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Negative correlation between caspase-3 and COX-2 expression in colon cancer: an immunohistochemical study

Shams, Tahany M.a; Atwa, Maha M.a; Shams, Mohamed E.b

Egyptian Journal of Pathology: July 2012 - Volume 32 - Issue 1 - p 68–74
doi: 10.1097/01.XEJ.0000417555.65230.8d

Aim of the study The aim of this study was to assess, using immunohistochemistry, the expression of cyclooxygenase-2 (COX-2) and caspase-3 in colon cancer and their possible correlation with different clinicopathological parameters; the correlation between the expression of both proteins was also studied.

Materials and methods This study included 32 patients with previously diagnosed colonic carcinoma at the Pathology Laboratory of Suez Canal University Hospital. Immunohistochemical expressions of caspase-3 and COX-2 were examined on formalin-fixed paraffin-embedded tissues for each patient.

Results Caspase-3 and COX-2 were expressed in 43.7 and 84.4% of the patients with colon cancer studied. Loss of caspase-3 expression and increased COX-2 expression were found in recurrent and metastatic liver tumors. Increased expression of COX-2 was observed in high-stage tumors and in cases with positive lymph node metastasis, as indicated by a significant correlation between the percentage of staining of COX-2 and tumor stage (P=0.008) and lymph node metastasis (P=0.006). No statistically significant relationship was found between both epitopes and other parameters. However, a statistically significant inverse relationship was found between the expressions of both oncoproteins (P=0.03).

Conclusion The negative correlation between COX-2 and caspase-3 expression shows the role played by COX-2 in inhibiting apoptosis by loss of caspase-3; COX-2 and caspase-3 also play a role in tumor recurrence and the metastatic potential of patients with colonic cancer. This led us to study the role of COX-2 inhibitors and caspase-3 initiators in therapeutic approaches for these patients.

Departments of aPathology

bGeneral Surgery, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Correspondence to Tahany Shams, MD, Department of Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt Tel: +20 1228790821; fax +20 643206604; e-mail:

Received November 23, 2011

Accepted December 8, 2011

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Every year, almost 142 570 new cases of colorectal cancer (CRC) and 51 370 colorectal cancer-related deaths occur in the USA (Jemal et al., 2010); therefore, it remains one of the leading causes of cancer death worldwide in men and women (Hawk et al., 2002). In Egypt, the digestive system is the third most common site for cancer in men after lymphohematopoietic tissues and the urinary system. For women, it is the third common site after breasts and lymphohematopoietic tissues (Mokhtar et al., 2007).

Early diagnosis of CRC and better knowledge of its prognostic factors have contributed to improved outcomes in affected patients. In recent years, several biological markers or indices have been studied as potential tools to determine the prognosis and the biological behavior of various types of neoplasia, and immunohistochemistry is probably the most affordable and simple technology to detect many such biomarkers (Roberts et al., 2002).

Cyclooxygenase (COX) is the key enzyme in the metabolism of prostaglandin; it catalyzes the formation of prostaglandins from arachidonic acid. Two isoforms of this enzyme have been characterized: a constitutive enzyme (COX-1) and an inducible form (COX-2; Zha et al., 2004). The COX-2 gene has been categorized as an immediate-early gene associated with inflammation (McAdam et al., 2000), cellular growth and differentiation (Williams et al., 2000), prevention of apoptosis (McGinty et al., 2000), and tumorigenesis (Ambs et al., 1998). It has also been reported that COX-2 induces angiogenesis, which is essential for tumor growth, increases the production of prostaglandin, and enhances the release of angiogenic growth factors by COX-2, which induces neovascularization (Williams et al., 2000).

Apoptosis is a selective process for the deletion of cells in various biological systems. This process, similar to proliferation, is strongly regulated, with both processes playing essential roles in the homeostasis of renewable tissues; failures in normal apoptosis pathways contribute toward carcinogenesis (Persad et al., 2004). Various molecules are involved in the apoptosis pathway. One set of mediators implicated in apoptosis belongs to asparate-specific cysteinyl proteases or caspases (Yamamoto et al., 1998).

Caspases are a group of proteolytic effector molecules that induce the morphological changes observed in apoptosis. More than a dozen caspases, most of which are homologous in structure, have been characterized in humans (Karam et al., 2007). The group includes initiator upstream caspases, for example caspase-8 and caspase-9, which may be activated by internal stress signals involving cytochrome c, or by interaction with cell surface death receptors through their large prodomains. Downstream or effector caspases, for example caspase-3 and caspase-7, which lack the protein interaction motifs of upstream caspases, are responsible for the specific proteolytic activity that results in cell disassembly (Aschfaq et al., 2007). In addition to their direct proteolytic activity, effector caspases can also cleave and activate initiator caspases, causing amplification of the original signal (Slee et al., 1999). A member of this family, caspase-3 (CPP32, apopain, YAMA), has been identified as a key mediator of apoptosis of mammalian cells (Persad et al., 2004).

To our knowledge, the relationship between COX-2 and caspase-3 expression and clinicopathological parameters has not been studied in colonic cancer of Egyptian patients. The aim of our study was to assess, by immunohistochemistry, the expressions of COX-2 and caspase-3 in colon cancer (CC), and to determine their role in tumorogenesis and correlate their expression with clinicopathological parameters [age, sex, histological grade and stage, tumor size, site and presence of bilharziasis or tumor-associated tissue eosinophilia (TATE), and presence of lymph node or distant metastasis]. One of the aims of this study was also to evaluate the relationship between the expression of both proteins.

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Materials and methods

This study included 32 patients with colonic carcinoma, data on whom were obtained from the surgical files of the Pathology Department at the Suez Canal University Hospital of the Faculty of Medicine, Ismailia, Egypt, during the period from January 2005 to December 2008. Ten samples of normal colonic tissues were also obtained from colonoscopic biopsies of cancer-free patients and served as controls; clinical data including patient age, sex, histological grade and stage, tumor size, site and presence of bilharziasis or TATE, and presence of lymph node or distant metastasis were retrieved from the files of the patients. The slides were reviewed to confirm the diagnosis, tumor grade, stage, and lymph node metastasis. Pathological staging was based on the AJCC – tumor–node–metastasis classification (Fredrick et al., 2002).

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Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue material that was sectioned at a 5 μm thickness and placed on positive-charged slides. All the slides were deparaffinized using xylene and then rehydrated in decreasing concentrations of ethanol. Antigen retrieval was carried out by heating in a microwave (20 min; 10 mmol/l citrate buffer, pH 6.0) after inhibition of endogenous peroxidase activity (0.3 mol/l hydrogen peroxidase for 15 min). The immunohistochemical staining for COX-2 and caspase-3 was performed with a ready-to-use rabbit polyclonal antibody (Lab Vision, New York, USA; cat.RB-9072 and RB-1197 for COX-2 and caspase-3, respectively) using the universal ABC peroxidase kit (ultravision detection system, anti-polyvalent, ready to use, Lab Vision). The slides were incubated for 2 h with the primary antibody at room temperature, washed using PBS, and then incubated with secondary antibody for 15 min, followed by a PBS wash. Finally, the detection of bound antibody was carried out by incubation with a modified labeled avidin–biotin peroxidase complex reagent for 20 min followed by washing with PBS. A 0.1% solution of diaminobenzidine was used for 5 min as a chromogen. Slides were counterstained with Mayer’s hematoxylin for 5–10 min. Gastric adenocarcinomas and lymphoid tissues such as those from tonsils was used as positive controls for COX-2 and caspase-3, respectively. Negative controls were obtained by excluding the primary antibody.

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Evaluation of antibody expression

The expression of COX-2 and caspase-3 was determined in 10 successive high-power fields (×400) according to Chen et al’s (2009) and Shen et al.’s (2004) scoring systems, respectively. Sections were examined without previous knowledge of the clinical data. Both showed mostly cytoplasmic expression. The intensity, distribution, and pattern of staining were evaluated for COX-2 and caspase-3 independently. The percentage of positively stained cells was determined semiquantitatively by assessing the entire tumor section (Vallmanya et al., 2006). Caspase-3 and COX-2 immunoreactivities were rated as follows:

  • (): Negative: no staining could be observed in the tumor cells or brownish cytoplasmic staining was found in less than 25% of the tumor population.
  • (+1): Weak reactivity: brownish cytoplasmic staining was observed in more than 25% up to 50% of the tumor cells.
  • (+2): Moderate reactivity: cytoplasmic staining was detected in more than 50% up to 75% of the tumor cells.
  • (+3): Intense (strong) reactivity: cytoplasmic staining was observed in more than 75% of the tumor cells.
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Statistical analysis

Statistical analysis of the results was carried out using Fisher’s exact test to determine the expression of COX-2 and caspase-3 (positive cases) in relation to different clinicopathological characteristics. The relationship between COX-2 and caspase-3 expression was evaluated using the χ2-square test and a linear regression coefficient test (SPSS software program, version 9; SPSS Inc., Chicago, Illinois, USA). Tests were considered significant when P-values were less than 0.05 and highly significant when P-values were less than 0.01 (Dawson and Trapp, 2001).

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Clinicopathologic characteristics of the studied group

The age of the patients with CC ranged from 32 to 78 years, with a mean of 59.3 years and a median of 50 years. Of the patients 18 were women (56.3%) and 14 were men (43.7%), with a male-to-female ratio of 1 : 1.3. Adenocarcinoma was the predominant histopathological tumor type diagnosed in all cases (100%). Twenty-one tumors (65.6%) were located in the right colon, whereas 11 (34.4%) were located in the left colon. Seventeen cases (53.1%) were moderately differentiated (grade II), 10 cases (31.3%) were poorly differentiated (grade III), and only five cases (15.6%) were well differentiated (grade I). According to the tumor–node–metastasis staging system, in 24 cases (75%) the tumor tissue had extended to invade the subserosal tissue (T3), whereas in eight cases (25%) it was limited to the muscularis propria (T2). Lymph node metastasis was detected in 19 cases (59.4%), with tumor metastatic deposits seen in one to 12 lymph nodes, whereas in 13 cases (40.6%) it was negative and in five cases (15.6%) liver metastasis had been diagnosed by an ultrasonographic-guided true-cut core biopsy and pathological examination.

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Expression of caspase-3 and cyclooxygenase-2 in the control group

All 10 samples of normal colonic mucosa were negative for a caspase-3 immunoreaction, whereas all samples showed very weak staining for COX-2.

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Caspase-3 expression in colon carcinoma

Caspase-3 immunopositivity was detected in 14/32 cases (43.7%), whereas 18 cases (56.3%) were negative. Among the 14 positive cases, eight cases (57.1%) were strongly positive for caspase-3 (Fig. 1), whereas five cases (35.7%) were moderately positive and only one case (7.1%) was weakly positive (Table 1).

Fig. 1

Fig. 1

Table 1

Table 1

Interestingly, the expression of caspase-3 was heterogeneous in all 14 positive cases as only individual cells in the malignant glandular tissue showed a strong expression of caspase-3, as observed on perinuclear staining, as compared with adjacent tumoral cells in the same neoplastic gland (Fig. 2), and this marked selectivity of the positive caspase-3 individual cells was highly evident in all 14 positive caspase-3 cases.

Fig. 2

Fig. 2

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Relationship between caspase-3 expression in colon carcinoma and clinicopathological parameters

In terms of patients’ age and sex, there was no statistically significant relationship between caspase-3 expression and both variables (P=0.734 and 0.489, respectively) (Table 1).

Comparison of tumor sites showed that in nine positive cases (42.9%) and five positive cases (45.5%), tumors were located in the right and the left side of the colon, respectively. In terms of tumor stage, 10 positive cases (41.7%) in stage T3 were compared with four positive cases (50.0%) in stage T2; in grade 1 tumors, 3/5 (60%) were caspase-3 positive compared with 8/17 (47.1%) and 3/10 (30%) in grades 2 and 3, respectively. The relationship between caspase-3 expression and tumor site, stage, and grade was insignificant (P=0.999, 0.703, and 0.446, respectively).

In cases with lymph node metastasis (19 cases), nine caspase-3-positive cases (47.4%) showed metastatic deposits in the involved lymph nodes whereas five cases (38.5%) had negative lymph node metastasis; this relationship was statistically insignificant (P=0.724).

Furthermore, patients with liver metastases showed a significant loss of caspase-3 expression as compared with that in patients without liver metastases (0.0 vs. 51.9%, P=0.053); in addition, patients with tumor recurrence showed a statistically significant loss of caspase-3 expression compared with that in patients without tumor recurrence (0.0 vs. 53.8%, P=0.023).

Six of the 32 patients studied showed associated bilharziasis, four of them (66.7%) positive for caspase-3 [10 (38.5%) were negative], and this relationship was statistically insignificant (P=0.364).

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Cyclooxygenase-2 expression in colon cancer

COX-2 immunopositivity was detected in 27/32 cases (84.4%), whereas five cases (15.6%) were negative. Among the 27 positive cases, 20 cases (74.1%) were strongly positive for COX-2 (Fig. 3), five cases (18.5%) were moderately positive, and two cases (7.4%) were weakly positive (Fig. 4; Table 1).

Fig. 3

Fig. 3

Fig. 4

Fig. 4

The expression of COX-2 was homogenous in 25/27 positive cases, whereas two cases showed a heterogeneous expression (Fig. 5). In addition, stronger immunoreactivity of COX-2 was detected more in the invasive front of the tumor and in regions of serosal infiltration by tumor cells compared with the mucosal surface (Fig. 6).

Fig. 5

Fig. 5

Fig. 6

Fig. 6

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Relationship between cyclooxygenase-2 expression in colon carcinoma and clinicopathological parameters

The statistical evaluation of COX-2 expression according to age, sex, tumor grade, tumor site, and associated bilharziasis showed no significant correlation (P=0.654, 0.354, 0.260, 0.999, and 0.227, respectively). However, there was a statistically significant correlation between COX-2 expression and tumor stage (P=0.008), in which 4/8 (50.0%) patients in stage T2 showed COX-2 expression, whereas 23/24 (95.8%) patients in stage T3 showed COX-2 expression (Table 1).

Moreover, 19/19 (100%) patients with lymph node metastasis showed COX-2 expression, whereas 8/13 (61.5%) patients without lymph node metastasis showed COX-2 expression; this relation was statistically significant (P=0.006). In patients with liver metastasis, there was a statistically significantly high COX-2 expression as compared with that in patients without liver metastasis (100 vs. 81.5%, P=0.054).

Moreover, in six recurrent cases, all of them (100%) were COX-2 positive compared with 21/26 (80.8%) nonrecurrent cases, and this difference was statistically significant, P=0.054. All tumors with eosinophil infiltration at the tumor site were positive for COX-2 compared with 58.3% of tumors without; this indicates a statistically significant relationship between COX-2 expression and TATE, P=0.003.

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Relationship between caspase-3 expression and cyclooxigenase-2 expression

As shown in Table 2, in 32 colonic carcinoma patients studied, 18/32 (56.3%) were positive for COX-2 and negative for caspase-3 expression; however, 5/32 (15.6%) were positive for caspase-3 and negative for COX-2 expression and only 9/32 (28.1%) patients were positive for both oncoproteins. This relationship between COX-2 and caspase-3 expressions was statistically significant, P=0.03, and this indicated a negative correlation between the expression of both oncoproteins (when COX-2 was positive, there was loss of caspase-3 expression).

Table 2

Table 2

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The apoptotic process is of widespread biological significance, being involved in the development, differentiation, and proliferation of cells; in addition, it is very important in the removal of abnormal harmful cells. Thus, defective apoptotic mechanisms can lead to cancer. Apoptosis is important in malignancy for two reasons. First, suppression of apoptosis appears to be a critical event in both cancer initiation and progression. Second, most cytotoxic anticancer agents cause tumor regression, at least in part, by inducing apoptosis; therefore, defects in apoptosis may cause drug resistance and result in treatment failure (Chowdhury et al., 2006).

Many caspases are involved in the process of apoptosis; it is initiated by initiator caspases such as caspase-8 and caspase-10, and its activation proteolytically activates downstream effector caspases, also called executioner caspases, such as caspase-3, which has been recognized as the main effector caspase of the apoptotic cascade (Lima et al., 2011). Caspase-3 is one of the most important executioner caspases that can cleave many important cellular substrates, and caspase-3-mediated cell death plays an important role in pathogenesis and therapy for a variety of malignancies (Kim et al., 2000).

In our study, we included 32 patients with colonic carcinoma; 14 patients (43.7%) expressed caspase-3-positive tumors and the rest of the tumors were negative for caspase-3. Loss of caspase-3 expression was observed in recurrent and metastatic liver tumors, which is in agreement with other studies (Heer et al., 2007); this can be attributed to the dysregulation of the apoptotic program associated with the impaired removal of mutated cells with propagating mutations and other genetic abnormalities that may lead to genomic instability and tumor progression (Philchenkoy, 2004).

In terms of clinicopathological parameters and caspase-3 expressions, conflicting results have been obtained; one study reported that loss of caspase-3 expression was associated with a high pathological grade, advanced pathological stage, and lymph node metastasis (Jonges et al., 2001). In contrast, another study found that a high expression of caspase-3 was correlated with unfavorable histological parameters such as high grade and advanced stage of tumor (Heer et al., 2007). In our study, no statistically significant correlation was found with tumor grade, stage, or lymph node metastasis, and this may be attributed to the limited number of cases in each category; therefore, this correlation must be studied in a larger number of patients.

COX-2 can potentially predispose an individual to carcinogenesis through multiple mechanisms. It can activate various types of procarcinogens to carcinogens by peroxidase activity, which may activate oncogenes or inactivate tumor suppressor genes (Tsunozaki et al., 2002). In addition, it was believed that elevated COX-2 expression was associated with tumor angiogenesis through the increased expression of the proangiogenic growth factor, vascular endothelial growth factor, and the production of the angiogenic prostaglandins such as prostaglandin E2 (Wu et al., 2010). There is increasing evidence suggesting that COX-2 inhibits apoptosis through the activation of the phosphatidylinositol-3-kinase/Akt pathway by prostaglandin E2, resulting in the upregulation of antiapoptotic molecules such as Bcl-2 and Mcl-1 (Sheng et al., 1998). The additional antiapoptotic effect of COX-2 could be because of the fact that it reduces the cellular level of arachidonic acid, which is an inducer of apoptosis; moreover, COX-2-enhanced production of prostaglandins contributes to the stimulation of cell growth (Miyata et al., 2003).

In our study, COX-2 was expressed in 84.4% of the cases studied, and interestingly, there was an inverse relationship with caspase-3 expression; this indicates the additional role of COX-2 in inhibition of apoptosis. Most of the COX-2-positive cases did not express caspase-3, indicating the loss of caspase-3 as a mechanism by which COX-2 inhibits apoptosis (Shureiqi et al., 2000). A significant negative correlation has been reported between the COX-2 protein expression and caspase-3 expression in lung cancer, endometrial carcinoma, and urothelial carcinoma (Chen et al., 2005; Karamitopoulou et al., 2010; Wanga et al., 2010); our results were preliminary in CC.

In terms of COX-2 expression in CC and its relationship with clinicopathologic variables, previous studies have reported increased COX-2 expression in colorectal cancer (Tsujii et al., 1997; Castells et al., 2006). In the current study, 84.4% of the patients studied showed a significant expression of COX-2. However, the correlation between COX-2 expression and the clinicopathologic features is still being debated. The present study could not find any significant differences with respect to tumor grade and COX-2 expression. Castells et al. (2006) reported an inverse relationship between COX-2 expression and tumor grade, in agreement with our findings; other studies have also reported no significant differences with respect to tumor grade and COX-2 expression (Tsujii et al., 1997; Chen et al., 2005). The lack of a significant relationship between tumor grade and COX-2 expression may indicate that COX-2 is not involved in the process of grade differentiation.

Lymph node metastasis is one of the important clinical parameters of colorectal cancer, and it is used for the determination of both the clinical stage and the treatment modalities. Although Castells et al. (2006), through their study, could not find any significant relationship with respect to COX-2 expression and lymph node metastasis, in this study, we found a significant relationship between COX-2 expression and lymph node metastasis (P=0.024), which is in agreement with the results of other studies (Tsujii et al., 1997; Castells et al., 2006).

In the current study, we reported a statistically significant correlation between pathological staging of CC and COX-2 expression (P=0.008), indicating that COX-2 expression may contribute toward the invasive growth of this carcinoma or advancement of the disease process. It was suggested that the expression of COX-2 in colonic cancers may downregulate apoptosis and thus enhance tumor invasion and metastasis (Jang et al., 2009).

Tumor recurrence is another important prognostic factor with respect to survival in patients with CC and other malignancies; some studies have reported a positive correlation between COX-2 expression and recurrence of CRC (Castell s et al., 2006; Ogino et al., 2008). Similarly, in the present study, a significant association (P=0.01) was found with respect to COX-2 expression and tumor recurrence.

In this study, we found a statistically significant relationship between COX-2 expression and TATE (P=0.003); the presence of COX-2-positive inflammatory eosinophils is associated with COX-2-positive tumor tissue and vice versa, as reported in a previous study (Young and Dixon, 2010). This observation might have biological as well as practical implications. The favorable prognostic significance of the presence of abundant inflammatory infiltrate in the stroma of CC has already been highlighted and is associated with the potentiation of the antitumor immune response.

Another important and debatable point in terms of COX-2 expression in CC is the responsiveness to therapy and survival; some studies have shown that increased COX-2 expression was significantly associated with reduced survival, an increased risk of local recurrences, and distant metastases in CC, irrespective of the histological type (Tsujii et al., 1997; Sheehan et al., 1999). Although this study did not include the relation with respect to COX-2 expression and survival, on the basis of other studies, it might be speculated that patients with COX-2 expression should be treated more aggressively and COX-2 expression may be incorporated into the criteria for the determination of postoperative adjuvant treatment, although further studies are required to clarify this.

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We found a significant negative correlation between the expression of COX-2 and caspase-3, which can be implicated in the inhibitory effect of COX-2 on the apoptotic process, and may also be useful as a therapeutic target in CC. There was an association between liver metastasis, tumor recurrence and loss of caspase-3 expression, and high COX-2 immunoreactivity; these findings indicated that COX-2 inhibitors and caspase-3 initiators may represent new potential targets not only for chemoprevention but also for new therapeutic approaches in CC. Selective COX-2 inhibitors have been developed; these compounds possess anticancer properties and appear to be safer than traditional nonsteroidal anti-inflammatory drugs. We recommended the study of patient survival in CC using both proteins in order to assess the effect of COX-2 and caspase-3 on prognoses.

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Conflicts of interest

There are no conflicts of interest.

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