Downregulation of Hedgehog Interacting Protein (HHIP) in Gastric Cancer: Implications for Tumorigenesis

The increasing incidence of gastric cancer (GC) in the Kashmir Valley is concerning, but its root causes are largely unknown. Dysregulated activation of the Hedgehog signaling pathway has been linked to various cancers, and the Human Hedgehog Interacting Protein (HHIP), a tumor suppressor, is frequently dysregulated in malignancies. However, the expression of the HHIP gene in GC is inconsistent and poorly understood. This study aimed to examine HHIP gene expression in gastric cancer. We used methylation-specific PCR, Western Blot analysis, and quantitative reverse transcription PCR (qRT-PCR) to assess the hypermethylation and expression levels of HHIP gene promoters. The correlation between these results and clinical parameters (e.g. age, gender, histological type, class, stage, and lymph node metastasis) was studied with samples from 53 GC patients confirmed by histology. In 69.81% (37 out of 53) of the tumor tissue, HHIP hypermethylation was found. Of the 45 cases examined for mRNA expression, 53.33% (24 out of 45) showed a decrease in the HHIP mRNA level compared to the normal sample. In addition, 49.05% (26 out of 53) showed a decline in the expression of HHIP proteins. Almost all GC samples with reduced protein expression also showed a reduction in mRNA levels. These results suggest that the hypermethylation of the HHIP promoter leads to a decrease in the regulation of HHIP, which contributes to the activation of the hedgehog signal path and may play a critical role in the progress of GC. Our study highlights the significant link between HHIP hypermethylation and reduced gene expression at both mRNA and protein levels, suggesting that target HHIP gene methylation could be a promising treatment strategy for gastric cancer.