Protein p53 is implicated in the control of cell cycle, apoptosis

Protein p53 is implicated in the control of cell cycle, apoptosis, DNA repair and angiogenesis and deregulation of p53 favors the development of liver tumor [31]. The loss of p53 has been described in many types of human tumors, particularly in 30%�C60% of hepatocelular carcinoma contributing with the tumor progression [32]. The increases of c-myc observed in hepatocytes obtained by CM2 and the Wnt/��-catenin activation could also suggest a transformation of these cells into CSC. This hypothesis is reinforced with data obtained in CM2-treated cells related to an abnormal proliferation, higher PCNA expression, cell cycle alteration and secondary spheroids formation. These results suggest that in contrast to undifferentiated or CM1-treated cells, CM2-treated cells conserve stemness capability.

This capability to form spheroids is intrinsic of stem cells or CSC. Sphere forming ability is known to be one of properties of CSCs [33], [34]. Secondary spheres formation after seeding cells at clonal density confirms that spheres formation reflects auto-renewal rather than cell aggregation. In addition the increased expression of CD13, CD49e, CD133, CD166 or VEGFR2 in CM2-treated cells suggests also similarities to CSC. Some proteins as CD13 or CD49e participate in process of chemotaxis, invasion and metastasis of malignant cells [35]. CD13 is an aminopeptidase N with matrix metalloproteinase activity that has been shown to play a role in tumor angiogenesis, invasion and metastasis, radiation resistance, and antiapoptosis [36], [37] and it has been involved with human liver CSC [38].

Haraguchi et al showed that the suppression of CD13 inhibited self renewal and the tumor initiation ability of CD13+cells [38]. CD49e, also known as integrin ��5, is identified as one of the fibronectin receptor and its expression is increased in the hepatocellular carcinoma cell lines MHCC97 [39] and SMMC-7721 [35]. Angiogenesis is important for tumor growth, and is regulated by vascular endothelial growth factor (VEGF). Hepatocellular carcinoma is a solid tumor with rich neovasculature and VEGFR2 overexpression has been localized in tumoral hepatocytes [40]. CD133 is a CSC marker associated with radioresistance and chemoresistance in various cancers and has been also identified as specific antigenic marker of liver CSC [41], [42].

Finally, our proteomic analysis showed a higher presence of hepatocellular carcinoma-related proteins, Carfilzomib such as cathepsin �� precursor, cathepsin D precursor, adenine phosphoribosyl transferase, L-lactate dehydrogenase, triosephosphate isomerase, inorganic pyrophosphatase or peptidyl prolyl cis-trans isomerase, in CM2 treated cells compared to CM1 treated cells. A high expression of these proteins has been observed in hepatic tumor and metastasis [43], [44], [45].

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