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CPAP enhances and maintains chronic inflammation in hepatocytes to promote hepatocarcinogenesis

ABSTRACT: Chronic and persistent inflammation is a well-known carcinogenesis promoter. Hepatocellular carcinoma (HCC) is one of the most common inflammation-associated cancers; most HCCs arise in the setting of chronic inflammation and hepatic injury. Both NF-κB and STAT3 are important regulators of inflammation. Centrosomal P4.1-associated protein (CPAP), a centrosomal protein that participates primarily in centrosome functions, is overexpressed in HCC and can increase TNF-α-mediated NF-κB activation and IL-6-induced STAT3 activation. A transgenic (Tg) mouse model with hepatocyte-specific CPAP expression was established to investigate the physiological role of CPAP in hepatocarcinogenesis. Obvious inflammatory cell accumulation and fatty change were observed in the livers of CPAP Tg mice. The alanine aminotransferase (ALT) level and the expression levels of inflammatory genes, such as IL-6, IL-1β and TNF-α, were higher in CPAP Tg mice than in wild type (WT) mice. High-dose/short-term treatment with diethylnitrosamine (DEN) increased the ALT level, proinflammatory gene expression levels, and STAT3 and NF-κB activation in CPAP Tg mice; low-dose/long-term DEN treatment induced more severe liver tumor formation in CPAP Tg mice than in WT mice. CPAP can increase the expression of chemokine (C-C motif) ligand 16 (CCL-16), an important chemotactic cytokine, in human hepatocytes. CCL-16 expression is positively correlated with CPAP and TNF-α mRNA expression in the peritumoral part of HCC. In summary, these results suggest that CPAP may promote hepatocarcinogenesis through enhancing the inflammation pathway via increasing the expression of CCL-16.

SUBMITTER: Chen R

PROVIDER: S-EPMC8536685 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Surgical resection is the preferred treatment for Hepatocellular carcinoma; however, it induces tumor recurrence. Our objective was to understand the molecular mechanisms linking liver regeneration under chronic-inflammation to tumorigenesis. Mdr2-knockout mice, a model of inflammation-associated cancer, underwent partial-hepatectomy which led to enhanced hepatocarcinogenesis. Yet, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage response machinery and altered genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis and cell-cycle arrest, and suggest their involvement in tumor recurrence subsequent to partial hepatectomy. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic-inflammation, escape apoptosis and reenter the cell-cycle, triggering the enhanced tumorigenesis At present, there is a great organ shortage worldwide, thus the main treatment for Hepatocellular carcinoma (HCC) is liver resection. However, liver resection induces recurrence and mortality. In our study, we decipher, for the first time, the contribution of the DNA damage response in HCC development and recurrence, the immediate and long term effect. This is an important finding regarding the association between carcinogenesis and DNA damage response. Additionally, we demonstrate yet another link between inflammation, inducing DNA damage and genome instability, and carcinogenesis that has not been explored in the past. These results may assist in developing treatments that will reduce tumor recurrence and additionally, new prophylactic therapies during early inflammatory stages. Keywords: time course, regeneration RNA was isolated from liver samples of 9-month-old Mdr2-/- and control mice obtained on days 0 (the removed lobe), 2 and 6 following PHx. Samples of d0 were obtained from the same mice that were sacrificed on later days. As we were concerned by the variability in the KO group 6 samples were obtained for d0. All other time points and groups contained 3 samples each.

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CPAP enhances and maintains chronic inflammation in hepatocytes to promote hepatocarcinogenesis

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