FUNCTIONAL AND TRANSCRIPTOMIC STUDY OF NEUTROPHILS IN EARLY HEPATOCARCINOGENESIS IN KRASG12V TRANSGENIC ZEBRAFISH MODEL

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with high malignancy and mortality. As HCC is frequently caused by chronic inflammation, it is important to understand its initiation events and inflammatory responses. Using a kras-induced zebrafish HCC model and a neutrophil reporter transgenic line, we observed a rapid migration of neutrophils towards oncogenic liver during the early hepatocarcinogenesis. By pharmaceutical treatments and genetic intervention of neutrophils, we demonstrated the pro-tumoral roles of these tumor-associated neutrophils (TANs). Increased TAN activity accelerated the proliferation of oncogenic hepatocytes, deterred their apoptosis, promoted liver fibrosis and thus contributed to the pathological malignancy. We further investigated the transcriptomes of isolated oncogenic hepatocytes and TANs. Our data indicate that oncogenic hepatocytes are under malignant transformation with various cancer hallmarks to create a tumor favorable microenvironment, while TANs allow the malignant growth by suppressing cytotoxicity and promoting angiogenesis.