Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Abstract

Background/Aims: Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/β-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. Methods: We performed immunostaining for β-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). Results: GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. β-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. Conclusion: GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/β-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG.

RETRACTED ARTICLE: Sedum sarmentosum Bunge extract ameliorates lipopolysaccharide- and D-galactosamine-induced acute liver injury by attenuating the hedgehog signaling pathway via regulation of miR-124 expression

“…Smo is a transmembrane protein that can activate the intracellular signaling pathway. After the transcription factor (Gli) in the cytoplasm is activated, it enters the nucleus and regulates the transcription of target genes [11]. Many studies have reported that the Hedgehog signaling pathway may be involved in acute inflammatory responses in tissues through the regulation of inflammatory factors [12,13].…”

Immunohistochemical Analysis of Sonic Hedgehog, Mucin and Her-2 in Gastric Adenocarcinoma

“…Stomach cancer is seen twice more frequently in men compared to women (8). This ratio has been reported around 1,8 -2,6/1 (1,21,22). In our study, male/female ratio was found to be higher (3,3/1).…”

“…Lee et al found a higher rate of SHH in intestinal cancers and tubular adenocarcinomas compared to mucinous and signet-ring cell cancers (20). Tajima et al found that this pathway was down-regulated in fundic gland-type gastric adenocarcinomas (21). The only study reporting that overexpression of SHH was a good prognostic factor was the one performed by Kim et al (22).…”

Activation of Sonic Hedgehog Signaling Is Associated with Human Osteosarcoma Cells Radioresistance Characterized by Increased Proliferation, Migration, and Invasion

“…The Shh signaling pathway plays crucial roles in regulating cell differentiation, adhesion, migration, transformation, and apoptosis [ 19 ]. It was found that Shh signaling was activated in many human cancers such as gastric cancer, liver cancer, breast cancer, and ovarian cancer [ 11 , 20 ]. Moreover, activation of Shh signaling was found to be highly associated with increased capacities of chemoresistance and radioresistance in human malignant tumors [ 21 , 22 ].…”