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this KRAS - GATA6 - EGFR - KRAS positive loop could significantly boost PDAC initiation and progression ( KRAS G12D -activated EGFR signaling enhanced Sox9 transcription and further promoted follicular-to-ductal transformation in mouse pancreatic tissue ( KRAS mutation can inhibit the senescence of primary pancreatic ductal cells and maintain these cells in a permanent growth arrest state, which could lead to tumorigenesis under certain conditions ( in situ mouse model, one study revealed that KRAS mutation may accelerate the malignant transformation of damaged pancreatic tissue ( KRAS mutation ( KRAS G12D could also interact with GNASR201C, a key pancreatic cancer maintenance factor, to promote the initiation of intraductal papillary mucinous neoplasia (IPMN) and, thereby, IPMN-induced PDAC (Patra et al., 2018)

However, it should be noted that the expression of a methylated gene can be increased when either the coding sequence is hypermethylated or the promoter or transcriptional start site is hypomethylated[130]