Mutual epitheliummacrophage dependency in liver carcinogenesis mediated by ST18

abstract: ...The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus far. Here, we demonstrate that ST18 is critical for tumor progression and maintenance in a mouse model of liver cancer, based on oncogenic transformation and adoptive transfer of primary precursor cells (hepatoblasts). ST18 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after subcutaneous engraftment and tumor growth. ST18 expression in liver cells was induced by inflammatory cues, including acute or chronic inflammation in vivo , as well as coculture with macrophages in vitro . Knocking down the ST18 mRNA in transplanted hepatoblasts delayed tumor progression. Induction of ST18 knockdown in preestablished tumors caused rapid tumor involution associated with pervasive morphological changes, proliferative arrest, and apoptosis in tumor cells, as well as depletion of tumorassociated macrophages, vascular ectasia, and hemorrhage. Reciprocally, systemic depletion of macrophages in recipient animals had very similar phenotypic consequences, impairing either tumor development or maintenance, and suppressing ST18 expression in hepatoblasts. Finally, RNA sequencing of ST18 depleted tumors before involution revealed downregulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa Bdependent transcription. Conclusion : ST18 expression in epithelial cells is induced by tumorassociated macrophages, contributing to the reciprocal feedforward loop between both cell types in liver tumorigenesis. Our findings warrant the exploration of means to interfere with ST18dependent epitheliummacrophage interactions in a therapeutic setting. (H epatology 2017;65:17081719).

...Hepatology Hepatology 10.1002/(ISSN)1527-3350 HEP Hepatology (Baltimore, Md.) 0270-9139 1527-3350 John Wiley and Sons Inc. Hoboken 27859418 5412898 10.1002/hep.28942 HEP28942 Experimental Models of Liver Disease Hepatoblastoma Hepatocellular Carcinoma Liver Biology/Pathobiology Liver Biology/Pathobiology Mutual epitheliummacrophage dependency in liver carcinogenesis mediated by ST18 Rava et al. Rava et al. Rav Micol 1 D'Andrea Aleco 2 Doni Mirko 2 Kress Theresia R. 1 9 Ostuni Renato

... of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons AttributionNonCommercialNoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made. The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus far. Here, we demonstrate that ST18 is critical for tumor progression and maintenance in a mouse model of liver cancer, based on oncogenic transformation and adoptive transfer of primary precursor cells (hepatoblasts). ST18 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after subcutaneous engraftment and tumor growth. ST18 expression in liver cells was induced by inflammatory cues, including acute or chronic inflammation in vivo , as well as coculture with macrophages in vitro . Knocking down the ST18 mRNA in transplanted hepatoblasts delayed tumor progression. Induction of ST18 knockdown in preestablished tumors caused rapid tumor involution associated with pervasive morphological changes, proliferative arrest, and apoptosis in tumor cells, as well as depletion of tumorassociated macrophages, vascular ectasia, and hemorrhage. Reciprocally, systemic depletion of macrophages in recipient animals had very similar phenotypic consequences, impairing either tumor development or maintenance, and suppressing ST18 expression in hepatoblasts. Finally, RNA sequencing of ST18 depleted tumors before involution revealed downregulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa Bdependent transcription. Conclusion : ST18 expression in epithelial cells is induced by tumorassociated macrophages, contributing to the reciprocal feedforward loop between

... familial intrahepatic cholestasis shRNA short hairpin RNA TAM tumorassociated macrophage ST18 was originally identified as a candidate tumor suppressor in breast cancer, hence its name (suppression of tumorigenicity 18). 1 Successive studies revealed activation of the same gene in pediatric acute myeloid leukemia 2 , 3 and hepatocellular carcinoma (HCC), 4 suggesting an oncogenic function of ST18 . In particular, the mapping of integration sites of the endogenous retrotransposon LINE1 (L1) in HCC led to the identification of 12 tumorspecific L1 insertions, one of which activated ST18 . 4 ST18 (also called NZF3 or MYT3) is a member of the NZF/MyT1 family of transcription factors, a nonclassical zinc finger family that includes two other members, NZF1 and Myt1, with six C 2 HCtype fingers arranged in two main clusters, each of which might in principle bind DNA. 1 , 5 , 6 The three genes are expressed in neural tissue and, based on expression patterns and overexpression experiments, are

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Gene: ST18 - suppression of tumorigenicity 18, zinc finger - (NCBI)

Protein : 2cs8

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