ABSTRACT
The liver has an inherent regenerative capacity via hepatocyte proliferation after mild-to-modest damage. When hepatocytes exhaust their replicative ability during chronic or severe liver damage, liver progenitor cells (LPC), also termed oval cells (OC) in rodents, are activated in the form of ductular reaction (DR) as an alternative pathway. LPC is often intimately associated with hepatic stellate cells (HSC) activation to promote liver fibrosis. The Cyr61/CTGF/Nov (CCN) protein family consists of six extracellular signaling modulators (CCN1-CCN6) with affinity to a repertoire of receptors, growth factors, and extracellular matrix proteins. Through these interactions, CCN proteins organize microenvironments and modulate cell signalings in a diverse variety of physiopathological processes. In particular, their binding to subtypes of integrin (αvß5, αvß3, α6ß1, αvß6, etc.) influences the motility and mobility of macrophages, hepatocytes, HSC, and LPC/OC during liver injury. This paper summarizes the current understanding of the significance of CCN genes in liver regeneration in relation to hepatocyte-driven or LPC/OC-mediated pathways. Publicly available datasets were also searched to compare dynamic levels of CCNs in developing and regenerating livers. These insights not only add to our understanding of the regenerative capability of the liver but also provide potential targets for the pharmacological management of liver repair in the clinical setting. Ccns in liver regeneration Restoring damaged or lost tissues requires robust cell growth and dynamic matrix remodeling. Ccns are matricellular proteins highly capable of influencing cell state and matrix production. Current studies have identified Ccns as active players in liver regeneration. Cell types, modes of action, and mechanisms of Ccn induction may vary depending on liver injuries. Hepatocyte proliferation is a default pathway for liver regeneration following mild-to-modest damages, working in parallel with the transient activation of stromal cells, such as macrophages and hepatic stellate cells (HSC). Liver progenitor cells (LPC), also termed oval cells (OC) in rodents, are activated in the form of ductular reaction (DR) and are associated with sustained fibrosis when hepatocytes lose their proliferative ability in severe or chronic liver damage. Ccns may facilitate both hepatocyte regeneration and LPC/OC repair via various mediators (growth factors, matrix proteins, integrins, etc.) for cell-specific and context-dependent functions.
ABSTRACT
Liver fibrosis is a common outcome of most chronic liver insults/injuries that can develop into an irreversible process of cirrhosis and, eventually, liver cancer. In recent years, there has been significant progress in basic and clinical research on liver cancer, leading to the identification of various signaling pathways involved in tumorigenesis and disease progression. Slit glycoprotein (SLIT)1, SLIT2, and SLIT3 are secreted members of a protein family that accelerate positional interactions between cells and their environment during development. These proteins signal through Roundabout receptor (ROBO) receptors (ROBO1, ROBO2, ROBO3, and ROBO4) to achieve their cellular effects. The SLIT and ROBO signaling pathway acts as a neural targeting factor regulating axon guidance, neuronal migration, and axonal remnants in the nervous system. Recent findings suggest that various tumor cells differ in SLIT/ROBO signaling levels and show varying degrees of expression patterns during tumor angiogenesis, cell invasion, metastasis, and infiltration. Emerging roles of the SLIT and ROBO axon-guidance molecules have been discovered in liver fibrosis and cancer development. Herein, we examined the expression patterns of SLIT and ROBO proteins in normal adult livers and two types of liver cancers: hepatocellular carcinoma and cholangiocarcinoma. This review also summarizes the potential therapeutics of this pathway for anti-fibrosis and anti-cancer drug development.
