5‐Hydroxytryptamine Receptor 1D Aggravates Hepatocellular Carcinoma Progression Through FoxO6 in AKT‐Dependent and Independent Manners

Zuo, Xueliang; Chen, Zhiqiang; Cai, Juan; Gao, Wen; Zhang, Yao; Han, Guoyong; Pu, Liyong; Wu, Zhengshan; You, Wei; Qin, Jianjie; Dai, Xinzheng; Shen, Hongbing; Wu, Junli; Wang, Xuehao

doi:10.1002/hep.30430

Cited by 39 publications

(37 citation statements)

References 45 publications

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“…Our studies show that the AKT signal activation is closely associated with the Tmod3 expression. On integrating the decrease in MMP proteins expression after Tmod3 knockdown and PIK3 enzyme activity assay, we conclude that Tmod3 influences MMP2, MM9 and MMP9 protein expression to promote of HCC cell metastasis by activating AKT signaling pathway, which has a crucial part in the HCC occurrence and development . Our data is also indicative of selective modulation by Tmod3 of EGFR‐PI3K‐AKT signaling in HCCs which, in turn, is modulated by EGF, without affecting HGF‐stimulated signaling.…”

Section: Discussionmentioning

confidence: 58%

Tropomodulin 3 modulates EGFR‐PI3K‐AKT signaling to drive hepatocellular carcinoma metastasis

Zheng

Yang

Hong

et al. 2019

Molecular Carcinogenesis

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The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss‐of‐function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase‐2, ‐7, and ‐9 which required PI3K‐AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K‐AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K‐AKT signaling pathway.

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Section: Discussionmentioning

confidence: 58%

Tropomodulin 3 modulates EGFR‐PI3K‐AKT signaling to drive hepatocellular carcinoma metastasis

Zheng

Yang

Hong

et al. 2019

Molecular Carcinogenesis

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“…However, we did find that changes in lncZEB1-AS1 expression were closely linked to changes in AKT activation and associated signaling in these cells. Through kinase activity assays and qRT-PCR, we ultimately found that lncZEB1-AS1 can enhance PI3K-AKT signaling in order to upregulate MMP2, MMP7, and MMP9 in HCC cells, thereby promoting tumor metastasis, consistent with prior reports highlighting the importance of AKT signaling in HCC onset and progression [35][36][37][38][39][40][41]. Our data further suggested that lncZEB1-AS1 promotes EGFR upregulation in HC cells, thereby enhanced EGF-but not HGF-mediated activation of PI3K-AKT signaling.…”

Section: Discussionsupporting

confidence: 88%

LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis

Ma¹,

Wang²,

Li³

et al. 2020

J. Cancer

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In patients with hepatocellular carcinoma (HCC), disease progression and associated bone metastasis (BM) can markedly reduce quality of life. While the long non-coding RNA (lncRNA) zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) has been shown to function as a key regulator of oncogenic processes in HCC and other tumor types, whether it plays a role in controlling HCC BM remains to be established. In the current study, we detected the significant upregulation of lncZEB1-AS1 in HCC tissues, and we found this expression to be associated with BM progression. When we knocked down this lncRNA in HCC cells, we found that this significantly reduced their migratory, invasive, and metastatic activity both in vitro and in vivo. At a mechanistic level, we found that lncZEB1-AS1 was able to target miR-302b and to thereby increase PI3K-AKT pathway activation and EGFR expression, resulting in the enhanced expression of downstream matrix metalloproteinase genes in HCC cells. In summary, our results provide novel evidence that lncZEB1-AS1 can promote HCC BM through a mechanism dependent upon the activation of PI3K-AKT signaling, thus highlighting a potentially novel therapeutic avenue for the treatment of such metastatic progression in HCC patients.

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“…6c). Rescue experiments were performed with IGF-1 (a potent activator of PI3K/AKT signaling 18,23 ) in AML12. The IGF-1 treatment upregulated p-AKT S473 , and effectively restored the proliferation in TCTP-KD hepatocytes ( Supplementary Figs.…”

Section: Tctp Facilitates the Proliferation Of Hepatocytes By Activatmentioning

confidence: 99%

Translationally controlled tumor protein promotes liver regeneration by activating mTORC2/AKT signaling

et al. 2020

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Translationally controlled tumor protein (TCTP), which is a protein characterized by its potent proliferation promoting activity, has been well studied in the area of growth and tumorigenesis. However, the specific role of TCTP in liver regeneration (LR) and its underlying mechanism remains unclear. In order to investigate the contribution of TCTP during LR, heterozygous TCTP mice were generated, and a mimic LR model was applied to TCTP-knockdown (KD) hepatic cell lines. The results revealed that TCTP-KD impaired LR in mice, and manifested as the following aspects: delayed proliferation of hepatocytes, accompanied by disruption of the mRNA expression of markers of the cell cycle, degenerated lipid metabolism, and abnormal immune response. Furthermore, it was found out that TCTP activated PI3K/AKT signaling by regulating mTORC2. Lastly, the increasing rate of serum TCTP positively correlated to the recovery of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) after liver resection in humans. In summary, the present study is the first to reveal the crucial role of intracellular TCTP in LR.

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5‐Hydroxytryptamine Receptor 1D Aggravates Hepatocellular Carcinoma Progression Through FoxO6 in AKT‐Dependent and Independent Manners

Cited by 39 publications

References 45 publications

Tropomodulin 3 modulates EGFR‐PI3K‐AKT signaling to drive hepatocellular carcinoma metastasis

Tropomodulin 3 modulates EGFR‐PI3K‐AKT signaling to drive hepatocellular carcinoma metastasis

LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis

Translationally controlled tumor protein promotes liver regeneration by activating mTORC2/AKT signaling

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