Identification of an intermediate signature that marks the initial phases of the colorectal adenoma-carcinoma transition

Abstract

Abstract. The colorectal adenoma-carcinoma sequence describes the stepwise progression from normal to dysplastic epithelium and then to carcinoma. Only a small proportion of colorectal adenomas (CRAs) progress to colorectal carcinomas (CRCs). Endoscopic intervention is currently being used on patients with high grade dysplasia CRAs, with diameters of >1 cm, or villous components of >25% who are at higher risk than other CRA sufferers. During the process, biopsy samples are taken for conventional histological diagnosis, but poor pathomorphological sensitivity and specificity greatly limit the diagnostic accuracy. Unfortunately, there are no reliable molecular criteria available that can predict the potential development of CRA to CRC. Gene expression profiles of normal colorectal mucosa (NOR), CRA and different Dukes' stages of CRC biopsy specimens, which represent the gradual progress of the CRA to CRC sequence, were determined by Affymetrix technology. Representative regulated genes were further analyzed by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). Intersectional analyses of discriminative expression signatures of CRC vs. CRA and CRA vs. NOR allowed the identification of an intermediate signature of 463 probe sets (psets) that mark the NOR➝ CRA➝CRC progression. This signature represents a reservoir of candidate markers for the early diagnosis of higher-risk CRA, thus allowing for timely therapeutic intervention and more selective treatment. A further 279 CRC-specific psets pointing to the malignant transition from CRA to CRC were identified and these could represent potential therapeutic targets for CRC. The reliability of the results was further confirmed by qRT-PCR and IHC analyses of the 4-gene sets randomly selected from the 463 psets.

Forkhead Box Q1 Is Critical to Angiogenesis and Macrophage Recruitment of Colorectal Cancer

“…Angiogenesis and macrophage recruitment are closely related to cancer progression, and these two biological processes share common pathways (39). In this study, we found that FOXQ1 inhibition in CRC cells results in suppressed proliferation and migration of CRC cells in vitro (Figure 2), this result was consistent with ours (12) and other previous reports in CRC (11,21). Furthermore, the impact of FoxQ1 on promoting tumor cell proliferation was also well established in other solid tumors including ovarian cancer (16), neuroblastoma (20), lung cancer (22), gastric cancer (23), and liver cancer (40).…”

“…IHC results showed that FOXQ1, Twist1, and CCL2 each were significantly upregulated in CRC tissues compared with adjacent nontumorous tissues, and that CD31 and CD68 were moderately upregulated ( Figure 7A). Furthermore, the overexpression of FOXQ1 was significantly correlated with lymph node metastasis or higher TNM stage (Table 1), which is consistent with our previous study (12). Further analysis verified the statistically significant correlation between FOXQ1 and Twist1 (P<0.01) ( Table 2).…”

“…Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family (8) with demonstrated functional roles in hair follicle morphogenesis and gastric epithelial differentiation (9). Studies have indicated that FOXQ1 is also an oncogene in multiple tumors, including colorectal cancer (CRC) (10)(11)(12), non-small cell lung cancer (13), breast cancer (14,15), ovarian cancer (16), bladder carcinoma (17), stomach cancer (18), liver cancer (19), and neuroglioma (20). Recent studies suggest that the tumorogenic function of FOXQ1 may be related to its ability to promote cell cycle progression (10,16), tumor angiogenesis (10), cell proliferation (11,21), stem cell-like properties (14), resistance to chemotherapy-induced apoptosis (14), modification of the TME (19), epithelial-mesenchymal transition (EMT) (22,23), senescence-associated inflammation (24), and Wnt signaling activation (25).…”

“…Recent studies suggest that the tumorogenic function of FOXQ1 may be related to its ability to promote cell cycle progression (10,16), tumor angiogenesis (10), cell proliferation (11,21), stem cell-like properties (14), resistance to chemotherapy-induced apoptosis (14), modification of the TME (19), epithelial-mesenchymal transition (EMT) (22,23), senescence-associated inflammation (24), and Wnt signaling activation (25). We previously demonstrated that aberrant expression of FOXQ1 is correlated with metastasis in CRC (12). Furthermore, FOXQ1 has been shown to be a regulator of cancer invasion and metastasis in CRC and a modulator of Twist1 expression (11).…”

Molecular characterization of FOX factors and Wnt signalling interplay in human cancers

“…Homozygous deletion of Foxq1 was associated with impaired gastric function and increased embryonic lethality [64,65]. Then, it became evident that overexpression of FOXQ1 is common in colorectal adenocarcinoma and associated with tumour growth and metastasis [45,66,67] (Figure 1.4). Later, FOXQ1 was described as putative oncogene in many human cancers, where it is generally associated with poor prognosis [68][69][70].…”