Increased expression of senescence-associated cell cycle regulators in the progression of biliary atresia: an immunohistochemical study.

ABSTRACT

AIMS: Cellular senescence plays a role in tumour suppression and in the pathogenesis of various non-neoplastic diseases, including primary biliary cholangitis and other adult cholangiopathies. Less is known about the role of cellular senescence in cholangiopathies in children. With that in mind, we examined the expression of senescence-associated cell cycle regulators in biliary atresia, the most common form of paediatric obliterative cholangiopathy. METHODS AND RESULTS: The expression of senescence-associated cell cycle regulators (p16Ink4a and p21WAF1/Cip1 ) and a ductular reaction related marker (neural cell adhesion molecule NCAM) was examined in bile ducts and bile ductules in liver samples taken from the patients with biliary atresia [n = 80; including 23 samples at the time of the Kasai procedure (KP) and 63 obtained from the explanted liver (LT) (six cases with samples at both surgical stages of disease)] and from appropriate controls (n = 17). The degree of ductular reaction and cholestasis was significantly more extensive in LT than KP (P < 0.01). The expression of p16INK4a and NCAM was significantly more extensive in bile ducts and bile ductules in ductular reaction in both KP and LT compared to controls and in LT compared to KP (P < 0.05). The expression of p21WAF1/Cip1 was significantly more extensive in bile ducts and bile ductules in KP compared to both LT and controls (P < 0.01). CONCLUSIONS: Cellular senescence may play a role in the progression of bile duct loss in biliary atresia in a manner similar to that of adult cholangiopathies.