Heat shock protein 22 (HSPB8) reduces the migration of hepatocellular carcinoma cells through the suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway

Abstract

Small heat shock proteins (HSPs) regulate a variety of cell functions. Among them, HSP22 and HSP20 are recognized to be ubiquitously expressed in various tissues. With regard to hepatocellular carcinoma (HCC) cells, we previously reported that phosphorylated HSP20 plays a suppressive role in transforming growth factor (TGF)-α-induced cell migration and invasion. In the present study, we investigated whether or not HSP22 is implicated in HCC cell migration. We detected HSP22 protein expression both in human HCC tumor (189.9±68.4ng/mg protein) and the adjacent non-tumor liver tissues (167.9±94.6ng/mg protein). The cases of low-quantity HSP22 protein level group (88.3≧ng/mg protein, the optimum cut-off value of HSP22) were increased in tumor tissues compared with the adjacent non-tumor tissues. The migration of human HCC-derived HuH-7 cells stimulated by TGF-α or hepatocyte growth factor (HGF) was significantly enhanced by the knockdown of HSP22 expression. Down-regulation of HSP22 protein in the cells markedly strengthened the AKT phosphorylation induced by TGF-α or HGF. Inhibitors of the phosphoinositide 3-kinase (PI3K)/AKT pathway, which suppressed the TGF-α-induced migration, significantly reduced the amplification by HSP22 knockdown. PI3K but not AKT was coimmunoprecipitated with HSP22 in HuH-7 cells. In addition, in human HCC tissues, a significantly lower HSP22 protein level in tumor tissues than in adjacent non-tumor tissues was observed more frequently in cases of moderately or poorly differentiated HCC than well-differentiated HCC. Taken together, our results strongly suggest that HSP22 represses HCC progression, especially HCC cell migration, by the down-regulation of the PI3K/AKT signaling pathway.

Olive oil polyphenols suppress the TGF‑α‑induced migration of hepatocellular carcinoma cells

“…This study group recently demonstrated that TGF-α induced the migration of HuH7 cells via the SAPK/JNK (18) and AKT (19) pathways. Therefore, the present study examined whether or not the ERK, p38 MAPK and Rho kinase pathways were also involved in the TGF-α-induced HuH7 cell migration.…”

“…A Transwell cell migration assay was performed using a Boyden chamber (polycarbonate membrane with 8 µm pores, Transwell; Costar; Corning, Inc.) as described previously (18,19). Briefly, the cultured cells were seeded (1x10 5 cells/well) onto the upper chamber in serum-free RPMI-1640 medium.…”

“…Blocking was performed prior to incubation with the primary antibodies using 5% skim milk for 1 h at room temperature. Western blot analyses were performed as described previously (18,19,21) using phospho-specific AKT (T308) (1:1,000), AKT (1:10,000), phospho-specific SAPK/JNK (1:1,000), SAPK/JNK (1:3,000), phospho-specific p38 MAPK (1:20,000), p38 MAPK (1:20,000), phospho-specific MYPT-1 (1:1,000), MYPT-1 (1:1,000) and GAPDH (1:1,000) antibodies with horseradish peroxidase (HRP)-labeled anti-rabbit IgG and anti-mouse IgG antibodies (1:1,000; cat. nos., 7074 and 7076, respectively, Cell Signaling Technology, Inc.) as secondary antibodies.…”

Association of HSP22 with mTOR in osteoblasts: regulation of TNF‐α‐stimulated IL‐6 synthesis

“…We have previously demonstrated that HSP22 is expressed in human ovarian cancer cells, and enhances the transforming growth factor (TGF)‐α‐induced cell migration . In our recent study , we have shown that HSP22 directly interact with phosphoinositide 3‐kinase (PI3K) in human hepatocellular carcinoma cells, and regulate the cell proliferation and the migration. However, the precise role of HSP22 remains to be clarified.…”

“…We have previously demonstrated that HSP22 is expressed in human ovarian cancer cells, and enhances the transforming growth factor (TGF)-a-induced cell migration [14]. In our recent study [15], we have shown that Abbreviations HSPs, heat shock proteins; IL, interleukin; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; TGF, transforming growth factor. HSP22 directly interact with phosphoinositide 3-kinase (PI3K) in human hepatocellular carcinoma cells, and regulate the cell proliferation and the migration.…”