Sonic hedgehog signaling may promote invasion and metastasis of oral squamous cell carcinoma by activating MMP-9 and E-cadherin expression

Fan, Haojun; Wang, Shan; Zhao, Hong; Liu, Nian; Chen, Dong; Sun, Miao; Jie, Zheng

doi:10.1007/s12032-014-0041-5

Cited by 80 publications

(68 citation statements)

References 35 publications

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“…The expression of MMP-2 and MMP-9 may be regulated by Hh pathways (32)(33)(34). Our results demonstrated that deguelin was capable of modulating migration and invasion in PC cells by regulating the expression of MMP-2 and MMP-9.…”

Section: Discussionmentioning

confidence: 59%

Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway

Zheng

Cai

et al. 2016

Oncology Letters

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Abstract. Pancreatic cancer (PC) is a highly lethal malignancy with few effective therapies. Deguelin, a natural compound of the flavonoid family of products, has been reported to have an inhibitory effect on various cancers. In the present study, we investigated whether deguelin had antitumor efficacy in PC. Deguelin treatment was observed to inhibit growth and induce apoptosis in two PC cell lines (Bxpc-3 and Panc-1). In addition, it inhibited migration and invasion in these two cell lines. The activation of the hedgehog (Hh) signaling pathway, as well as matrix metalloproteinases (MMP)-2 and MMP-9, was suppressed by deguelin. These results suggest that deguelin may be a potential chemotherapeutic agent for PC, possibly through the suppression of the Hh signaling pathway.

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Section: Discussionmentioning

confidence: 59%

Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway

Zheng

Cai

et al. 2016

Oncology Letters

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“…Previous studies suggested additional effects of Shh signaling on metastasis and CSCs besides its function in promoting cancer cell proliferation (34)(35)(36). Upregulated Shh signaling was found to facilitate metastasis and to be associated with poor prognosis in various types of cancer, possibly due to its role in regulating stemness of CSCs, which remains to be fully elucidated (37).…”

Section: Discussionmentioning

confidence: 98%

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

Cheng

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The sonic hedgehog (Shh) pathway has been proven to be involved in embryonic development and cancer growth. GDC-0449, an antagonist of the hedgehog signaling receptor Smoothened (Smo), was recently approved by the US Food and Drug Administration as a prescription for skin basal cell carcinoma. However, the efficacy of GDC-0449 in the treatment of colon cancer and other malignancies, such as basal cell carcinoma and pancreatic cancer, has remained to be proven. The present study assessed the effect of GDC-0449 on the colon cancer cell lines Caco-2 and Ht-29. A Cell Counting Kit-8 assay was applied to assess the cell proliferation rate and apoptosis was tested by flow cytometry. Reverse-transcription quantitative PCR and western blot analysis were used for analyzing expression levels of target genes. Cell proliferation was inhibited, while apoptosis was increased by GDC-0449, whereas the expression of B-cell lymphoma 2 (Bcl-2), a downstream target of Shh signaling, was decreased. Consistent with the inhibition of Gli1 expression, the cancer stem cell markers CD44 and ALDH were decreased in the presence of GDC-0449. In conclusion, GDC-0449 was shown to inhibit the replication of colon cancer cells and trigger apoptosis through downregulating Bcl-2. This may also influence the stemness of cancer stem cells as indicated by the decreased stem cell surface markers.

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“…Additionally, there are reports of canonical and non-canonical Hh signaling in other tumor types, such as breast, lung, prostate, and colon, where Hh signaling is not the driving mutation but is involved in tumor progression and contributes to treatment failure and tumor recurrence [13, 33]. There have also been several published findings on Hh signaling in OSCC, where it is known that Hh signaling contributes to growth, migration and invasion [34, 35]. In our system, OSCC signals through both canonical and non-canonical Hh signaling to increase Gli2 activation and expression of downstream target genes.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma

et al. 2016

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Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC invasion into the lymph nodes and mandible correlates with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly and induce bone destruction. While survival rates have increased 12% over the last 20 years, this improvement is attributed to general advances in prevention, earlier detection, and updated treatments. Additionally, despite decades of research, the molecular mechanisms of OSCC invasion into the mandible are not well understood. Parathyroid Hormone-related Protein (PTHrP), has been shown to be essential for mandibular invasion in OSCC animal models, and our previous studies demonstrate that the transcription factor Gli2 increases PTHrP expression in tumor metastasis to bone. In OSCC, we investigated regulators of Gli2, including Hedgehog, TGFβ, and Wnt signaling to elucidate how PTHrP expression is controlled. Here we show that canonical Hedgehog and TGFβ signaling cooperate to increase PTHrP expression and mandibular invasion in a Gli2-dependent manner. Additionally, in an orthotopic model of mandibular invasion, inhibition of Gli2 using shRNA resulted in a significant decrease of both PTHrP expression and bony invasion. Collectively, our findings demonstrate that multiple signaling pathways converge on Gli2 to mediate PTHrP expression and bony invasion, highlighting Gli2 as a therapeutic target to prevent bony invasion in OSCC.

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Sonic hedgehog signaling may promote invasion and metastasis of oral squamous cell carcinoma by activating MMP-9 and E-cadherin expression

Cited by 80 publications

References 35 publications

Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway

Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma

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