Abstract
Tectonic family member 2 (TCTN2) encodes a transmembrane protein that belongs to the tectonic family, which is involved in ciliary functions. Previous studies have demonstrated the role of tectonics in regulating a variety of signaling pathways at the transition zone of cilia. However, the role of tectonics in cancer is still unclear. Here we identify that TCTN2 is overexpressed in colorectal, lung and ovary cancers. We show that different cancer cell lines express the protein that localizes at the plasma membrane, facing the intracellular milieu. TCTN2 over-expression in cancer cells resulted in an increased ability to form colonies in an anchorage independent way. On the other hand, downregulation of TCTN2 using targeted epigenetic editing in cancer cells significantly reduced colony formation, cell invasiveness, increased apoptosis and impaired assembly of primary cilia. Taken together, our results indicate that TCTN2 acts as an oncogene, making it an interesting cancer-associated protein and a potential candidate for therapeutic applications.
Highlights
Cilia are microtubule-based organelles extending from the cell surface, which play a pivotal role in eukaryotic biology
During the screening of this antibody library on Tissue microarrays (TMAs) containing cancerous and normal formalin-fixed paraffinembedded (FFPE) samples from breast, colorectum, lung, ovary and prostate (5 tumor and 5 matched normal samples, in duplicate), we found that a polyclonal antibody raised against a recombinant domain of TCTN2, encompassing the protein region from amino acid 170 to amino acid 443, detected the expression of its target protein in cancer samples of colon (3/5), lung (2/5) and ovary cancers (2/5) whereas it gave a negligible staining in the corresponding normal tissues (Supplementary Figure 1)
An IHC scoring system based on a combined evaluation of the intensity of mAb staining multiplied by the percentage of positive cancer cells, showed that a higher fraction of samples with strong or moderate staining (IHC score >100) in colorectal (30%) vs lung (10%) and ovary (0%) cancers, suggesting a highest expression of TCTN2 in colorectal cancer (Table 1)
Summary
Cilia are microtubule-based organelles extending from the cell surface, which play a pivotal role in eukaryotic biology. A number of critical cell signaling and adhesion molecules are clustered in the cilium, and require an intact cilium for normal function [3, 5, 14] These include components of the Shh and Wnt signaling pathways, whose activation/inactivation has been linked to several types of cancer [15]. TCTN1 is important to maintain active Hh signaling during neural tube development [19] Tectonics could exert their activity in signal transduction through their functional interaction with MKS1, a ciliary basal body protein that has a potential role in regulating both Wnt signaling, which regulates cell proliferation and its alteration causes different diseases, including cancer. All these data together suggest that TCTN2 could be a novel oncogene and that it could be exploited as potential candidate for therapeutic applications
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