a b s t r a c tDiabetic nephropathy (DN) is a major diabetic complication. However, the initiating molecular events triggering DN are unknown. In this study we focused on microRNA-451 (miR-451), which is downregulated during early DN. We found that miR-451 negatively regulated the expression of Ywhaz through Ywhaz 3 0 UTR and that Ywhaz was required for the miR-451-mediated downregulation of p38 MAPK signalling. Moreover, over-expression of miR-451 inhibits glomerular mesangial cell proliferation in vitro and in vivo. These findings suggest that the growth-inhibitory effect of miR-451 may be explained in part by miR-451-induced suppression of Ywhaz and p38 MAPK signalling, providing evidence for the potential role of miR-451 in early DN.

The S100 protein family member S100A4 regulates various cellular functions. Previous studies have shown that elevated expression of S100A4 is associated with progression and metastasis of colorectal cancer (CRC). However, little is known about whether and how S100A4 contributes to CRC development. In our present study, the elevated expression of S100A4 in CRC tissues compared to matched adjacent normal tissues was confirmed by immunohistochemistry, semi-quantitative RT-PCR and Western blot. Adenovirus-mediated S100A4 overexpression obviously enhanced viability and migration of CRC cells, which was detected by MTT assay and transwell assay, respectively. Additionally, S100A4 overexpression increased the phosphorylation levels of Akt, mTOR and p70S6K. These effects of S100A4 were abolished by treatment with either the specific PI3K/Akt inhibitor LY294002, or the specific mTOR/p70S6K inhibitor rapamycin. Furthermore, overexpression of S100A4 resulted in upregulation of VEGF and downregulation of E-cadherin, which were strongly reversed by either LY294002 or rapamycin. Altogether, our results demonstrate that activation of the PI3K/Akt/mTOR/p70S6K signaling pathway is involved in S100A4-induced viability, migration, upregulation of VEGF and downregulation of E-cadherin in CRC cells.

No abstract

The S100A6 protein, a member of the S100 protein family, is overexpressed in many tumors including colorectal carcinoma (CRC). Although recent studies showed that the elevated expression of S100A6 was associated with the stage and lymphatic permeation of CRC, little is known about whether and how S100A6 contributes to CRC development. Here we investigated the S100A6 expression in CRC tissues and cell lines, and explored the molecular mechanisms underlying the role of S100A6 in CRC development by examining cell proliferation and migration in vitro, and tumorigenicity in nude mice. The results show that S100A6 expression was markedly increased in CRC tissues and cell lines compared to normal colon tissues and a normal colon mucosal epithelial cell line, respectively. Recombinant adenovirus-mediated overexpression of S100A6 or treatment with recombinant S100A6 protein in HCT116, a CRC cell line with relative low S100A6 expression, resulted in enhanced cell proliferation and migration, and the mitogen-activated protein kinase (MAPK) activation in vitro, and tumor growth in vivo. Conversely, RNAi-mediated knockdown of S100A6 in LoVo, a CRC cell line with relative high S100A6 expression, resulted in reduced cell proliferation, migration and MAPK activity. S100A6-induced proliferation was partially attenuated by an ERK inhibitor while migration was suppressed by a p38 inhibitor. Taken together, our results suggest that the cellular effects of S100A6 are mediated by the ERK and p38 MAPK pathways, and modulation of these pathways may be employed for CRC prevention and therapy.

No abstract