera from older adults without or with severe aortic arch calcification. Results: TGF-β1 treatment induced a significant dose-responsive increase in ASMC calcification without or with OM at the mature but not early or mid-term VC period. On the other hand, OM alone induced VC accompanied by suppressed TGF-β1 expressions over time; this phenomenon paralleled the declining miR-378a-3p and CTGF expressions since early VC. TGF-β1 treatment led to an upregulation of CTGF since early VC but not miR-378a-3p until mid-term VC, while miR-378a-3p overexpression suppressed CTGF expressions without altering TGF-β1 levels. The OM-induced down-regulation of TGF-β1 and CTGF was also observed in the ex vivo models, with compatible results identified from human sera. Conclusions: We showed that TGF-β1 played a context-dependent role in VC, involving a time-dependent selfregulatory loop of TGF-β1/miR-378a-3p/CTGF signaling. Our findings may assist subsequent studies in devising potential therapeutics against VC.

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“…BYSL overexpression enhanced NRF2-driven downstream signaling in osteosarcoma cells (Zhang et al, 2022). There was a notable reduction in the levels of BYSL and NRF2 in osteosarcoma cells transfected with miR-378a-3p mimics.…”

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confidence: 87%

“…Importantly, there was significantly regression of tumor growth in mice inoculated with miR-378a-3poverexpressing-MG63 osteosarcoma cells (Zhang et al, 2022). MAFG (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G) is a bZIP (basic leucine zipper) transcription factor (Shan et al, 2021).…”

mentioning

confidence: 99%

Interplay between Non-Coding RNAs and NRF2 in Different Cancers: Spotlight on MicroRNAs and Long Non-Coding RNAs

Yaylım

Farooqı

Telkoparan-Akillilar

et al. 2022

J Pharmacol Exp Ther

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Cancer is a multifactorial disease and wealth of information has enabled basic and clinical researchers to develop a better conceptual knowledge of highly heterogeneous nature of cancer. Deregulations of spatiotemporally controlled transduction pathways played central role in cancer progression. NRF2-driven signaling has engrossed significant attention because of its fundamentally unique features to dualistically regulate cancer progression. Context dependent diametrically opposed roles of NRF2-induced signaling are exciting. More importantly non-coding RNA (ncRNA) mediated regulation of NRF2 and interplay between NRF2 and ncRNAs have added new layers of complexity to already intricate nature of NRF2 signaling. There is a gradual enrichment in the existing pool of knowledge related to interplay between microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in different cancers. However, surprisingly, there are no clues about interplay between circular RNAs and NRF2 in various cancers.Therefore, future studies must converge on the functional characterization of additional important lncRNAs and circular RNAs, which regulated NRF2-driven signaling or conversely NRF2 transcriptionally controlled their expression to regulate various stages of cancer. Significance StatementRecently, many researchers have focused on the NRF2-driven signaling in cancer progression. Excitingly, discovery of non-coding RNAs has added new layers of intricacy to already complicated nature of KEAP1/NRF2 signaling in different cancers. These interactions are shaping the NRF2-driven signaling landscape and better knowledge of these pathways will be advantageous in pharmacological modulation of non-coding RNA-mediated NRF2 signaling in various cancers. Introduction:Nuclear factor erythroid 2-related factor 2(NRF2) is a master transcriptional regulator. NRF2 contextually integrates cellular stress signals and responds by regulation of myriad of transcriptional networks. NRF2 sequestration is regulated by an inhibitory molecule, Kelch-like ECH-associated protein-1 (KEAP1), until inducers undergo an interaction with cysteine thiol residues of KEAP1. These chemical modifications are This article has not been copyedited and formatted. The final version may differ from this version.

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Hypoxia-Induced miR-378a-3p Inhibits Osteosarcoma Invasion and Epithelial-to-Mesenchymal Transition via BYSL Regulation

Cited by 5 publications

References 45 publications

MiR-378a-3p acts as a tumor suppressor in gastric cancer via directly targeting RAB31 and inhibiting the Hedgehog pathway proteins GLI1/2

MiR-378a-3p acts as a tumor suppressor in gastric cancer via directly targeting RAB31 and inhibiting the Hedgehog pathway proteins GLI1/2

The context-dependent role of transforming growth factor-β/miR-378a-3p/connective tissue growth factor in vascular calcification: a translational study

Interplay between Non-Coding RNAs and NRF2 in Different Cancers: Spotlight on MicroRNAs and Long Non-Coding RNAs

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