Id‐1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/AKT signaling pathway

Abstract

Id-1 (inhibitor of differentiation or DNA binding) is a helix-loophelix protein that is overexpressed in many types of cancer including esophageal squamous cell carcinoma (ESCC). We previously reported that ectopic Id-1 expression activates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in human esophageal cancer cells. In this study, we confirmed a positive correlation between Id-1 and phospho-AKT (Ser473) expressions in ESCC cell lines, as well as in ESCC on a tissue microarray. To investigate the significance of Id-1 in esophageal cancer progression, ESCC cells with stable ectopic Id-1 expression were inoculated subcutaneously into the flank of nude mice and were found to form larger tumors that showed elevated Ki-67 proliferation index and increased angiogenesis, as well as reduced apoptosis, compared with control cells expressing the empty vector. The Id-1-overexpressing cells also exhibited enhanced metastatic potential in the experimental metastasis assay. Treatment with the PI3K inhibitor LY294002 attenuated the tumor promotion effects of Id-1, indicating that the effects were mediated by the PI3K/AKT signaling pathway. In addition, our in vitro experiments showed that ectopic Id-1 expression altered the expression levels of markers associated with epithelial-mesenchymal transition and enhanced the migration ability of esophageal cancer cells. The Id-1-overexpressing ESCC cells also exhibited increased invasive potential, which was in part due to PI3K/AKTdependent modulation of matrix metalloproteinase-9 expression. In conclusion, our results provide the first evidence that Id-1 promotes tumorigenicity and metastasis of human esophageal cancer in vivo and that the PI3K inhibitor LY294002 can attenuate these effects. ' UICCKey words: Id-1; PI3K/AKT; esophageal; tumorigenicity; metastasis Esophageal cancer is the 8th most common cancer and the 6th most frequent cause of cancer death in the world.1 Despite modern multimodality therapy, the overall 5-year survival rate of patients with esophageal cancer remains low partly due to rapid progression, and local and distant metastasis at diagnosis. [2][3][4] Understanding the mechanisms involved in the progression of esophageal cancer is the key to effective treatment. A recent immunohistochemical study of esophageal squamous cell carcinoma (ESCC) showed that aberrant expression of Id-1 (inhibitor of differentiation or DNA binding) is associated with tumor invasion and metastasis.5 Id-1 is a helix-loop-helix (HLH) protein, which heterodimerizes with the basic helix-loop-helix transcription factors and inhibits them from DNA binding, therefore regulating gene transcription.6 It is overexpressed in many types of human cancer, 7 and its expression levels in uterine cervical, 8 breast, 9 prostate, 10 and lung 11 cancers are associated with cancer progression and poor prognosis.We previously reported that Id-1 induced esophageal cancer cell proliferation 4 and activation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B ...

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

“…19,20,34,48 Recent studies have also shown that the in vitro proliferation of ESCC cell lines was reduced by inhibition of PI3K or MEK1/2. 49,50 Here we demonstrated that GDF15 increased the growth of ESCC cell lines dose-dependently. Moreover, this study is the first to report that both the Akt and Erk1/2 pathways with the induction of proliferation were activated by GDF15 in ESCC cell lines and that treatment with a MEK1/2 inhibitor (PD98059) and a PI3K inhibitor (LY294002) abolished the growth of ESCC cell lines.…”

ID1 Facilitates the Growth and Metastasis of Non-Small Cell Lung Cancer in Response to Nicotinic Acetylcholine Receptor and Epidermal Growth Factor Receptor Signaling

“…It has also been reported that nicotine can induce the Akt pathway, and Akt has been shown to elevate the levels of ID1 (29); the phosphatidylinositol 3-kinase (PI3K) Akt pathway also intersects with Src kinase activity. To examine whether the PI3K/Akt pathway contributes to nicotine-mediated induction of ID1, A549 cells were rendered quiescent and stimulated with 1 M nicotine in the presence of 1 M Src inhibitor PP2 or PI3K inhibitor LY294002 (Fig.…”

miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma

“…INPP5J, a member of the 5-phosphatase family, has been recently demonstrated to function as a vital negative regulator of PI3K/ Akt signalling 12 , which is constitutively activated in numerous types of human cancers, including ESCC 26 . However, the clinical significance and biological role of INPP5J in ESCC remain unknown.…”