Expression and clinical significance of mammalian target of rapamycin/P70 ribosomal protein S6 kinase signaling pathway in human colorectal carcinoma tissue

Abstract

The activation of mammalian target of rapamycin (mTOR) has been reported in tumor development, but the role of mTOR in colorectal carcinomas remains unclear. The aim of the present study was to investigate the significance of mTOR and its downstream effector 70 kDa ribosomal protein S6 kinase (P70S6K) in human colorectal carcinomas. The phosphorylated (p-)mTOR and p-P70S6K proteins were examined by immunohistochemistry performed on tissue microarray containing tissue samples obtained from colorectal carcinoma (n=111), adenomatous polyps (n=40) and normal colonic mucosa (n=40), with a comparison between the expression of these proteins and the clinicopathological parameters of patients with carcinomas. The positive expression rates of p-mTOR and p-P70S6k were 60.4 and 65.8%, respectively, in colorectal carcinoma tissue, which was significantly increased compared with the tissue from adenomatous polyps (27.5 and 20%, respectively) and normal colonic mucosa (10.0 and 5.0%, respectively) (P<0.05). Overexpression of the p-mTOR and p-P70S6K proteins was significantly associated with the tumor-node-metastasis stage, the occurrence of distal and lymph node metastasis and the degree of differentiation. Aberrant expression of p-mTOR and p-P70S6K may contribute to the pathogenesis, growth, invasion and metastasis of colorectal carcinoma. The phosphorylation of these proteins was considered to be a promising marker to indicate the aggressive behaviors and prognosis of colorectal carcinomas. The overexpression of the mTOR/P70S6K signaling pathway may play an important role in colorectal carcinoma carcinogenesis. The expression of p-mTOR and p-P70S6K was considered as a promising marker to indicate the aggressive behaviors and prognosis of human colorectal carcinomas.

Keywords: colorectal cancer; immunohistochemistry; mammalian target of rapamycin/70 kDa ribosomal protein S6 kinase; reverse transcription-polymerase chain reaction.

Figure 1.

Immunohistochemical staining in normal colonic mucosa, adenomatous polyps and colorectal adenocarcinoma tissue samples. Strong staining for p-mTOR was observed in the cytoplasm, while p-P70S6K was strongly expressed in the cytoplasm and nucleus. p-mTOR expression was observed in normal colonic mucosa, adenomatous polyps and colorectal adenocarcinomas, whereas the p-P70S6K protein was immunoreactive in non-neoplastic mucosa, adenoma and carcinoma. p-mTOR, phosphorylated mammalian target of rapamycin; p-P70S6K, posphorylated 70 kDa ribosomal protein S6 kinase.

Figure 2.

Immunohistochemistry scores for the expression of the (A) phosphorylated mammalian target of rapamycin and (B) phosphorylated 70 kDa ribosomal protein S6 kinase proteins in human colorectal cancer and matched normal colorectal tissues. *P<0.05 compared to cancer tissue.

Figure 3.

Reverse transcription-polymerase chain reaction analysis of p-P70S6K and p-mTOR from colorectal cancer and normal colorectal tissue specimens. *P<0.05 and **P<0.01 compared to control tissue.p-P70S6K, phosphorylated 70 kDa ribosomal protein S6 kinase; p-mTOR, phosphorylated mammalian target of rapamycin.

Figure 4.

Western blot analysis of the expression of p-mTOR and p-P70S6K from three paired (A) colorectal cancer and (B) normal colorectal tissue specimens. p-mTOR, phosphorylated mammalian target of rapamycin; p-P70S6K, phosphorylated 70 kDa ribosomal protein S6 kinase.