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Insulin receptor substrate 1 may play divergent roles in human colorectal cancer development and progression

World Journal of Gastroenterology 2020年第28期26卷 4140-4150页

作者： Karolina Lomperta Katarzyna Jakubowska Malgorzata Grudzinska Luiza Kanczuga-Koda Andrzej Wincewicz Eva Surmacz stanislaw sulkowski Mariusz Koda Department of General Pathomorphology Medical University of BialystokBialystok 15269Poland Department of Pathomorphology Comprehensive Cancer CentreBialystok 15027Poland Department of Pathology Nonpublic Health Care UnitKielce 25734Poland Allysta Pharmaceuticals Incorporated BelmontCA 94002United States

BACKGROUND Despite effective prevention and screening methods,the incidence and mortality rates associated with colorectal cancer(CRC)are still *** receptor substrate 1(IRS-1),a signaling molecule involved in cell proliferation,survival and metabolic responses has been implicated in carcinogenic processes in various cellular and animal ***,the role of IRS-1 in CRC biology and its value as a clinical CRC biomarker has not been well *** To evaluate if and how IRS-1 expression and its associations with the apoptotic and proliferation tumor markers,Bax,Bcl-xL and Ki-67 are related to clinicopathological features in human *** The expression of IRS-1,Bax,Bcl-xL and Ki-67 proteins was assessed in tissue samples obtained from 127 patients with primary CRC using immunohistochemical *** assays were performed using specific antibodies against IRS-1,Bax,Bcl-xL,*** associations between the expression of IRS-1,Bax,Bcl-xL,Ki-67 were analyzed in relation to clinicopathological parameters,i.e.,patient age,sex,primary localization of tumor,histopathological type,grading,staging and lymph node *** between variables were examined by Spearman rank correlation test and Fisher exact test with a level of significance at P<*** Immunohistochemical analysis of 127 CRC tissue samples revealed weak cytoplasmatic staining for IRS-1 in 66 CRC sections and strong cytoplasmatic staining in 61 ***-1 expression at any level in primary CRC was associated with tumor grade(69%in moderately differentiated tumors,G2 vs 31%in poorly differentiated tumors,G3)and with histological type(81.9%in adenocarcinoma vs 18.1%in adenocarcinoma with mucosal component cases).Strong IRS-1 positivity was observed more frequently in adenocarcinoma cases(95.1%)and in moderately differentiated tumors(85.2%).We also found statistically significant correlations between expression of IRS-1 and both Bax and Bcl-xL in all CRC cases *** relat

关键词： Colorectal cancer Insulin receptor substrate-1 Bax protein Bcl-xL protein Apoptosis Antigen Ki-67

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Proteolytic-antiproteolytic balance and its regulation in carcinogenesis

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World Journal of Gastroenterology 2005年第9期11卷 1251-1266页

作者： Elzbieta Skrzydlewska Mariola Sulkowska Mariusz Koda stanislaw sulkowski Department Department of Pathology

Cancer development is essentially a tissue remodeling process in which normal tissue is substituted with cancer tissue. A crucial role in this process is attributed to proteolytic degradation of the extracellular matrix (ECM). Degradation of ECM is initiated by proteases, secreted by different cell types, participating in tumor cell invasion and increased expression or activity of every known class of proteases (metallo-, serine-, aspartyl-, and cysteine) has been linked to malignancy and invasion of tumor cells. Proteolytic enzymes can act directly by degrading ECM or indirectly by activating other proteases, which then degrade the ECM. They act in a determined order, resulting from the order of their activation. When proteases exert their action on other proteases, the end result is a cascade leading to proteolysis. Presumable order of events in this complicated cascade is that aspartyl protease (cathepsin D) activates cysteine proteases (e.g. cathepsin B) that can activate pro-uPA. Then active uPA can convert plasminogen into plasmin. Cathepsin B as well as plasmin are capable of degrading several components of tumor stroma and may activate zymogens of matrix metalloproteinases, the main family of ECM degrading proteases. The activities of these proteases are regulated by a complex array of activators, inhibitors and cellular receptors. In physiological conditions the balance exists between proteases and their inhibitors. Proteolytic-antiproteolytic balance may be of major significance in the cancer development. One of the reasons for such a situation is enhanced generation of free radicals observed in many pathological states. Free radicals react with main cellular components like proteins and lipids and in this way modify proteolytic-antiproteolytic balance and enable penetration damaging cellular membrane. All these lead to enhancement of proteolysis and destruction of ECM proteins and in consequence to invasion and metastasis.

关键词： Proteases Protease inhibitors Reactive oxygen species

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Evaluation of serum catnepsin B and D in relation to diniGopatnological staging of colorectal cancer

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World Journal of Gastroenterology 2005年第27期11卷 4225-4229页

作者： Elzbieta Skrzydlewska Mariola Sulkowska Andrzej Wincewicz Mariusz Koda stanislaw sulkowski Department of Analytical Chemistry Department of Pathology

AIM: Proteolytic degradation of the extracellular matrix facilitates cancer invasion and promotes metastasis. The study aims at evaluation of preoperative and postoperative serum cathepsins B and D levels in correlation with selected anatomoclinical features of colorectal ***: Blood samples were collected from 63colorectal cancer patients before curative operation of the tumor 10 d later. Blood that was obtained from 20healthy volunteers, served as a control. The activity of cathepsin B was measured with Bz-DL-arginine-pNA as a substrate at pH 6.0, while cathepsin D activity was determined with urea-denatured hemoglobin (pH 4.0).RESULTS: The preoperative and postoperative activities of cathepsin B were significantly (P＜0.00001) lower in serum of colorectal cancer patients than in control ***, postoperative values of this protease were significantly increased in comparison with preoperative ones (P = 0.031). Activity of cathepsin D appeared to be significantly higher in colorectal cancer sera (P＜0.00001)compared with controls. No statistically significant differences between preoperative and postoperative activity of cathepsin D were noted (P = 0.09). We revealed a strong linkage of cathepsins' levels with lymph node status and pT stage of colorectal ***: Blood serum activities of cathepsin B and D depend on the time of sampling, tumor size and lymph node involvement. Significantly, increased activity of cathepsin D could indicate a malignant condition of the large intestine. In our work, the serum postoperative decrease of cathepsin B activity appears as an obvious concomitant of local lymph node metastasis-the wellknown clinicopathological feature of poor prognosis.

关键词： Proteases Cathepsin D Cathepsin B Colorectalcancer

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Connexin 26 correlates with Bcl-xL and Bax proteins expression in colorectal cancer

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World Journal of Gastroenterology 2005年第10期11卷 1544-1548页

作者： Luiza Kanczuga-Koda stanislaw sulkowski Mariusz Koda Elzbieta Skrzydlewska Mariola Sulkowska Department of Pathology Department of Analytical Chemistry

AIM: To evaluate of Cx26 in correlation with Bcl-xL and Bax proteins in colorectal cancer. METHODS: Immunohistochemical staining using specific antibodies was performed to evaluate the protein expression of Cx26, Bax and Bcl-xL in 152 colorectal cancer samples and the correlations among studied proteins as well as the relationships between the expression of Cx26, Bax, Bcl-xL and clinicopathological features were analyzed. RESULTS: Both normal epithelial cells and carcinoma cells expressed Cx26, Bax and Bcl-xL, but Cx26 in cancer cells showed aberrant, mainly cytoplasmic staining. Expression of Cx26, Bax and Bcl-xL was observed in 55.9%, 55.5% and 72.4% of evaluated colorectal cancers respectively. We found the positive correlation between Cx26 and Bax expression (r= 0.561, P<0.0001), Cx26 and Bcl-xL (P=0.409, P<0.0001) as well as between Bax and Bcl-xL (P=0.486, P<0.0001). Association of Cx26, Bax and Bcl-xL expression with histological G2 grade of tumors was noted (P<0.005, P<0.001 and P<0.002 respectively). CONCLUSION: Cytoplasmic presence of Cx26 and its association with apoptotic markers could indicate a distinct role from physiological functions of Cx26 in cancer cells and it could suggest that connexins might be a target point for modulations of apoptosis with therapeutic implications.

关键词： Cx26 Bcl-xL Bax Apoptosis Colorectal cancer Immunohistochemistry

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Lipid peroxidation and antioxidant status in colorectal cancer

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World Journal of Gastroenterology 2005年第3期11卷 403-406页

作者： Elzbieta Skrzydlewska stanislaw sulkowski Mariusz Koda Bogdan Zalewski Luiza Kanczuga-Koda Mariola Sulkowska Department of Analytical Chemistry Department of Pathology Department of General Surgery

AIM: Reactive oxygen species (ROS) can induce carcinogenesis via DNA injury. Both enzymatic and non-enzymatic parameters participate in cell protection against harmful influence of oxidative stress. The aim of the present study was to assess the levels of final lipid peroxidation products like malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE) in primary colorectal cancer. Moreover, we analysed the activity of main antioxidative enzymes, superoxide dismutase (Cu, Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GSSRG-R) and the level of non-enzymatic antioxidants (glutathione, vitamins C and E). METHODS: Investigations were conducted in 81 primary colorectal cancers. As a control, the same amount of sample was collected from macroscopically unchanged colon regions of the most distant location to the cancer. Homogenisation of specimens provided 10% homogenates for our evaluations. Activity of antioxidant enzymes and level of glutathione were determined by spectrophotometry. HPLC revealed levels of vitamins C and E and served as a method to detect terminal products of lipid peroxidation in colorectal cancer. RESULTS: Our studies demonstrated a statistically significant increase in the level of lipid peroxidation products (MDA-Adc. muc.-2.65±0.48 nmol/g, Adc.G3-2.15±0.44 nmol/g, clinical IV stage 4.04±0.47 nmol/g, P<0.001 and ***. -0.44±0.07 nmol/g, Adc.G3-0.44±0.10 nmol/g, clinical IV stage 0.52±0.11 nmol/g, P<0.001) as well as increase of Cu,Zn-SOD (***.-363±72 U/g, Adc.G3-318?8 U/g, clinical IV stage 421±58 U/g, P<0.001), GSH-Px (***. -2143±623 U/g, Adc.G3-2005±591 U/g, clinical IV stage 2467±368 U/g, P<0.001) and GSSG-R (***.-880±194 U/g, Adc.G3-795±228 U/g, dinical IV stage 951±243 U/g, P<0.001) in primary tumour comparison with normal colon (MDA-1.39±0.15 nmol/g, HNE-0.29±0.03 nmol/g, Cu, Zn-SOD-117±25 U/g, GSH-Px-1723±189 U/g, GSSG-R-625±112 U/g) especially in mucinous and G3-grade adenocarcinomas as we

关键词： Colorectal cancer Lipid Peroxidation Oxidative Stress Carcinogenesis

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