Cecati Monia, Giulietti Matteo, Righetti Alessandra, Sabanovic Berina, Piva Francesco
Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona 60126, Italy.
World J Gastroenterol. 2021 Apr 21;27(15):1616-1629. doi: 10.3748/wjg.v27.i15.1616.
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 (α, β, γ, δ, ε, θ) but their role in PDAC has not yet been characterized.
To investigate the specific role of α, β, and γ CXCL12 isoforms in PDAC onset.
We used hTERT-HPNE E6/E7/KRasG12D (Human Pancreatic Nestin-Expressing) cell line as a pancreatic pre-tumour model and exposed it to the α, β, and γ 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 α, β, and γ CXCL12 isoforms.
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 α and β isoforms showed an alteration in expression of different genes, whereas γ isoform affected the expression of genes also common with α and β isoforms. The β 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 γ isoform showed higher induction of migration than α and β isoforms.
Our data suggests an involvement and different roles of CXCL12 isoforms in PDAC onset. However, more investigations are needed to confirm these preliminary observations.
胰腺导管腺癌（PDAC）是癌症死亡的第四大主要原因，其特点是预后差和化疗耐药性强。在PDAC微环境中，基质细胞释放不同的细胞外成分，包括CXCL12。CXCL12是一种促进肿瘤细胞与基质细胞之间通讯的趋化因子。已知CXCL12有六种不同的剪接异构体（α、β、γ、δ、ε、θ），但其在PDAC中的作用尚未明确。
研究α、β和γ CXCL12异构体在PDAC发病中的具体作用。
我们使用hTERT-HPNE E6/E7/KRasG12D（人胰腺巢蛋白表达）细胞系作为胰腺肿瘤前模型，并将其暴露于α、β和γ CXCL12异构体。通过微阵列分析评估表达谱的变化，并通过实时聚合酶链反应进行确认。使用Enrichr工具进行功能富集分析，以突出富集的基因本体论术语。此外，还进行了伤口愈合试验，以评估α、β和γ CXCL12异构体诱导的迁移能力方面的表型变化。
对用三种不同CXCL12异构体处理的hTERT-HPNE细胞进行微阵列分析，结果表明只有少数基因的表达发生了改变。此外，α和β异构体显示不同基因的表达发生了改变，而γ异构体影响的基因表达也与α和β异构体有共同之处。β异构体改变了主要参与细胞周期调控的基因的表达。此外，所有异构体都影响与细胞迁移、粘附和细胞骨架相关的基因的表达。体外细胞迁移试验证实，CXCL12增强了hTERT-HPNE细胞的迁移能力。在CXCL12剪接异构体中，γ异构体显示出比α和β异构体更高的迁移诱导作用。
我们的数据表明CXCL12异构体在PDAC发病中起作用且具有不同的作用。然而，需要更多的研究来证实这些初步观察结果。
