Paracrine effects of CCN3 from non-cancerous hepatic cells increase signaling and progression of hepatocellular carcinoma

Since the authors first reviewed this subject in 2016 significant progress has been documented in the CCN field with advances made in the understanding of how members of the CCN family of proteins, CCN1‐6, contribute to the pathogenesis and progression, positive and negative, of a larger variety of cancers. As termed matricellular proteins, and more recently the connective communication network, it has become clearer that members of the CCN family interact complexly with other proteins in the extracellular microenvironment, membrane signaling proteins, and can also operate intracellularly at the transcriptional level. In this review we expand on this earlier information providing new detailed information and insights that appropriate a much greater involvement and importance of their role in multiple aspects of cancer. Despite all the new information many more questions have been raised and intriguing results generated that warrant greater investigation. In order to permit the reader to smoothly integrate the new information we discuss all relevant CCN members in the context of cancer subtypes. We have harmonized the nomenclature with CCN numbering for easier comparisons. Finally, we summarize what new has been learned and provide a perspective on how our knowledge about CCN1‐6 is being used to drive new initiatives on cancer therapeutics.

Section: Lymphoma and Leukemiasmentioning

confidence: 99%

Section: Liver Cancermentioning

confidence: 99%

The CCN axis in cancer development and progression

Yeger

Perbal²

2021

“…1 CCN3 binds to cell surface receptors and mediates cell proliferation, differentiation, adhesion and chemotaxis regulatory effect of CCN3 on CCN2 and the inhibitory effect of CCN3 on collagen deposition were investigated in a diabetic nephropathy model (Riser et al 2010). Similar results were also observed in skin fibroblasts (Riser et al 2012), hepatic stellate cells (Li et al 2019), human mesangial cells (Liu et al 2018), progressive glomerulonephritis model (Roeyen et al 2012), scleroderma mouse model (Lemaire et al 2010). However, overexpression of CCN3 in TGFβ-stimulated human mesangial cells (HMCs) upregulates the expression of matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2) at both mRNA and protein levels, and downregulates the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) (Liu et al 2018).…”

Section: The Inhibitory Effect Of Ccn3 On Fibrosismentioning

confidence: 77%

The advance of CCN3 in fibrosis

Yin

Liu

Zhou

et al. 2023

The extracellular matrix (ECM) is comprised of various extracellular macromolecules, including collagen, enzymes, and glycoproteins, which offer structural and biochemical support to neighboring cells. After tissue injury, extracellular matrix proteins deposit in the damaged tissue to promote tissue healing. However, an imbalance between ECM production and degradation can result in excessive deposition, leading to fibrosis and subsequent organ dysfunction. Acting as a regulatory protein within the extracellular matrix, CCN3 plays a crucial role in numerous biological processes, such as cell proliferation, angiogenesis, tumorigenesis, and wound healing. Many studies have demonstrated that CCN3 can reduce the production of ECM in tissues through diverse mechanisms thereby exerting an inhibitory effect on fibrosis. Consequently, CCN3 emerges as a promising therapeutic target for ameliorating fibrosis.

“…In hepatic fibrosis, CCN3 is increased expressed and mainly found in non‐parenchymal cells, stimulate the migration of HSC and induce hepatocyte apoptosis, while the suppression of CCN3 enhanced expression of profibrotic marker proteins in primary HSC (Borkham‐Kamphorst et al 2012a, 2012b). Moreover, increased CCN3 is associated with metastasis, more severe cirrhosis, increased EMT, and further inversely related to the prognosis of HCC (Li et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Expression and biological function of the cellular communication network factor 5 (CCN5) in primary liver cells

Borkham-Kamphorst

Meurer

Weiskirchen

2023

The cellular (centralized) communication network (CCN) factor protein family contains six small secreted cysteine-rich proteins sharing high structural similarity. These matricellular proteins have vital biological functions in cell adhesion, migration, cell cycle progression, and control of production and degradation of extracellular matrix. However, in liver the biological functions of CCN proteins become most visible during hepatic injury, disease, and remodeling. In particular, most of the hepatic functions of CCN proteins were derived from CCN2/CTGF, which becomes highly expressed in damaged hepatocytes and acts as a profibrogenic molecule. On the contrary, CCN1/CYR61 seems to have opposite effects, while the biological activity during hepatic fibrosis is somewhat controversially discussed for other CCN family members. In the present study, we analyzed the expression of CCN5/WISP2 in cultures of different types of primary liver cells and in an experimental model of hepatic fibrosis. We found that CCN5 is expressed in hepatic stellate cells, myofibroblasts and portal myofibroblasts, while CCN5 expression is virtually absent in hepatocytes. During hepatic fibrogenesis, CCN5 is significantly upregulated. Overexpression of CCN5 in portal myofibroblasts reduced expression of transforming growth factor-β receptor I (ALK5) and concomitant Smad2 activation, whereas JunB expression is upregulated. Moreover, elevated expression of CCN5 induces endoplasmic reticulum stress, unfolded protein response and apoptosis in portal myofibroblasts. We suggest that upregulated expression of CCN5 might be an intrinsic control mechanism that counteracts overshooting fibrotic responses in profibrogenic liver cells. Graphical abstract