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).
Physiologically, 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).
However, 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).
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
2012pharmaceutical
Amandeep Kaur
Aashir Awan, Phd
Abhisar Anand
Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
alexcrystal6
anamikasarkar
apreconasia
aviralvatsa
David Orchard-Webb, PhD
danutdaagmailcom
Demet Sag, Ph.D., CRA, GCP
Dror Nir
dsmolyar
Ethan Coomber
evelinacohn
Gail S Thornton
Irina Robu
jayzmit48
jdpmd
jshertok
kellyperlman
Ed Kislauskis
larryhbern
Madison Davis
marzankhan
megbaker58
ofermar2020
Dr. Pati
pkandala
Rosalind Codrington, PhD
ritusaxena
Rick Mandahl
sjwilliamspa
Srinivas Sriram
stuartlpbi
Dr. Sudipta Saha
tildabarliya
vaishnavee24
zraviv06
zs22