CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78)

Abstract

CD5-like (CD5L) is a soluble scavenger cysteine-rich protein that modulates inflammatory responses. We studied the involvement of CD5L in liver cancer. Immunohistochemistry (IHC) of CD5L in 60 hepatocellular carcinomas and 34 adjacent nontumor livers, showed that CD5L staining was higher in tumor than in nontumor tissue (Mann-Whitney test; P = 0.0039). High CD5L correlated with elevated proliferation (Ki67, linear regression; P < 0.0001) and lower patient event-free survival (log-rank; P = 0.0185). Accordingly, CD5L expression was detected in the liver cancer cell lines Huh7, HepG2, and SNU-398. In vitro technologies using these cell lines, including small interfering RNA (siRNA) and cDNA transfection, showed that CD5L promoted colony formation and cell proliferation and protected against cisplatin-induced apoptosis. To find a molecular explanation for these roles, novel CD5L-interacting protein ligands in liver cancer cells were identified by immunoprecipitation followed by mass spectrometry. Among these, the molecular chaperone of the unfolded protein response (UPR), heat shock protein (HSP)-A5, was selected for validation. The interaction was confirmed by confocal microscopy in the Huh7 and HepG2 cell lines. Furthermore, functional experiments revealed that CD5L activates the UPR and autophagy mechanisms in Huh7 cells, thereby providing a novel molecular link between the UPR and autophagy in liver cancer.-Aran, G., Sanjurjo, L., Bárcena, C., Simon-Coma, M., Téllez, É., Vázquez-Vitali, M., Garrido, M., Guerra, L., Díaz, E., Ojanguren, I., Elortza, F., Planas, R., Sala, M., Armengol, C., Sarrias, M.-R. CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78).

CD5L‑induced activation of autophagy is associated with hepatoprotection in ischemic reperfusion injury via the CD36/ATG7 axis

“…A recent study has demonstrated that increasing the level of autophagy decreases hepatic I/R injury (36). Previous studies have reported that CD5L increases macrophage survival and liver cancer cell survival by enhancing autophagy (12,16). These data indicate the participation of CD5L in promoting autophagy.…”

“…Various disease models, including cancer, have demonstrated that CD5L participates in cellular functions by preventing apoptosis (33,34). Human CD5L has also been demonstrated to inhibit apoptosis in liver cancer cell lines in response to cisplatin by inducing autophagy (12). A previous study has suggested that CD5L serves cytoprotective effects by binding to the CD36 receptor (16).…”

“…CD5L serves diverse roles in the relationship between lipid homeostasis and the immune response (11). CD5L localizes to cell surface receptor cluster of differentiation 36 (CD36) to promote the transcription of genes involved in the regulation of mitochondrial biogenesis to maintain energy and metabolic homeostasis; thus, CD5L may promote antiapoptotic effects in hepatocellular carcinoma (12,13). Therefore, exogenous CD5L may have beneficial effects in protecting liver from I/R induced injury.…”

“…Autophagy is a process of degradation and recycling of large molecules and dysfunctional organelles, protecting cells from apoptosis (15). As an inducer of autophagy, CD5L may serve a functional role in cytoprotection processes in macrophages and hepatocytes (12,16).…”

Serum proteins differentially expressed in early- and late-onset preeclampsia assessed using iTRAQ proteomics and bioinformatics analyses

“…LYVE1, CST3, and NCAM1 are also reportedly involved in placental vascular remodeling (Pawlak et al, 2019;Song et al, 2010;Zhang, Xu & Han, 2019). GRN, CD5L, ENO1, CHL1, CRISP3, VASN, and TNIK promote the invasive ability of tumor cells (Aran et al, 2018;Bhandari et al, 2019;Buhusi et al, 2003;Chon et al, 2016;Song et al, 2014;Voshtani et al, 2019;Wang et al, 2019). By contrast, SEMA4B, KRT1, KRT9, FBLN1, and PTGDS are involved in the anti-invasive activity of tumor cells (Blanckaert et al, 2015;Jian et al, 2015;Marano et al, 2018;Zhang et al, 2018).…”