Interaction between CHOP, GRP۹۴, and stemness state in gastric cancer samples with Helicobacter pylori infection

Gastric cancer (GC) is the fifth most frequent malignancy worldwide, with a higher incidence in Iran's northern and northwest areas. The disease is linked to chronic inflammation, which can transform healthy gastric cells into cancerous ones through various mechanisms. Inflammation can be attributed to factors such as alcohol consumption, smoking, cellular stress, and excessive synthesis of folded proteins within cells. Helicobacter pylori infection often causes inflammation in the stomach lining, leading to chronic gastritis. The production of folding proteins can result in defective proteins, causing endoplasmic reticulum (ER) stress, which can lead to the development of GC. Cellular stress activates the BAK and C/EBP homologous protein (CHOP) signaling pathways, which can cause GC formation. The CHOP pathway activity is essential in initiating apoptosis in response to microbial infections and neoplastic diseases in the ER. Gastrin-releasing peptide (GRP) is another potential factor in carcinogenesis and ER stress. GRP interacts with defective proteins to cause their destruction and trigger an immune response. It affects cell survival, angiogenesis, invasion, and inhibits cell death by reducing stress-related mRNAs expressed in the ER. Cell stem cells (CSCs) are crucial markers for distinguishing gastric CSCs from tumor tissue. CD۴۴ upregulation is a key factor in GC progression, enhancing cell growth, epithelial-mesenchymal transition (EMT), migration, metastasis, and resistance to apoptosis. SALL۴ expression is essential for maintaining embryonic stem cells' pluripotency and inhibiting carcinogenic processes. This study aimed to examine the correlation between stemness markers in response to cellular stress conditions, with particular attention to their potential association with GC development. Methods: RNA-seq data from GC samples and normal tissues were analyzed for differentially expressed lncRNAs. Fresh tissues from GC and adjacent normal samples were used to quantify the mRNA expression profiling of CHOP, GRP۹۴, CD۴۴, and SALL۴ by quantitative real-time PCR. Results: Overexpression of CHOP, GRP۹۴, CD۴۴, and SALL۴ were displayed in ۲۲% (۳۲/۸۶), ۲۷% (۳۹/۸۶), ۳۰% (۴۳/۸۶), and ۳۵% (۴۹/۸۶) GC samples, respectively. Dysregulation of GRP۹۴ and CHOP was significantly related to metastasis to the lymphatic nodes and H. pylori infection (P < ۰.۰۵). While there was a significant correlation between CD۴۴ and SALL۴ expression and H. pylori infection (P < ۰.۰۵). Moreover, the expression pattern of CD۴۴ was significantly associated with the type of tumor (P < ۰.۰۵). The results indicated a significant correlation between concomitant expression of CHOP, GRP۹۴, CD۴۴, and SALL۴ with each other in some clinicopathological characters in GC tissue specimens (P < ۰.۰۵). Conclusion: Our findings confirmed that dysregulation of CHOP, GRP۹۴, CD۴۴, and SALL۴ was related to pathogenesis, invasive phenotype, metastasis, and poor prognosis in GC patients. Our results demonstrated the interplay between the CSC-like phenotype, the induction of inflammation, and the stress pathway in GC development. These findings develop our knowledge about GRPs, stemness states, and the ER stress-mediated apoptosis pathway, proposing a possible target axis for the creation of GC-related therapeutic approaches and mechanisms.

کلیدواژه ها:

H. Pylori ، CHOP ، GRP۹۴ ، CD۴۴ ، SALL۴