Stanniocalcin-1 (STC1) is an endocrine hormone originally discovered in the corpuscles of Stannius, endocrine glands on kidneys of bony fishes, and also has been identified in mammals. The mammalian STC1 gene is widely expressed in various tissues and appears to be involved in diverse biological processes. There is growing evidence to suggest that altered patterns of gene expression have a role in human cancer development. Recently STC1 has been identified as a stimulator of mitochondrial respiration and has been hypothesized to be functionally related to the Warburg effect, of which hypoxia-inducible factor (HIF)-1 plays a key role in reprogramming tumor metabolism. This prompted us to examine the involvement of HIF-1 in the regulation of STC1 expression in tumor hypoxia. Our data reveal that hypoxia can stimulate STC1 gene expression in various human cancer cell lines, including those derived from colon carcinomas, nasopharyngeal cancer (CNE-2, HONE-1, HK-1), and ovarian cancer (CaOV3, OVCAR3, SKOV3). By far, the greatest response was observed in CNE-2 cells. In further studies on CNE-2 cells, desferrioxamine, cobalt chloride, and O2 depletion all increased HIF-1α protein and STC1 mRNA levels. Desferrioxamine treatment, when coupled with Fe replenishment, abolished these effects. RNA interference studies further confirmed that endogenous HIF-1α was a key factor in hypoxia-induced STC1 expression. The ability of vascular endothelial growth factor to stimulate STC1 expression in CNE-2 cells was comparatively low. Collectively, the present findings provide the first evidence of HIF-1 regulation of STC1 expression in human cancer cells. The studies have implications as to the role of STC1 in hypoxia induced adaptive responses in tumor cells.

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The aim of the present project is to determine the feasibility of measuring hepatic cytochrome P4501A1 (CYP1A1) and metallothionein (MT) mRNA in fish as an integrative measurement of persistent organic pollutants (POPs) and heavy metal contamination in sediment arising in Hong Kong. Sediment samples were collected from different sites, including Victoria Harbour (VS6), Yim Tin Tsai (YTT) at Tolo Harbour, Mai Po marshes (MPM) at Deep Bay, and Southern Waters (SS6) of coastal waters. The samples were analyzed for total and extractable concentrations of Cd, Cu, Ni, Zn, and Pb, as well as PCBs and PAHs. In addition, biomarker responses were studied in tilapia exposed experimentally to coastal sediment for 7 days. Using RT-PCR technique, hepatic CYP1A1 and MT mRNA were measured. Three control groups were used, including one negative control group maintained in sea water only; the second and third positive control groups were in sea water but were intraperitoneally injected with either beta-naphthoflavone (40 microg/g body weight) or cadmium chloride (10 microg/g body weight), respectively. The chemical data showed that VS6, YTT, and MPM were classified as Class C sediment according to the sediment quality criteria defined by the Hong Kong Environmental Protection Department, indicating the sites were heavily polluted. The exposure of tilapia to the sediment induced hepatic CYP1A1 (VS6 > YTT > MPM > SS6) and MT (VS6 > MPM > YTT > SS6) levels. The induction patterns were comparable to the levels of POPs and metal contamination in the sediment, indicating that the biomarker responses could be used to differentiate low to high levels of contamination among sediment.

Stanniocalcin is a polypeptide hormone that was first reported in fish as a regulator of mineral metabolism. Its recent identification in mammals has opened a new area of investigation in basic and clinical endocrinology. In the present study, regulation of the stanniocalcin (STC) and stanniocalcin related protein (STCrP) genes were investigated in mouse neuroblastoma cells (Neuro-2A) in relation to neuronal cell differentiation. Neuro-2A is an undifferentiated cell line that contains measurable levels of STCrP mRNA, but undetectable levels of STC mRNA. Treatment of the cells with either dbcAMP (1-4 mM) or 50 µM euxanthone (PW1) resulted in extensive differentiation and neurite outgrowth. However, only neurites of dbcAMP-treated cells developed varicosities, a phenotypic marker of axon formation. Furthermore, following differentiation induced by dbcAMP, there was an upregulation of STC and downregulation of STCrP mRNA levels. In the first 24 and 48 h of treatments, there was a maximum twofold induction and 1·5-fold reduction in STC and STCrP mRNAs respectively. Following 96 h of treatment, an additional 14-fold STC induction and 1·2-fold STCrP reduction were observed. The increase in STC mRNA levels was accompanied by a concomitant increase in axon-specific low molecular form microtubuleassociated protein (MAP-2c) mRNA and varicosities on the neurites, suggesting a possible role for STC in axonogenesis. There was no induction of STC mRNA levels when PW1 was added into the culture media, whereas ionomycin (1-10 µM) had no observable effects on cell differentiation or STC/STCrP mRNA. Immunocytochemical staining of dbcAMP-treated cells revealed abundant levels of immunoreactive STC, particularly in the varicosities, with only weak staining in control, untreated cells. Antisense oligodeoxynucleotides transfection studies indicated that the expression of STC was a cause of varicosity formation and a consequence of cell differentiation. Our findings lend further support to the notion that STC is involved in the process of neural differentiation.

A case of angiosarcoma (malignant hemangioendothelioma) developing in a chronic goitrous thyroid gland of an elderly Chinese woman is described. Histologically it showed the same classical appearance of angiosarcoma occurring in the skin and soft tissue. The endothelial origin of this tumor was confirmed by demonstrating Factor VIII-related antigen in the neoplastic cells with the immunoperoxidase technique and Weibel-Palade bodies by electron microscopic study. Because of its extreme rarity outside the European Alpine regions, many authorities are reluctant to accept it as a distinct entity and merely consider it as a variant of an undifferentiated carcinoma. Our report not only provides additional evidence that angiosarcoma of the thyroid gland is a specific condition of endothelial origin but also documents the first case among Chinese.

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Stanniocalcin (STC) is a new mammalian polypeptide hormone and appears to be a regulator of neuronal function. We have already shown that the induction of STC mRNA and protein expression by cAMP is integral to neuroblastoma cell differentiation, particularly neurite outgrowth. In this study, we examined the cAMP pathway in greater detail. Some common neuritogenic agents, euxanthone (PW1) and trans-retinoic acid (RA), were studied for possible interactions with the dibutyryl cAMP (dbcAMP)-mediated response. Our results showed that STC mRNA induction by dbcAMP was mediated by protein kinase A-cAMP response element binding protein (CREB) pathway, accompanied with phosphorylation of CREB and a reduction of p50, p65, and phosphorylated inhibitor kappaBalpha levels. Using a synthetic peptide nuclear factor-kappaB SN50, stimulation of dbcAMP-mediated STC expression was observed; indicating the nuclear translocation of nuclear factor kappaB might possibly repress STC expression. dbcAMP-induced STC mRNA expression was enhanced by PW1. In contrast, RA had highly suppressive effects. Cotreatment of cell with PW1 and cAMP provoked an increase in phosphorylated CREB (pCREB). Conversely, cotreatment with RA suppressed pCREB. The results highlighted the importance of phosphorylation of CREB in mediating STC gene expression. Taking a step further to dissect the possible regulatory pathways involved, with the aid of phorbol 12-myristate 13-acetate or ionomycin, additive effects on STC gene expression were observed. The induction was aided by further elevation of pCREB, which was completely abolished by Gö 6976, a Ca2+-dependent protein kinase C (PKC) alpha and PKCbeta1 inhibitor. Our results indicated that cross-talk with PKC and/or Ca2+ signaling pathways might sensitize cAMP-mediated effects, on CREB phosphorylation and STC gene expression.

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