Comprehensive Analysis of DCLK Family Kinases in Gastrointestinal Cancers and Neoplastic Progression

The doublecortin-like kinase (DCLK) family genes encode protein kinases that are critical for cell development, signaling pathways, and tumor progression across various cancers. Understanding the diagnostic and prognostic relevance of DCLK family genes in gastric cancers (GCs) is therefore essential. This study utilized data from The Cancer Genome Atlas (TCGA) and public databases such as GEPIA۲, UALCAN, OncoDB, and cBioPortal to analyze the expression, methylation, and genetic alterations of DCLK family genes, along with their association with overall survival (OS). Gene regulatory networks, including transcription factors and competing endogenous RNAs, were explored using tools like htfTarget, mirTarbase, circBank, and TISIDB, while correlations with immune cell infiltration were also assessed. Additionally, DCLK gene expression was validated via quantitative real-time PCR (qRT-PCR) in ۱۲۰ colon lesions (۶۰ precancerous samples with adjacent normal tissues and ۶۰ cancerous/non-cancerous samples) and ۳۰ pancreatic ductal adenocarcinoma (PDAC) lesions with ۳۰ corresponding non-cancerous tissues from surgical patients. ROC curve analyses were performed to assess the biomarker potential of DCLK genes. Our findings indicate that DCLK genes exhibit frequent mutations across multiple gastric cancer subtypes. Aberrant DCLK gene expression was notably linked to the progression of colon adenocarcinoma (COAD), rectal adenocarcinoma (READ), and pancreatic adenocarcinoma (PAAD). Elevated DCLK۱ expression correlated with poorer prognosis in stomach adenocarcinoma (STAD), while reduced expression was associated with worse outcomes in cholangiocarcinoma (CHOL). Similarly, DCLK۲ upregulation predicted poor prognosis in STAD, whereas downregulation correlated with unfavorable OS in PAAD. Importantly, DCLK genes influenced the tumor immune microenvironment, with DCLK۱ and DCLK۲ linked to immune cell infiltration, including CD۸, CD۴, Th۱, NK cells, and macrophages in GCs. Experimental results further confirmed significant upregulation of DCLK۱ and DCLK۳ in precancerous and cancerous colon lesions compared to normal tissues. In PDAC samples, DCLK۲ showed notable upregulation compared to non-cancerous tissues. ROC analyses highlighted the DCLK family's potential as prognostic biomarkers, particularly in PDAC. These results underscore the significant prognostic value of DCLK family genes, highlighting their potential as biomarkers for improving patient outcomes through individualized and targeted treatment approaches.

کلیدواژه ها:

DCLK family kinases ، gastrointestinal cancers ، neoplasia ، bioinformatics ، biomarkers