Effects of CXCL12 isoforms in a pancreatic pre-tumour cellular model: Microarray analysis

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death among cancers, it is characterized by poor prognosis and strong chemoresistance. In the PDAC microenvironment, stromal cells release different extracellular components, including CXCL12. The CXCL12 is a chemokine promoting the communication between tumour and stromal cells. Six different splicing isoforms of CXCL12 are known (alpha, beta, gamma, delta, epsilon, theta) but their role in PDAC has not yet been characterized. AIM To investigate the specific role of alpha, beta, and gamma CXCL12 isoforms in PDAC onset. METHODS We used hTERT-HPNE E6/E7/KRasG12D (Human Pancreatic Nestin-Expressing) cell line as a pancreatic pre-tumour model and exposed it to the alpha, beta, and gamma CXCL12 isoforms. The altered expression profiles were assessed by microarray analyses and confirmed by Real-Time polymerase chain reaction. The functional enrichment analyses have been performed by Enrichr tool to highlight Gene Ontology enriched terms. In addition, wound healing assays have been carried out to assess the phenotypic changes, in terms of migration ability, induced by the alpha, beta, and gamma CXCL12 isoforms. RESULTS Microarray analysis of hTERT-HPNE cells treated with the three different CXCL12 isoforms highlighted that the expression of only a few genes was altered. Moreover, the alpha and beta isoforms showed an alteration in expression of different genes, whereas gamma isoform affected the expression of genes also common with alpha and beta isoforms. The beta isoform altered the expression of genes mainly involved in cell cycle regulation. In addition, all isoforms affected the expression of genes associated to cell migration, adhesion and cytoskeleton. In vitro cell migration assay confirmed that CXCL12 enhanced the migration ability of hTERT-HPNE cells. Among the CXCL12 splicing isoforms, the gamma isoform showed higher induction of migration than alpha and beta isoforms. CONCLUSION Our data suggests an involvement and different roles of CXCL12 isoforms in PDAC onset. However, more investigations are needed to confirm these preliminary observations.

Automated summary

This study investigates the specific roles of different splicing isoforms of CXCL12 in the onset of PDAC. The results show that the gamma isoform has a greater impact on the migration ability of tumor cells compared to the alpha and beta isoforms. Further research is needed to confirm these initial observations.