Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP‐9

Chen, Jingsong; Wang, Qian; Fu, Xiaohong; Huang, Xiaohui; Chen, Xi-lin; Cao, Liangqi; Chen, Lianzhou; Tan, Hao-Xiang; Li, Wen; Bi, Jiong; Zhang, Longjuan

doi:10.1111/j.1872-034x.2008.00449.x

Cited by 315 publications

(272 citation statements)

References 28 publications

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“…Previous studies have demonstrated that p21 inhibits DNA synthesis and results in a delay in the G1–S transition in the regenerating liver 28, 29. Meanwhile, Pten represses the AKT/PI3K signalling cascade, functioning as a regeneration suppressor 30, 31, 32. Indeed, we found that the loss of miR‐17~92 noticeably reduced AKT phosphorylation in the female mice, particularly at 24 and 36 hrs post‐operation (Fig.…”

Section: Resultsmentioning

confidence: 65%

MiR‐17~92 ablation impairs liver regeneration in an estrogen‐dependent manner

Zhou

Zhang

et al. 2016

J Cellular Molecular Medi

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As one of the most important post‐transcriptional regulators, microRNAs (miRNAs) participate in diverse biological processes, including the regulation of cell proliferation. MiR‐17~92 has been found to act as an oncogene, and it is closely associated with cell proliferation. However, its role in liver regeneration is still unclear. We generated a hepatocyte‐specific miR‐17~92‐deficient mouse and used a mouse model with 70% partial hepatectomy (PH) or intraperitoneal injection of carbon tetrachloride to demonstrate the role of MiR‐17~92 in liver regeneration. In quiescent livers, the expression of the miR‐17~92 cluster showed a gender disparity, with much higher expression in female mice. The expression of four members of this cluster was found to be markedly reduced after 70% PH. The ablation of miR‐17~92 led to obvious regeneration impairment during the early‐stage regeneration in the female mice. Ovariectomy greatly reduced miR‐17~92 expression but significantly promoted liver regeneration in wild‐type mice. In addition, early regeneration impairment in miR‐17~92‐deficient livers could be largely restored following ovariectomy. The proliferation suppressors p21 and Pten were found to be the target effectors of miR‐17~92. MiR‐17~92 disruption resulted in elevated protein levels of p21 and Pten in regenerating livers. MiR‐17~92 functions as a proliferation stimulator and acts in an oestrogen‐dependent manner. The loss of this miRNA results in increases in p21 and Pten expression and therefore impairs liver regeneration in female mice.

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Section: Resultsmentioning

confidence: 65%

MiR‐17~92 ablation impairs liver regeneration in an estrogen‐dependent manner

Zhou

Zhang

et al. 2016

J Cellular Molecular Medi

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“…Invasion and metastasis are two fundamental properties, which determine the prognosis of the HCC patients [4,5] . Many signaling pathways are thought to be involved in the development and invasion of HCC, including the MAPK pathway [6,7] , phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway [8][9][10] , the wnt/beta-catenin pathway [9,11] , hepatocyte growth factor/c-MET pathway [12,13] , hedgehog (Hh) signaling pathway, and so on.…”

Section: Introductionmentioning

confidence: 99%

“…Matrix metalloproteinase-9 (MMP-9 or gelatinase-B) is mostly associated with tumor migration, invasion and metastasis for various human cancers [10,47,48] . The Hh signaling pathway up-regulates cell migration and invasion in human gliomas and in pancreatic cancer by increasing the expressions of MMP-9 [49,50] .…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

Lü

Zhao

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the role of Hedgehog (Hh) signaling pathway in the invasion and metastasis of human hepatocellular carcinoma (HCC). Methods: Eighty six HCC tissues samples and HCC cell line Bel-7402 were examined. The protein expression of sonic hedgehog (Shh), nuclear glioma-associated oncogene-1 (Gli1), MMP-9 and p-ERK1/2 in HCC was analyzed using immunohistochemistry and Western blot analysis. Boyden chamber assay and wound-healing assay were used to quantify the invasion and metastasis of Bel-7402 cells. Results: In 86 HCC tissue samples, the positive ratio of Shh and nucleus Gli1 was 67.44% (58/86) and 60.47% (52/86), respectively; the expression of nucleus Gli1 was correlated with the tumor pathological grade (P=0.034), and with the ability of the tumor to invade and metastasize (P=0.001); the expression of nucleus Gli1 was also correlated with p-ERK1/2 (P=0.031) and with MMP-9 (P=0.034). Neither Shh, nor nucleus Gli1 was observed in normal liver tissue. KAAD-cyclopamine (KAAD-cyc), a specific inhibitor of the Hh pathway, at the concentrations of 1 and 4 μmol/L inhibited the invasion and migration of Bel-7402 cells and decreased the expression of Gli1 in nucleus and MMP-9, p-ERK1/2 proteins in Bel-7402 cells. On the other hand, Shh, a ligand of the Hh pathway, at the concentration of 0.5 μg/mL produced opposite effects. The MAPK pathway inhibitors U0126 and PD98059 at the concentrations of 5 and 10 μmol/L inhibited invasion and metastasis of Bel-7402 cells induced by Shh, and decreased the expression of p-ERK1/2 and MMP-9. However, U0126 and PD98059 had no effect on the expression of Gli1. Conclusion: Hh signaling pathway mediates invasion and metastasis of human HCC by up-regulating the protein expression of MMP-9 via ERK pathway.

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“…Existing studies have demonstrated that PPARγ activation exerts an inhibitory effect on tumor growth by activating the tumor suppressor gene PTEN (10,11). In addition, several studies have also indicated that PTEN has a tumor suppressor role via regulating a series of factors, including MMP-2 (11,13,14).…”

Section: Pparγ Activation Regulates Mmp-2 Expression Through Ptenmentioning

confidence: 99%

“…In addition, Farrow et al (10) reported that the selective PPARγ agonist RGZ enhanced the expression of phosphatase and tensin homolog (PTEN) in pancreatic cancer AsPC-1 cells and inhibited AKT phosphorylation, while application of the PPARγ inhibitor GW9662 suppressed PTEN expression, suggesting that PPARγ ligands attenuate pancreatic cancer cell growth via inhibiting phosphoinositide 3-kinase (PI3K) activity through upregulating the expression of the tumor suppressor gene PTEN. PTEN was identified in 1997 as a tumor suppressor gene closely associated with cancer (11) w. It is important in tumor cell apoptosis and migration and is the main component of signaling pathways that control cell cycle initiation and exit, promote differentiation, initiate repair and regulate apoptosis (11). Therefore, PPARγ activation may possibly regulate the expression of MMPs through PTEN and thereby inhibit the invasion of pancreatic cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-γ inhibits pancreatic cancer cell invasion and metastasis via regulating MMP-2 expression through PTEN

Zhang

Lin

et al. 2015

Molecular Medicine Reports

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Abstract. The invasive and metastatic behavior of pancreatic cancer is associated with a poor prognosis. Therefore, understanding the molecular mechanisms underlying the invasion and metastasis of pancreatic cancer has important application values theoretically and clinically. In previous years, with increasing studies focusing on tumor pathogenesis, it has been revealed that peroxisome proliferator-activated receptor-γ (PPARγ) and phosphatase and tensin homolog (PTEN) are closely associated with the occurrence and development of pancreatic cancer. Thus, in the present study, a scratch wound assay, western blotting and transwell assays were used to investigate their function. The scratch wound assay demonstrated that treatment with the PPARγ ligand rosiglitazone (RGZ) could reduce the movement and migration of pancreatic cancer cells. Western blotting results indicated that while RGZ inhibited the expression of matrix metalloproteinase (MMP)-2, PPARγ inhibitors promoted MMP-2 expression. However, PPARγ ligands and inhibitors did not affect the expression of MMP-9. Further investigation indicated that the regulation of MMP-2 by PPARγ activation occurred through PTEN. In addition, PPARγ activation promoted PTEN expression, thereby inhibiting the expression of MMP-2. Subsequent transwell experiments demonstrated that RGZ treatment significantly inhibited the invasiveness of pancreatic cancer cells and the inhibitory effect of RGZ was completely reversed by simultaneous transfection of the MMP-2-overexpressing vector, which increased the invasiveness of pancreatic cancer cells. Therefore, PPARγ activation can activate PTEN expression, thereby suppressing the expression of MMP-2 and hence inhibiting the invasion and metastasis of pancreatic cancer cells.

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Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP‐9

Cited by 315 publications

References 28 publications

MiR‐17~92 ablation impairs liver regeneration in an estrogen‐dependent manner

MiR‐17~92 ablation impairs liver regeneration in an estrogen‐dependent manner

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

Peroxisome proliferator-activated receptor-γ inhibits pancreatic cancer cell invasion and metastasis via regulating MMP-2 expression through PTEN

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