Study of the expression and regulation of L-CAD in breast and colorectal cancers and its role in tumor progression

Breast cancer (BC) and colorectal cancer (CRC) are the most diagnosed cancers worldwide. Both BC and CRC cells have the ability to metastasize to different parts of the body such as liver, bone, lung and brain. Many factors play a role in tumorgenesis and enhancing cells to lose the control of growth and to move to other parts in metastatic stage. The epithelial to mesenchymal transition (EMT) is a cellular program that is involved in tumorigenesis of most cancers causing drug resistance and death. The process is begins when alterations in the cytoskeletal organization and associated changes in cell morphology dissolution of epithelial cell–cell junction acquisition of motility occur, as well as an ability to degrade and reorganize the extracellular matrix (ECM), enabling cell invasion. All of this depends on the assembly and disassembly of actin filaments which is part of the contractile apparatus, in muscle and nonmuscle cells. Many actin-binding proteins (ABPs) are also critical in maintaining cell structure and organize cytoskeletal one of which our study is about, Caldesmon (CALD-1). CALD-1 was initially identified as a regulatory factor for the actin-myosin interaction. Via alternative splicing, CALD-1 is found in two isoforms, the high-molecular weight, is restricted to smooth muscle cells while the low-molecular- weight isoforms are present in non-smooth muscle cells (L-CAD; 70-80 kDa). L-CAD is broadly implicated in many aspects of cell motility, including cell migration and focal adhesion assembly. L-CAD is emerging as an attractive biomarker of tumor progression and response to therapy in carcinomas but very few studies have been done on it. In normal tissues CALD-1 expression is found to be fairly high in CRC and next is GI tract. CALD-1 in BC is relatively high compared to other tissue (Bioinformatics, genecard.org). In cancers cases as found in the Human Protein Atlas, CALD-1 is highly expressed in GI and next is prostate, pancreatic followed by BC which is more than CRC. Many researchers found to be done on CALD-1 in different types of cancers such as gastric cancer, lung cancer, prostate cancer and bladder cancer, but different expressions of the gene play different role regarding tumor progression. CALD-1 siRNA had promigratory and pro-invasive effects in human BC cells with low invading cell number as described in (Darren E.etal 2013). In this study we selected a specific caldesmon isoform (L-CAD) in BC cell line and performed silencing experiment, we found that there is a reduction in cell motility and invasion.
This need to be investigated and more molecular function of CALD-1 need to be studied. CALD- 1 expression and function have been controversial in many carcinomas regarding the expression level and how it effects on tumor. In some studies, overexpression of caldesmon is associated with increase cell motility and induce EMT and metastasis. However, it is also found that CALD1 expression was significantly lower in malignant compared to benign ovarian tumor tissue. These conflicting results found in different malignancies might be due to different caldesmon 1 isoforms, produced by alternative splicing that we need to investigate and to study the effect of P53 status and its role in the L-CAD expression in CRC cell lines. As well as to study the expression with some functional analysis in BC cell lines and in BC tissues with different molecular subtypes. Clinical implication of CALD-1 in caner is needed and by exploring the potential value of its isoforms expression in BC and CRC more insight into the molecular function will be revealed.