Catenin - Clinical Significance

Clinical Significance

As previously mentioned, the same properties of catenin that give it an important role in normal cell fate determination, homeostasis and growth, also make it susceptible to alterations that can lead to abnormal cell behavior and growth. Any changes in cytoskeletal organization and adhesion can lead to altered signaling, migration and a loss of contact inhibition that can promote cancer development and tumor formation. In particular, catenins have been identified to be major players in aberrant epithelial cell layer growth associated with various types of cancer. Mutations in genes encoding these proteins can lead to inactivation of cadherin cell adhesions and elimination of contact inhibition, allowing cells to proliferate and migrate, thus promoting tumorigenesis and cancer development. Catenins are known to be associated with colorectal and ovarian cancer, and they have been identified in pilomatrixoma, medulloblastoma, pleomorphic adenomas, and malignant mesothelioma.

While less is known about the exact mechanism of α-catenin, its presence in cancer is widely felt. Through the interaction of β-catenin and α-catenin, actin and E-cadherin are linked, providing the cell with a means of stable cell adhesion. However, decreases in this adhesion ability of the cell has been linked to metastasis and tumor progression. In normal cells, α-catenin may act as a tumor suppressor and can help prevent the adhesion defects associated with cancer. On the other hand, a lack of α-catenin can promote aberrant transcription, which can lead to cancer. As a result, it can be concluded, that cancers are most often associated with decreased levels of α-catenin.

β-catenin also likely plays a significant role in various forms of cancer development. However, in contrast to α-catenin, heightened β-catenin levels may be associated with carcinogenesis. In particular, abnormal interactions between epithelial cells and the extracellular matrix are associated with the over-expression of these β-catenins and their relationship with cadherins in some cancers. Stimulation of the Wnt/β-catenin pathway, and its role in promoting malignant tumor formations and metastases, has also been implicated in cancers.

The role of catenin in epithelial-mesenchymal transition (or EMT) has also received a lot of recent attention for its contributions to cancer development. It has been shown that HIF-1α can induce the EMT pathway, as well as the Wnt/β-catenin signaling pathway, thus enhancing the invasive potential of LNCaP cells (human prostate cancer cells). As a result, it is possible that the EMT associated with upregulated HIF-1α is controlled by signals from this Wnt/β-catenin pathway. Catenin and EMT interactions may also play a role in hepatocellular carcinoma. VEGF-B treatment of hepatoma carcinoma cells can cause α-catenin to move from its normal location on the membrane into the nucleus and E-cadherin expression to decrease, thus promoting EMT and tumor invasiveness.

There are other physiological factors that are associated with cancer development through their interactions with catenins. For instance, higher levels of collagen XXIII have been associated with higher levels of catenins in cells. These heightened levels of collagen helped facilitate adhesions and anchorage-independent cell growth and provided evidence of collagen XXIII’s role in mediating metastasis. In another example, Wnt/β-catenin signaling has been identified as activating microRNA-181s in hepatocellular carcinoma that play a role in its tumorigenesis.