Hedgehog pathway aberrations and gastric cancer; evaluation of prognostic impact and exploration of therapeutic potentials

Abdel‐Rahman, Omar

doi:10.1007/s13277-015-3216-6

Cited by 20 publications

(12 citation statements)

References 34 publications

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“…In cancer, SHH deregulated activation was first described in nevoid basal cell carcinoma syndrome, where the inherited loss-of-function mutations of the PTCH1 gene was associated with tumour development ( 29 , 30 ). Abnormal Shh signalling is now associated with the progression and maintenance of several malignant tumours, e.g., glioblastomas, lung cancer, prostate cancer and gastric cancer ( 24 , 31 - 34 ). Additionally, it can participate in tumour development via somatic mutations in upstream pathway proteins (SMO and PTC1), overexpression of GLI transcription factors or in a ligand-dependent manner ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Rodrigues

Miguita²,

Andrade³

et al. 2018

Int J Oncol

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Oral squamous cell carcinoma (OSCC) is an extremely aggressive disease associated with a poor prognosis. Previous studies have established that cancer stem cells (CSCs) actively participate in OSCC development, progression and resistance to conventional treatments. Furthermore, CSCs frequently exhibit a deregulated expression of normal stem cell signalling pathways, thereby acquiring their distinctive abilities, of which self-renewal is an example. In this study, we examined the effects of GLI3 knockdown in OSCC, as well as the differentially expressed genes in CSC-like cells (CSCLCs) expressing high (CD44high) or low (CD44low) levels of CD44. The prognostic value of GLI3 in OSCC was also evaluated. The OSCC cell lines were sorted based on CD44 expression; gene expression was evaluated using a PCR array. Following this, we examined the effects of GLI3 knockdown on CD44 and ESA expression, colony and sphere formation capability, stem-related gene expression, proliferation and invasion. The overexpression of genes related to the Notch, transforming growth factor (TGF)β, FGF, Hedgehog, Wnt and pluripotency maintenance pathways was observed in the CD44high cells. GLI3 knockdown was associated with a significant decrease in different CSCLC fractions, spheres and colonies in addition to the downregulation of the CD44, Octamer-binding transcription factor 4 (OCT4; also known as POU5F1) and BMI1 genes. This downregulation was accompanied by an increase in the expression of the Involucrin (IVL) and S100A9 genes. Cellular proliferation and invasion were inhibited following GLI3 knockdown. In OSCC samples, a high GLI3 expression was associated with tumour size but not with prognosis. On the whole, the findings of this study demonstrate for the first time, at least to the best of our knowledge, that GLI3 contributes to OSCC stemness and malignant behaviour. These findings suggest the potential for the development of novel therapies, either in isolation or in combination with other drugs, based on CSCs in OSCC.

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Section: Introductionmentioning

confidence: 99%

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Rodrigues

Miguita²,

Andrade³

et al. 2018

Int J Oncol

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“…Gastric cancer (GC) has attracted much attention for its high morbidity and mortality worldwide; in the rank of cancer-related death, it lies in the fourth in males and fifth in females [1]. A 5-year survival rate after surgical tumor resection is less than 30% and the response rate to chemotherapy is less than 40% in unresectable and recurrent cases.…”

Section: Introductionmentioning

confidence: 99%

Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells

Hou

Huang

et al. 2017

J Exp Clin Cancer Res

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BackgroundItraconazole has been proved therapeutically effective against a variety of human cancers. This study assessed the effect of itraconazole on the Hedgehog (Hh) pathway and proliferation of human gastric cancer cells.MethodsCCK-8 assay and colony formation assay were used to assess the effects of itraconazole on proliferation of gastric cancer cells. The expression of Hh signaling components in gastric cancer cells treated with itraconazole was evaluated by reverse-transcription polymerase chain reaction, immunoblotting and dual luciferase assay. Tumor xenograft models were used to assess the inhibitory effect of itraconazole on the proliferation of gastric cancer cells in vivo.ResultsItraconazole could remarkably inhibit the proliferation of gastric cancer cells. When in combination with 5-FU, itraconazole significantly reduced the proliferation rate of cancer cells. Furthermore, itraconazole could regulate the G1-S transition and induce apoptosis of gastric cancer cells. Hh signaling was abnormally activated in human gastric cancer samples. In vitro, studies showed that the expression of glioma-associated zinc finger transcription factor 1 (Gli1) was decreased at both transcriptional and translational levels after treatment with itraconazole. Dual luciferase assay also indicated that itraconazole could inhibit the transcription of Gli1. In vivo studies demonstrated that monotherapy with itraconazole by oral administration could inhibit the growth of xenografts, and that itraconazole could significantly enhance the antitumor efficacy of the chemotherapeutic agent 5-FU.ConclusionsHh signaling is activated in gastric tumor and itraconazole can inhibit the growth of gastric cancer cells by inhibiting Gli1 expression.

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“…Since Hedgehog signaling pathway plays an important role in the pathogenesis and the prognosis of gastric cancer, targeting this pathway is a new potential therapeutic opportunity in gastric cancer [94]. Vitamin D 3 may act as an antagonist of hedgehog signaling to suppress viability of gastric cancer cells, and it also has a synergistic effect with other anticancer drugs by reducing mRNA expression of the target genes of hedgehog signaling ( Ptch1, Gli1, cyclin D1 and bcl2) [95].…”

Section: Vitamin D/vdr and Gastric Cancer: Laboratorial Researchmentioning

confidence: 99%

Pathogenic roles of alterations in vitamin D and vitamin D receptor in gastric tumorigenesis

Yang

Zhao

et al. 2017

Oncotarget

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Gastric cancer is currently the second leading cause of cancer-related death worldwide, especially in Japan, Korea and China, and the 5-year survival rate of gastric cancer is less than 30%. Thus, it is important to shed more lights on novel agents to prevent gastric cancer or to improve survival rate of the patients. Vitamin D not only maintains calcium and bone homeostasis, but also mostly inhibits tumor genesis, invasion, and metastasis through activation of vitamin D receptor. Although epidemiological results are not consistent, accumulating evidence from gastric cancer cells, animal models, and clinical trials suggest that vitamin D deficiency may increase the risk and mortality of gastric cancer, but vitamin D supplement might be a safe and economical way to prevent or treat gastric cancer. Here, we reviewed the current studies on vitamin D and its receptor and focused on the pathogenic roles of their alterations in gastric tumorigenesis.

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Hedgehog pathway aberrations and gastric cancer; evaluation of prognostic impact and exploration of therapeutic potentials

Cited by 20 publications

References 34 publications

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells

Pathogenic roles of alterations in vitamin D and vitamin D receptor in gastric tumorigenesis

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