Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors

Abstract

Background: The signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule implicated in the regulation of growth and malignant transformation. Constitutive activation of STAT3 is seen in several tumour derived cell lines, and in a wide variety of human malignancies.

Aims: To examine the relation between p-STAT3 (activated form of STAT3) expression and clinicopathological factors in human colorectal adenocarcinoma and adenoma.

Methods: Immunohistochemical analyses were carried out on tissues from 44 colorectal adenomas and 95 colorectal adenocarcinomas, comprising 18 intramucosal carcinomas and 77 invasive carcinomas.

Results: Seventy seven of these 139 samples (55.4%) showed immunoreactivity for p-STAT3. Positive staining for p-STAT3 was seen in 69 of the 95 carcinomas. Only eight of the 44 adenomas showed immunopositivity for p-STAT3, resulting in a significant difference between total adenocarcinomas and adenomas (p < 0.001). Among the 95 cases of colorectal adenocarcinoma, p-STAT3 immunoreactivity was significantly correlated with the depth of tumour invasion (p < 0.05), venous invasion (p < 0.05), lymph node metastasis (p < 0.05), and increasing stages of the Dukes' classification (p < 0.01). Expression of p-STAT3 was detected by Western blot analysis in two different cultured human colorectal carcinoma cell lines and six colon carcinoma tissue samples obtained at surgery.

Conclusion: This is the first study to report a significant correlation of p-STAT3 expression with the depth of tumour invasion. These findings suggest that p-STAT3 expression is an important factor related to carcinogenesis and/or tumour invasion of colorectal adenocarcinoma.

Figure 1

(A) Immunohistochemistry for phosphorylated (activated) signal transducer and activator of transcription (p-STAT3) in colorectal adenocarcinomas. p-STAT3 shows strong nuclear and cytoplasmic expression. (immunoalkaline phosphatase staining; original magnification, ×400). (B) Expression of p-STAT3 was seen in all layers of this adenocarcinoma (immunoalkaline phosphatase staining; original magnification, ×10).

Figure 2

In almost all of the carcinomas studied, the intensity of phosphorylated (activated) signal transducer and activator of transcription (p-STAT3) expression was stronger in the deeper parts of invasion than in the superficial areas. (A) Expression of p-STAT3 in a carcinoma invading the submucosa (original magnification, ×60). (B) (original magnification, 60×). Expression of p-STAT3 in a carcinoma invading the muscularis propria. (C) Expression of p-STAT3 in a carcinoma invading the subserosa (original magnification, ×60).

Figure 3

The expression of phosphorylated (activated) signal transducer and activator of transcription (p-STAT3) is lower in normal mucosa (lanes 1 and 2) than in adenocarcinoma (lanes 3–8). There is no difference in the expression of STAT3 between the normal mucosa and carcinoma tissues. β Actin was used as an internal protein control.

Figure 4

Phosphorylated (activated) signal transducer and activator of transcription (p-STAT3) is constitutively expressed without interferon α (IFNα) stimulation in the DLD-1 cell line. Colo320DM expressed p-STAT3 only after the stimulation with IFNα.