Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions

Abstract

Since its initial discovery in Drosophila, Hedgehog (HH) signaling has long been associated with foregut development. The mammalian genome expresses 3 HH ligands, with sonic hedgehog (SHH) levels highest in the mucosa of the embryonic foregut. More recently, interest in the pathway has shifted to improving our understanding of its role in gastrointestinal cancers. The use of reporter mice proved instrumental in our ability to probe the expression pattern of SHH ligand and the cell types responding to canonical HH signaling during homeostasis, inflammation, and neoplastic transformation. SHH is highly expressed in parietal cells and is required for these cells to produce gastric acid. Furthermore, myofibroblasts are the predominant cell type responding to HH ligand in the uninfected stomach. Chronic infection caused by Helicobacter pylori and associated inflammation induces parietal cell atrophy and the expansion of metaplastic cell types, a precursor to gastric cancer in human subjects. During Helicobacter infection in mice, canonical HH signaling is required for inflammatory cells to be recruited from the bone marrow to the stomach and for metaplastic development. Specifically, polarization of the invading myeloid cells to myeloid-derived suppressor cells requires the HH-regulated transcription factor GLI1, thereby creating a microenvironment favoring wound healing and neoplastic transformation. In mice, GLI1 mediates the phenotypic shift to gastric myeloid-derived suppressor cells by directly inducing Schlafen 4 (slfn4). However, the human homologs of SLFN4, designated SLFN5 and SLFN12L, also correlate with intestinal metaplasia and could be used as biomarkers to predict the subset of individuals who might progress to gastric cancer and benefit from treatment with HH antagonists.

Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation

“…SLFN5 also influences renal carcinoma cell motility by uncertain mechanism [35]. Both long SLFN5 and intermediate SLFN12L have been linked to intestinal metaplasia and gastric cancer [36]. In contrast to long Schlafens, SLFN12 is like rodent intermediate Slfn3, lacking a nuclear targeting sequence and localizing at least predominantly in the cytoplasm.…”

Rab23 promotes the cisplatin resistance of ovarian cancer via the Shh-Gli-ABCG2 signaling pathway

“…The dysregulated activation of the Shh signaling pathway in cancer cells is associated with tumor occurrence, drug resistance and poor cancer prognosis (18). Gli1 activates the target genes downstream of the Shh pathway (19,20).…”

Evaluation of serum markers for gastric cancer and its precursor diseases among high incidence and mortality rate of gastric cancer area

“…1, 2). Recent review summarized the pathogenesis of inflammation derived GC explained by hedgehog signaling pathways [35] and stem cell theory [36]. Since chronic gastritis is the fundamental status for atrophy, IM and GC progression (Fig.…”