Members of Shc (src homology and collagen homology) family, p46shc, p52shc, p66shc have known to be related to cell proliferation and carcinogenesis. Whereas p46shc and p52shc drive the reaction forward, the role of p66shc in cancers remains to be understood clearly. Hence, their expression in cancers needs to be evaluated carefully so that Shc analysis may provide prognostic information in the development of carcinogenesis. In the present study, the expression of p66shc and its associate targets namely Eps8 (epidermal pathway substrate 8), Rac1 (ras-related C3 botulinum toxin substrate1) and Grb2 (growth factor receptor bound protein 2) were examined in fresh tissue specimens from patients with esophageal squamous cell carcinoma and esophageal adenocarcinoma using western blot analysis. A thorough analysis of both esophageal squamous cell carcinoma and adenocarcinoma showed p66shc expression to be significantly higher in both types of carcinomas as compared to the controls. The controls of adenocarcinoma show a higher basal expression level of p66shc as compared to the controls of squamous cell carcinoma. The expression level of downstream targets of p66shc i.e., eps8 and rac1 was also found to be consistently higher in human esophageal carcinomas, and hence correlated positively with p66shc expression. However the expression of grb2 was found to be equal in both esophageal squamous cell carcinoma and adenocarcinoma. The above results suggest that the pathway operated by p66shc in cancers does not involve the participation of Ras and Grb2 as downstream targets instead it operates the pathway involving Eps8 and Rac1 proteins. From the results it is also suggestive that p66shc may have a role in the regulation of esophageal carcinomas and represents a possible mechanism of signaling for the development of squamous cell carcinoma and adenocarcinoma of esophagus.
Expression analysis of MKK6 protein in solid tumors has never been investigated. Here, we report systematic analysis of MKK6 protein in different types of human tumor samples using western blotting and immunofluorescence techniques. We observed significant increase in the expression of MKK6 in Esophageal, Stomach, and Colon cancers as compared to controls. Results were alternately confirmed by Immunofluorescence studies. Upregulation of MKK6 protein is indicative of its role in human cancers and could possibly be used as a novel diagnostic or prognostic marker in these cancers.
We studied the expression of α1-syntrophin (SNTA1) protein in histologically confirmed esophageal, stomach, lung, colon, rectal and breast cancerous tissue samples. Our results suggest a significant decrease in the expression level of SNTA1 protein in both esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) compared with their respective controls while a significant increase in expression of SNTA1 protein compared with the normal tissue was observed in breast carcinoma samples. No significant difference in expression of SNTA1 protein was observed in stomach, lung, colon and rectal cancers. Our results suggest that SNTA1 has a role in carcinogenesis and could possibly be used as a novel diagnostic or prognostic marker in esophageal and breast cancers.
The oxidative role(s) of p66Shc protein has been increasingly expanded over the last decade. However, its relation with the most potent antioxidant molecule, i.e. ascorbic acid has never been studied. We have previously shown that p66Shc mediates rac1 activation, reactive oxygen species (ROS) production and cell death. Here we studied the effect of ascorbic acid on the pathway involving p66Shc and rac1. Our results indicate a decrease in the expression of p66Shc in a dose- and time-dependent manner. We studied the effect of ascorbic acid on rac1 expression and its activity. Ascorbic acid has no effect on total rac1 expression; however, rac1 activation was inhibited in a dose-dependent manner. Results suggest that the decrease in rac1 activity is mediated through ascorbic acid-modulated p66Shc expression. The decrease in rac1 activity was evident in cells transfected with the p66shc mutant (proline motif mutant, at residues P47 to P50). Our studies indicate that p66Shc-mediated ROS upregulation is significantly decreased in the presence of ascorbic acid. Cell migration experiments point towards the inhibition of p66Shc-rac1-mediated migration in the presence of ascorbic acid. Finally, results are suggestive that ascorbic acid-mediated decrease in Shc expression occurs through an increased Shc ubiquitination. Overall, the study brings out the novel role of ascorbic acid in antioxidant signal transduction.
MKK6 expression analysis has been reported in various primary tumors, like esophagus, stomach, colon and prostate cancers but its significance in primary breast tumor patients remains unclear. We investigated the expression of MKK6 in cancer tissues through immunoblotting and immunofluorescence techniques in 25 resected cases of human breast carcinomas. Increased MKK6 protein expression was observed in 56% (14 ⁄ 25) of breast cancer cases. These results indicate that the upregulated expression of MKK6 in cancer tissues has significant role in tumor progression and the clinical prognosis of patients with primary breast carcinoma. …………………………………………………………………………………………………….... Introduction:-Breast cancer is one of the most common cancers with more than 1.3 million cases and 0.45 million deaths each year worldwide [1]. It is the number one cancer amongst females accounting for 5.59% of total cancers in females of Kashmir valley only [2]. Breast cancer development involves progression through chain of intermediate processes, which starts with ductal hyper-proliferation, followed by subsequent progression to carcinoma in situ, invasive carcinoma, and finally into metastatic disease [3]. Studies have shown that metastasis is a series of diverse events, generally known as a metastatic cascade. These steps include fleeing of malignant cells from the site of primary tumor, propagation and shifting to a discontinuous secondary site(s), and lastly, the survival and growth into clinically detectable metastases, a process termed metastatic colonization [4]. In order to significantly augment our understanding of the metastatic process and to identify the specific targets for cancer therapy we need to single out the proteins and signaling pathways necessary for regulation of metastasis. In various cancers many proteins show differential expression and regulation [5][6][7]. One such protein is mitogen-activated protein kinase 6 (which from now onwards will be referred to as MKK6). MKK6 belongs to the mitogen-activated protein (MAP) kinase super family and has a role in both apoptosis [8,9] as well as proliferation [10]. MKK6 has been implicated in regulating tumorigenesis. MKK6 has been shown to play contradictory roles in suppressing metastatic colonization in human ovarian carcinoma [11] on other hand it has been shown to be up-regulated in prostate cancers [12]. As of now, very little is known about the regulation of expression of MKK6 in the cell [13]. MKK6 activates downstream all the isoforms of p38 MAPK [14]. P38α has been implicated in regulating cancer progression, by regulating invasion, inflammation and angiogenesis which are key oncogenic steps in tumorogenesis [15][16][17].
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