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Stanniocalcin: A Cancer Biomarker.

Author:  Aashir Awan, PhD

Recently, a lot of attention has been given to developing better cancer diagnostic methods. Finding and validating cancer biomarkers has become an important tool for scientists and physicians in the frontline battle against this chronic epidemic. Various methods (e.g. microarray analysis) have been used to glean which specific proteins whose perturbations (upregulation or downregulation) are an indication of cancerous (or pre-cancerous) activity. One such molecule that is often mentioned is stanniocalcin (Chang et al., 2003).
It is a small family with two members, STC1 and STC2, that are thought to be secreted glycosylated proteins. And, both are found in a wide variety of cancers. Originally found in bony fish as a calcium/phosphate-regulating hormone, it is a homodimeric phosphoglycoprotein structurally. And, the proteins are thought to function in an autocrine/paracrine (rather than the classic endocrine) loop regulating intracellular calcium and/or phosphate levels (Yoskiko and Aubin, 2004).

Originally, STC1 showed up in a screen for mRNA differential display for genes that were related to cellular immortalization (Chang et al., 1995). While STC1 and STC2 are expressed in different tissues, they seem to have a special relationship to the reproductive tissues, hinting at a role in reproduction: STC1 expression is highest in the ovaries and STC2 is induced by the estrogen receptor. And, both are involved in breast cancer pathology. Other tissues where they are highly expressed include the kidney, bones, muscle, neurons (Worthington et al., 1999).
Fig2Physiologically, the proteins play a role in calcium and Pi homeostasis as demonstrated by studies on mouse transgenic models. In addition to cancer, the protein has been linked to atherosclerosis, hypoxia response and in wound repair (Lal et al., 2001; Iyer et al., 1999). Pharmacologically, an STC1 receptor has been deduced from studies and thought to be localized to the mitochondria where it has been shown to have a relationship with the mitochondrial electron transfer (McCudden et al., 2002).  Recent studies show that STC1 activates the mitochondrial antioxidant pathway through its regulation of intracellular calcium (Sheikh-Hamad, 2010).  Overall, STC1 and STC2 are thought to be secreted as phosphoproteins as demonstrated by coimmunoprecipitations of cellular lysates. And, it’s thought the proteins play a role in mineralizing tissues (e.g. bone) to control the levels of calcium and Pi via their influence on calcium channels and sodium/Pi co-transporters.  A schematic diagram showing how stannniocalcin might be have pro-apoptic functions is shown in Figure 1 (Yeung et al., 2012).

Table1However, stanniocalcin’s more prominent role is arguably as a cancer biomarker. Its expression has been shown to be affected in a number of different cancer pathologies. Table 1 shows a representative list of cancers where stanniocalcin levels are differentially expressed depending on the cancer. Thus, it appears that stanniocalcin is a good candidate cancer biomarker.  It is hypothesized that this is due in part to its role in tumor vasculature (Chang et al., 2003).  It should be noted that the list is but a brief compilation while stanniocalcin has been linked to other cancers as well.

At Vanderbilt University, studies were being done to evaluate the expression levels of YAP1 (Hippo pathway) during CNS development. Surprisingly, it was restricted to the choroid plexus (CP), a layer of epithelial cells lining the ventricles of the brain which are thought to act as a filtration system removing metabolic wastes. As such, primary cultures from mice (P=4) were cultured and evaluated. And, it was reported previously that stanniocalcin is expressed highly in CP. The expression of STC1 in choroid plexus epithelium would be consistent with the notion that stanniocalcin may have a role in regulation of calcium and Pi levels in cerebrospinal fluid (Franzén  et al., 2000). To verify that the primary culture were indeed CP cells, an immunofluorescent (IF) assay was done with CP markers including STC1 and STC2.  The following IF micrograph shows a generally a nuclear localization of STC2. In addition, since an extra channel was available for immunofluorescence, an acetlyated tubulin antibody was used to evaluate the cytoskelton.  Surprisingly, there was colocalization of this protein to the primary cilia/centriole (Fig. 2: Blue = DAPI (Nucleus); Red = Acetylated tubulin (primary cilia/centriole); Green = STC2.  The boxed regions show representative colocalizations of STC2 to the primary cilium/centriole).

Fig1

If the colocalization of the STC2 antibody is correct, this will be the first time that stanniocalcin has been localized to the primary cilium. Since the primary cilium has already been linked to different cancer pathologies due to its role as the gatekeeper of the cell cycle (Veland et al., 2009), it seems interesting that another cancer biomarker may now also be linked to the primary cilium.  Studies have shown that STC1 affects the cell cycle by regulating cyclin D1 and ERK 1/2 (Wang et al., 2012).  Thus, it raises more questions:

Is there cross-talk between the mitochondria and the primary cilium via stanniocalcin which might then have further repercussions on cell cycle fate?

Is the the primary cilia helping to coordinate calcium/Pi signal systems?

It almost seems logical that there would be a link between the primary cilium and this important class of protein due to their respective roles in cancer.  But, further research (including validation) is needed to further delineate whether this relationship exists.

REFERENCES

Chang AC, Janosi J, Hulsbeek M, de Jong D, Jeffrey KJ, Noble JR, Reddel RR 1995 A novel human cDNA highly homologous to the fish hormone stanniocalcin. Mol Cell Endocrinol. 112:241-247.

Chang AC, Jellinek DA, Reddel RR. 2003 Mammalian stanniocalcins and cancer. Endocr Relat Cancer 10:359-373.

Franzén AM, Zhang KZ, Westberg JA, Zhang WM, Arola J, Olsen HS, Andersson LC 2000 Expression of stanniocalcin in the epithelium of human choroid plexus. Brain Res 887:440-443.

Iyer VR, Eisen MB, Ross DT, Schuler G, Moore T, Lee JCF, Trent JM, Staudt LM, Hudson J Jr, Boguski MS, Lashkari D, Shalon D, Botstein D & Brown PO 1999 The transcriptional program in the response of human fibroblasts to serum. Science 283 83–87.

Lal A, Peters H, St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, Kaanders JHAM, van der Kogel AJ & Riggins GJ 2001 Transcriptional response to hypoxia in human tumors. J National Cancer Institute 93 1337–1343.

McCudden CR, James KA, Hasilo C & Wagner GF 2002 Characterization of mammalian stanniocalcin receptors: mitochondrial targeting of ligand and receptor for regulation of cellular metabolism. J Biol Chem 277: 45249–45258.

Sheikh-Hamad D. 2010  Mammalian stanniocalcin-1 activates mitochondrial antioxidant pathways: new paradigms for regulation of macrophages and endothelium. Am J Physiol Renal Physiol. 298:F248-F254.

Veland IR, Awan A, Pedersen LB, Yoder BK, Christensen ST 2009 Primary cilia and signaling pathways in mammalian development, health and disease. Nephron Physiol 111:39-53.

Wang H, Wu K, Sun Y, Li Y, Wu M, Qiao Q, Wei Y, Han ZG, Cai B. 2012 STC2 is upregulated in hepatocellular carcinoma and promotes cell proliferation and migration in vitro. BMB Rep. 45:629-634.

Worthington RA, Brown L, Jellinek D, Chang AC, Reddel RR, Hambly BD, Barden JA. 1999 Expression and localisation of stanniocalcin 1 in rat bladder, kidney and ovary. Electrophoresis 20:2071-2076.

Yeung BH, Law AY, Wong CK 2012 Evolution and roles of stanniocalcin. Mol Cell Endocrinol 349:272-280.

Yoshiko Y and Aubin JE 2004 Stanniocalcin 1 as a pleiotropic factor in mammals. Peptides 25:1663-1669.

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