Hepatocellular carcinoma development requires hepatic stem cells with altered transforming growth factor and interleukin-6 signaling

Abstract

Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ "cancer stem cells," such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000-50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-beta-receptor type II (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. elf(؉/؊) mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-beta signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in elf(؉/؊) mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGFbeta signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting IL-6 in HCCs lacking a functional TGF-beta pathway.

Pseudogene OCT4-pg4 functions as a natural micro RNA sponge to regulate OCT4 expression by competing for miR-145 in hepatocellular carcinoma

“…selecting cells with high aldehyde dehydrogenase activity or isolating the side population cells by Hoechst dye staining (26). Moreover, accumulating evidence has demonstrated that several signaling pathways that are critical for inducing the HCC stemness are dysregulated during hepatocarcinogenesis, such as Wnt/β-catenin, transforming growth factor-beta and IL-6/STAT3 pathways (27,28). However, the molecular genetics and the mechanisms responsible for the highly aggressive clinical picture of HCC still remain poorly understood.…”

Norcantharidin inhibits IL-6-induced epithelial-mesenchymal transition via the JAK2/STAT3/TWIST signaling pathway in hepatocellular carcinoma cells

“…Interleukin 6 (IL-6) a multifunctional cytokine in the tumor microenvironment, has been regarded as the main factor involved in EMT, contributing to tumor invasion and metastasis (9)(10)(11). Previous studies revealed that IL-6 leads to the development of HCC (12,13), as an independent predictor of HCC tumor recurrence, poor survival, and tumor metastasis (14). Furthermore, IL-6 appears to contribute as a potent factor to the initiation of EMT via activation of Janus kinase (JAK) family members (JAK1, JAK2, and TYK2), leading to the activation of transcription factors of the signal transducer and activator of transcription 3 (STAT3) signaling (15)(16)(17).…”

Bone marrow stem cells and the liver: Are they relevant?

“…The role of bone marrow stem and progenitor cells in the development and progression of liver cancer, in particular, hepatocellular carcinoma (HCC), is another area of intense research. The stem cell contribution to cancer development, including HCC development, is now well established 69,70 . The contribution of the bone marrow in the development of epithelial cancers was first demonstrated in the gastric system 71 .…”

“…The stem cell contribution to cancer development, including HCC development, is now well established. 69,70 The contribution of the bone marrow in the development of epithelial cancers was first demonstrated in the gastric system. 71 This study involved infecting bone marrow chimeric mice with the carcinogen, Helicobacter, and subsequent tracking of the bone marrow-derived cells.…”