Molecular Pathways Regulating Pro-migratory Effects of Hedgehog Signaling

Hochman, Eldar; Castiel, Asher; Jacob‐Hirsch, Jasmine; Amariglio, Ninnette; Izraeli, Shai

doi:10.1074/jbc.m605905200

Cited by 66 publications

(53 citation statements)

References 53 publications

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“…Studies conducted by Hochman and colleagues have suggested that the components of the Shh signaling pathway participate directly in cell migration and angiogenesis, whereas inhibition of this pathway blocks Shhinduced cell migration and angiogenesis (4). In addition, Shh and Gli1 expression has also been shown to affect epithelial-tomesenchymal transition (EMT) in pancreatic cancer cell lines and lymphatic metastasis in esophageal squamous cell carcinoma (5,6).…”

Section: Introductionmentioning

confidence: 99%

Sonic Hedgehog Pathway Promotes Metastasis and Lymphangiogenesis via Activation of Akt, EMT, and MMP-9 Pathway in Gastric Cancer

et al. 2011

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Activation of sonic hedgehog (Shh) signaling has been implicated in progression of a variety of tumors. In this study, we elucidated a role for Shh in the invasion of gastric tumors and determined the mechanism by which Shh is regulated. Immunohistochemical analysis of 178 primary human gastric tumor biopsies indicated that Shh expression was positively correlated with lymph node metastasis, high lymphatic vessel density, and poor prognosis. In mouse xenograft models of human gastric cancer, enforced expression of Shh significantly enhanced the incidence of lung metastasis compared with nonexpressing controls. Mechanistic investigations revealed that phosphoinositide 3-kinase (PI3K)/Akt inhibition blocked Shh-induced epithelial-mesenchyme transition, the activity of matrix metalloproteinase 9 (MMP-9), and lymphangiogenesis, reducing tumor invasiveness and metastasis. Taken together, our findings establish that Shh signaling promotes the metastasis of gastric cancer through activation of the PI3K/Akt pathway, which leads to mesenchymal transition and MMP-9 activation. These findings offer preclinical validation of Shh as a candidate therapeutic target for treatment of metastatic gastric cancers. Cancer Res; 71(22); 7061-70. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Sonic Hedgehog Pathway Promotes Metastasis and Lymphangiogenesis via Activation of Akt, EMT, and MMP-9 Pathway in Gastric Cancer

et al. 2011

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“…Although it has been confirmed that the Hh pathway participates in cell migration and angiogenesis processes and is correlated with the severity of the associated tumor (27)(28)(29), additionally, disruption of Hh pathway has been shown to inhibit metastasis in pancreatic cancer and gastric cancer (29)(30)(31), the relationship between the Hh signaling pathway and aggressiveness of HCC cells remains unclear. It is necessary to investigate whether the signaling influences proliferative and invasive potential of HCC cells.…”

Section: Discussionmentioning

confidence: 99%

Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells

Cheng

Xu²,

Tian³

et al. 2009

Int J Oncol

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Abstract. The Hedgehog (Hh) pathway has been confirmed a contributor to the carcinogenesis and progression of various tumor types. To investigate the Hh signaling activity in human hepatocellular carcinoma (HCC), we detected the expression levels of Hh pathway components (Shh, Ptch1 and Gli2) in 57 samples of HCC and corresponding adjacent-tumor liver tissues. The Hh pathway was overexpressed in cancer tissues compared with non-cancer tissues and correlated closely with histologic differentiation and portal venous invasion of HCC. To elucidate the relationship between Hh signaling and HCC progression, we performed a further study in vitro. First, the expression levels of the signaling were detected in a subset of hepatoma cell lines and SMMC-7721 cells selected with high level of Hh signaling expression. Next, we employed KAAD-cyclopamine (a specific inhibitor of Hedgehog pathway) to block the Hh pathway in SMMC-7721 cells and assessed the changes of their biological behaviors. The results showed that the blockade of Hh signaling pathway by KAAD-cyclopamine induced reduction of DNA synthesis leading to marked cell growth inhibition and also caused significant attenuation in invasiveness and motility of HCC cells. Collectively, our data demonstrated that the Hh pathway plays an important role in HCC development and invasion. Blockade of the Hh signaling pathway may be a potential target of new therapeutic strategy for HCC.

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“…SHH CM was prepared as described previously (Ingram et al 2002, Hochman et al 2006, Park et al 2011. Briefly, media were collected from SHHN-923 cells, which were transfected to secrete active SHH (N-terminal domain) in a pMT21 (pSHH-N-PMT21) plasmid.…”

Section: Shh Studymentioning

confidence: 99%

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

Zaitseva¹,

Holdsworth-Carson²,

Waldrip³

et al. 2013

Reproduction

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Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared with myometrium, it is likely that most of these differences are a consequence of the fibroid presence and are not causal. The aim of this study was to investigate the expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used real-time quantitative RT-PCR, western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid (RA) and sonic hedgehog (SHH) conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared with matched myometrium, with strong blood vessel-specific localisation. Although the SHH pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and RA combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures.In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared with normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development.

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Molecular Pathways Regulating Pro-migratory Effects of Hedgehog Signaling

Cited by 66 publications

References 53 publications

Sonic Hedgehog Pathway Promotes Metastasis and Lymphangiogenesis via Activation of Akt, EMT, and MMP-9 Pathway in Gastric Cancer

Sonic Hedgehog Pathway Promotes Metastasis and Lymphangiogenesis via Activation of Akt, EMT, and MMP-9 Pathway in Gastric Cancer

Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

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