Abstract
Stanniocalcin-1 (STC1) is a paracrine factor associated with inflammation and carcinogenesis. Using clinicopathological data, we previously reported that a greater expression of STC1 in hepatocellular carcinoma (HCC) was significantly correlated with smaller tumor size. The underlying mechanism on the correlation is not known. In this study, using a metastatic HCC cell-line (MHCC-97L, P) and lentiviral vector mediated-STC1 overexpression, the inoculation of STC1-overexpressing MHCC-97L (S1) cells in a nude mice xenograft model demonstrated reductions in tumor mass and volume. As compared with P cells, S1 cells exhibited epithelial phenotype with significantly lower plating efficiency and reduced migratory and proliferative potential. Using coulter counter for cell-sizing, S1 cells (17.6 μm) were significantly smaller than P cells (19.6 μm). Western blot analysis revealed that S1 cells exhibited reduced expression level of phosphorylated ribosomal protein S6 (p-rpS6). Moreover, an inhibition of the upstream kinase p70S6K was evident with the dephosphorylation of Thr389 in the linker domain of the kinase. The inhibition of p70S6K/p-rpS6 pathway was accompanied with reduced cellular ATP level and increase of p-AMPK in S1 cells. Significantly lower rates of glycolysis and extracellular O2 consumption in S1 cells exhibited a lower cellular energy status. Since a faster rate of ATP production is essential to support cancer growth and metastasis, the present study identified the effect of STC1-overexpression on reducing energy metabolism, leading to an activation of AMPK pathway but an inhibition of p70S6K/p-rpS6 signaling to reduce tumor growth.
Highlights
Stanniocalcin-1 (STC1) is a fish hypocalcemic hormone that targets on fish gills to inhibit Ca2+transport
STC1 overexpression was established in the metastatic human hepatocellular carcinoma (MHCC-97L) using lentivirus approach
Boyden chamber assay revealed that the migratory responses of STC1-overexpressing MHCC97L (S1) was significantly lesser than P cells, with or without the addition of the hepatocyte growth factor (HGF) (Figure 2E)
Summary
Stanniocalcin-1 (STC1) is a fish hypocalcemic hormone that targets on fish gills to inhibit Ca2+transport. Recent works have revealed the association of STC1 expressions with various pathological mechanisms and diseases phenotypes, in particular to inflammation, tumor growth and metastasis [4, 5]. Considerable numbers of studies have shown differential expressions of STC1 in paired human tumor and normal tissues. Increased STC1 expression was mostly detected in human tumor samples of colorectal cancers and hepatocellular carcinomas (HCC) [8, 9], nonsmall cell lung cancer [10], ovarian cancer [11], breast carcinoma [12,13,14] and leukemia [15]. Many laboratory experiments have revealed that STC1 expression was associated with tumorigenesis in renal [16], breast and ovarian cancers [11, 17]. The association of greater expressions of STC1 in tumors with either poor or good prognosis is still not conclusive [5]
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