MiR-223 modulates hepatocellular carcinoma cell proliferation through promoting apoptosis via the Rab1-mediated mTOR activation

Zheng, Dong; Qi, Ruizhao; Guo, Xiaodong; Zhao, Xin; Li, Yinyin; Zeng, Zhen; Bai, Wenlin; Chang, Xiujuan; Hao, Liyan; Chen, Yan; Lou, Min; Li, Zhiwei; Lu, Yinying

doi:10.1016/j.bbrc.2016.12.091

Cited by 43 publications

(30 citation statements)

References 33 publications

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“…Previous studies have suggested that miR-223 was lowly expressed HCC [31,32]. Moreover, miR-223 has been suggested to repress HCC cell growth and accelerate apoptosis through the Rab1-mediated mTOR activation [33]. In agreement with these findings, we proved that miR-223-3p abundance was reduced in HCC tissues and cells, and its interference abated the repressive impact of circ_LRIG3 downregulation on progression of HCC cells.…”

Section: Discussionsupporting

confidence: 88%

CircRNA LRIG3 knockdown inhibits the progression of hepatocellular carcinoma by regulating miR-223-3p/MAP2K6 axis and inactivating MAPK/ERK pathway

Sun

Zhai

Zhang³

et al. 2020

Preprint

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Background: Emerging evidence suggests that circular RNAs (circRNAs) play critical roles in tumorigenesis. However, the roles and molecular mechanism of circRNA leucine-rich repeat immunoglobulin domain-containing protein 3 (circ_LRIG3) in hepatocellular carcinoma (HCC) have not been investigated.Methods: The expression levels of circ_LRIG3, microRNA-223-3p (miR-223-3p), and mitogen-activated protein kinase kinase 6 (MAP2K6) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Flow cytometry was applied to determine the cell cycle distribution and cell apoptosis. Cell proliferation, migration and invasion were assessed by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and transwell assay, respectively. Western blot assay was employed to measure the protein levels of snail, E-cadherin, MAP2K6, mitogen-activated protein kinase (MAPK), phospho-MAPK (p-MAPK), extracellular signal-regulated kinases (ERKs), and phospho-ERKs (p-ERKs). The relationship between miR-223-3p and circ_LRIG3 or MAP2K6 was predicted by bioinformatics tools and verified by dual-luciferase reporter assay. A xenograft tumor model was established to confirm the functions of circ_LRIG3 in vivo.Results: Circ_LRIG3 and MAP2K6 expression were enhanced while miR-223-3p abundance was reduced in HCC tissues and cells. Knockdown of circ_LRIG3 inhibited the progression of HCC cells via reducing cell proliferation, metastasis and increasing apoptosis. MiR-223-3p was a target of circ_LRIG3 and its downregulation reversed the inhibitory effect of circ_LRIG3 knockdown on progression of HCC cells. Moreover, MAP2K6 could bind to miR-223-3p, and MAP2K6 upregulation also abolished the suppressive impact of circ_LRIG3 interference on progression of HCC cells. Additionally, silence of circ_LRIG3 suppressed the activation of MAPK/ERK pathway and tumor growth by upregulating miR-223-3p and downregulating MAP2K6.Conclusion: Circ_LRIG3 knockdown inhibited HCC progression through regulating miR-223-3p/MAP2K6 axis and inactivating MAPK/ERK pathway, providing a potential therapeutic approach for patients with HCC.

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Section: Discussionsupporting

confidence: 88%

CircRNA LRIG3 knockdown inhibits the progression of hepatocellular carcinoma by regulating miR-223-3p/MAP2K6 axis and inactivating MAPK/ERK pathway

Sun

Zhai

Zhang³

et al. 2020

Preprint

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“…Moreover, we found several proteins involved in the apoptotic pathway, as the transcription factor Stwl 23 , the mitochondrial carrier homolog 1 (Mtch) 24 , ALG-2 interacting protein X 21 and the GTPase Rab1 25 , 26 . Among these proteins, we focused our attention on the ALG-2 interacting protein X, also called Alix.…”

Section: Resultsmentioning

confidence: 99%

The multifunctional polydnavirus TnBVANK1 protein: impact on host apoptotic pathway

Salvia

Grossi

Amoresano

et al. 2017

Sci Rep

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Toxoneuron nigriceps (Hymenoptera, Braconidae) is an endophagous parasitoid of the larval stages of the tobacco budworm, Heliothis virescens (Lepidoptera, Noctuidae). The bracovirus associated with this wasp (TnBV) is currently being studied. Several genes expressed in parasitised host larvae have been isolated and their possible roles partly elucidated. TnBVank1 encodes an ankyrin motif protein similar to insect and mammalian IκB, an inhibitor of the transcription nuclear factor κB (NF-κB). Here we show that, when TnBVank1 was stably expressed in polyclonal Drosophila S2 cells, apoptosis is induced. Furthermore, we observed the same effects in haemocytes of H. virescens larvae, after TnBVank1 in vivo transient transfection, and in haemocytes of parasitised larvae. Coimmunoprecipitation experiments showed that TnBVANK1 binds to ALG-2 interacting protein X (Alix/AIP1), an interactor of apoptosis-linked gene protein 2 (ALG-2). Using double-immunofluorescence labeling, we observed the potential colocalization of TnBVANK1 and Alix proteins in the cytoplasm of polyclonal S2 cells. When Alix was silenced by RNA interference, TnBVANK1 was no longer able to cause apoptosis in both S2 cells and H. virescens haemocytes. Collectively, these results indicate that TnBVANK1 induces apoptosis by interacting with Alix, suggesting a role of TnBVANK1 in the suppression of host immune response observed after parasitisation by T. nigriceps.

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“…However, in lung squamous cell carcinoma, miR‐223 functions as a tumor suppressor (Luo et al ., 2019). In hepatocellular carcinoma cells, miR‐223 is found to target Rab1, which is critical for mTOR pathway, and to promote apoptosis (Dong et al ., 2017). Interestingly, a report indicates that miR‐223 suppresses cell proliferation by targeting IGF‐1R in HeLa cells, which models cervical adenocarcinoma (Jia et al ., 2011).…”

Section: Discussionmentioning

confidence: 99%

The STAT3‐miR‐223‐TGFBR3/HMGCS1 axis modulates the progression of cervical carcinoma

Jiang

Qian

et al. 2020

Molecular Oncology

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Cervical cancer is induced by persistent infections with high‐risk human papillomaviruses (HPVs), which produce the early protein 6 of HPVs (E6)/E7 protein that is involved in cell transformation by interacting with several oncoproteins or tumor suppressors. However, the role of noncoding RNA in mediating the pathogenesis of cervical cancer remains unclear. Here, we report that the novel signal transducer and activator of transcription 3 (STAT3)‐microRNA‐223‐3p (miR‐223)‐TGFBR3/HMGCS1 axis regulated by the E6 protein controls cervical carcinogenesis. miR‐223 was highly expressed in cervical tumor tissues, whereas TGFBR3 or HMGCS1 was significantly downregulated. miR‐223 targeted the 3′‐UTRs of TGFBR3 and HMGCS1 and suppressed their expression, leading to increased anchorage‐independent growth and cervical squamous cell carcinoma (CSCC) tumor growth in vitro and in vivo. The increased expression of miR‐223 was mediated by the transcription factor STAT3, whose activity was enhanced by E6 in the context of interleukin (IL)‐6 stimulation. In addition, exosomal miR‐223 derived from CSCC cells induced IL‐6 secretion by monocyte/macrophage in a coculture system in vitro, and IL‐6 secretion, in turn, led to enhanced STAT3 activity in CSSC cells, forming a positive feedback loop. Furthermore, modified miR‐223 inhibitor effectively suppressed tumor growth in cell line‐derived xenograft model, suggesting that miR‐223 is a potential promising therapeutic target in CSCC. In conclusion, our results demonstrate that the STAT3‐miR‐223‐HMGCS1/TGFBR3 axis functions as a key signaling pathway in cervical cancer progression and provides a new therapeutic target.

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MiR-223 modulates hepatocellular carcinoma cell proliferation through promoting apoptosis via the Rab1-mediated mTOR activation

Cited by 43 publications

References 33 publications

CircRNA LRIG3 knockdown inhibits the progression of hepatocellular carcinoma by regulating miR-223-3p/MAP2K6 axis and inactivating MAPK/ERK pathway

CircRNA LRIG3 knockdown inhibits the progression of hepatocellular carcinoma by regulating miR-223-3p/MAP2K6 axis and inactivating MAPK/ERK pathway

The multifunctional polydnavirus TnBVANK1 protein: impact on host apoptotic pathway

The STAT3‐miR‐223‐TGFBR3/HMGCS1 axis modulates the progression of cervical carcinoma

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