Crosstalk between SHH and stemness state signaling pathways in esophageal squamous cell carcinoma

Abstract

The expression of GLI1 as a downstream gene of sonic hedgehog (Hh) pathway, studied in a variety of cancers including esophageal squamous cell carcinoma (ESCC). However, the interaction of Hh with other developmental pathways needs to be elucidated. In this study, we aimed to investigate the correlation of GLI1 expression with transcription factors (TFs) of stem cell signaling pathways, and their association with clinico-pathological data of ESCC. Using real-time PCR, we assessed the expression of GLI1 mRNA in 49 ESCC patients, and analyzed the correlation between GLI1 and selected TFs. The results showed overexpression of GLI1 in ESCC tissues in significant correlation with lymph node metastasis. The GLI1 up-regulation was also correlated to the SOX2 and SIZN1 (Smad-interacting zinc finger protein) expression. These correlations may confirmed the role of GLI1 in crosstalk among different cell signaling pathways in ESCC. To our knowledge, this is the first study to demonstrate the correlation of GLI1 expression with stemness marker and BMP signaling in ESCC.

Correlation between SALL4 stemness marker and bone morphogenetic protein signaling genes in esophageal squamous cell carcinoma

“…SIZN1 may regulate the expression of SALL4 and has a key role in inducing CSC phenotypes in ESCC. It has been found that the overexpression of GLI1 , a member of the SHH signaling pathway, is significantly correlated with SIZN1 in ESCC patients suggesting a regulatory role of SIZN1 on GLI1 gene expression, and subsequently, a crosstalk between hedgehog (Hh) and BMP signaling pathways to induce SNAIL activation as well as epithelial‐mesenchymal transition (EMT) process . Since CSCs properties occur in part of EMT process, we may suggest that induction of EMT through Hh and BMP signaling pathways crosstalk may activate expression of stemness markers such as SALL4 , to emerge CSC phenotype in ESCC (Figure ) …”

Co‐targeting FAK and Gli1 inhibits the tumor‐associated macrophages‐released CCL22‐mediated esophageal squamous cell carcinoma malignancy

“…These studies have shown that Gli1 can be activated by several intracellular signaling proteins independent of the canonical HH signaling, indicating that Gli1 may possibly be the excellent candidate for combination therapy. Importantly, Gli1 was tightly correlated with the malignancy of ESCC according to previous studies 26–28 . The more complete understanding toward Gli1‐regulating mechanisms in ESCC could be beneficent for ESCC‐targeted therapies.…”

Molecular Signaling in Tumorigenesis of Gastric Cancer

“…Furthermore, the overexpression of sonic Hh has been detected in progenitor cells (in gastric mucosa), which restore the damaged gastric mucosa [11] . In addition, overexpression of GLI1 was correlated to the lymph node metastasis in esophageal squamous cell carcinoma (ESCC) patients [12] . The expression changes of this pathway in GC are summarized in Table 2.…”