TP53 and cholangiocarcinoma: CypA is upregulated in CCA cells, and several carcinogenic factors including cell stress response genes, HIF-1a and activated p53, may increase CypA expression [44,45]; the high CypA levels could directly or indirectly activate the ERK1/2 signaling pathway and NF-κB pathway [46], which in turn mediate gene transcription of interleukin (IL)-8, and matrix metalloproteinase (MMP) 3 and 9 [47].