Mutual epithelium‐macrophage 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 pre‐established tumors caused rapid tumor involution associated with pervasive morphological changes, proliferative arrest, and apoptosis in tumor cells, as well as depletion of tumor‐associated 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 down‐regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B–dependent transcription. Conclusion: ST18 expression in epithelial cells is induced by tumor‐associated macrophages, contributing to the reciprocal feed‐forward loop between both cell types in liver tumorigenesis. Our findings warrant the exploration of means to interfere with ST18‐dependent epithelium–macrophage interactions in a therapeutic setting. (Hepatology 2017;65:1708‐1719).

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

“…No exonic tumor-specific mouse L1 insertions were detected. In this regard, the genomic distribution of mouse tumor-specific L1 insertions, although involving at this stage a handful of events, resembles patterns reported for human cancers, where L1 insertions found in exons of known cancer genes (Miki et al 1992;Helman et al 2014;Scott et al 2016) are far rarer than such events located in introns , including the example of the ST18 oncogene (Shukla et al 2013;Rava et al 2017) and a more recent instance in the tumor suppressor gene BRCA1 (Tang et al 2017). Although the oncogenic impact of intronic tumor-specific L1 insertions is more difficult to mechanistically assess than exonic events, they are also far more numerous and are therefore a potentially important and underexplored class of mutation encountered in mammalian cancers .…”

“…One intronic insertion resulted in the activation of the transcriptional repressor and putative oncogene ST18 by disrupting a binding site required for its own repression, demonstrating the capacity for intronic tumor-specific L1 insertions to contribute to cancer progression. Notably, a recent study confirmed ST18 as a liver oncogene, highlighting the value of mapping L1 insertions in cancer genomes as an endogenous mutagenesis screen (Rava et al 2017).…”

Macrophages and hepatocellular carcinoma

“…ST18 is critical for liver cancer progression and maintenance in a mouse model. TAMs induced epithelial cells expression ST18, ST18 mediated mutual epithelium-macrophage dependency in liver carcinogenesis [64]. In a cohort from Australia, this study showed that soluble CD163 which is a specific macrophage activation marker may predict a rapid HCC progression [65].…”

<p>Comprehensive Characterization of Stage IIIA Non-Small Cell Lung Carcinoma</p>

“…22 Another important marker, ST18 (suppression of tumorigenicity 18, breast carcinoma, zinc-finger protein), was over-expressed in LUSC, as suggested by Rava et al 2017. 23 They suggested that ST18 expression is increased in epithelial cells due to tumor-associated macrophages and leads to liver tumorigenesis. 23 Hence, overexpression in LUSC suggests enhanced tumorigenicity.…”