Tumor suppressive mechanisms in hepatocellular carcinoma through inhibition of IL-6 signaling

Abstract

Hepatocellular carcinoma (HCC) is the most frequent malignant tumor in the liver and the third leading cause of cancer death worldwide (696,000 deaths, 9.2%). Although significant progress has been made in the HCC field, the molecular mechanisms and signaling pathways underlying HCC development and progression are still poorly understood. This is probably the case because HCC is very heterogeneous in terms of clinical presentation, genomic alterations and gene expression patterns. In a recent study, we applied an integrative approach of high-resolution array-based comparative genomic hybridization (arrayCGH) and gene expression profiling coupled with patient prognosis to identify tumor 'driver' genes which have genomic aberrations in HCC clinical specimens and functionally contribute to tumor progression. This analysis led to the identification of 10 potential cancer driver genes. Six of these genes were located on chromosome 8 p which is associated with poor outcome. Importantly, the six genes on chromosome 8 p included the tumor suppressor gene DLC1 that had been shown previously to be involved in HCC development. Next we performed clonogenicity, cell migration assays and xenograft mouse models to analyze the five additional genes' for tumor suppressive properties. These experiments confirmed the tumor suppressor function of two additional tumor suppressor genes on chromosome 8 p, SH2D4A and SORBS3. Furthermore, functional analysis revealed that SH2D4A and SORBS3 function in a convergent manner to inhibit the IL-6 pathway. Thereby, SORBS3 inhibits the IL-6 pathway via activation of the estrogen receptor alpha and SH2D4A via inhibition of STAT3 signaling. Taken together, in this study we identified two novel tumor suppressor genes on chromosome 8 p which functionally cooperate to inhibit IL-6 signaling.