TWIST1 and SNAI1 as markers of poor prognosis in human colorectal cancer are associated with the expression of ALDH1 and TGF-β1

Abstract

Epithelial-mesenchymal transition (EMT) is an important factor in cancer invasiveness and metastatic progression. During EMT, cancer cells acquire stem cell properties. The role of EMT and stemness in colon cancer has not been fully understood. We aimed to demonstrate the clinical significance of EMT and the stem cell phenotype in colorectal cancer. Two hundred and thirty-one surgically resected colon cancer cases were included in the present study. mRNAs of E-cadherin, TWIST1 and SNAI1 were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) (n=109). Immunohistochemical staining was performed for six markers (ALDH1, TGF-β1, E-cadherin, β-catenin, TWSIT1 and SNAI1) (n=231). We assessed clinicopathological characteristics according to the expression of the stem cell phenotype and EMT markers. Based on the results of qRT-PCR, TWIST1 and SNAI1 significantly influenced node metastasis (P=0.04 and P=0.02, respectively). High TWIST1 and SNAI1 mRNA expression was associated with poor overall survival according to the univariate analysis (P<0.01 and P=0.01, respectively) and the multivariate analysis (P=0.04 and P=0.04, respectively). ALDH1 expression as detected by immunohistochemical staining was associated with high nodal stage, advanced clinical stage, lymphatic invasion and poor survival (P=0.01, P=0.04, P<0.05 and P<0.01, respectively) and with the expression of TGF-β1 and β-catenin. In conclusion, in human colorectal cancer, the EMT markers TWIST1 and SNAI1 are suggested as important markers of poor prognosis. Their expression is associated with the expression of putative stem cell marker ALDH1, and ALDH1 is associated with the expression of TGF-β1.

The integrated pathway of TGFβ/Snail with TNFα/NFκB may facilitate the tumor-stroma interaction in the EMT process and colorectal cancer prognosis

“…The TGFβ/Snail pathway and the TNFα/NFκB pathway have been confirmed to be classical regulators in the EMT process 18, 36 . By regulating the expression levels and nuclear translocation of transcription factors in cancer cells and their microenvironment, both the TGFβ/Snail pathway and the TNFα/NFκB pathway participate in various stages of cancer development, including oncogenesis and cancer metastasis, as well as in the prognosis of cancer patients 37, 38 . Ongoing research indicates that TGFβ has close interactions with the inflammatory environment in the development of EMT, especially with the inflammatory factors TNFα and NFκB 39 .…”

Hedgehog Signaling Drives Radioresistance and Stroma-Driven Tumor Repopulation in Head and Neck Squamous Cancers

“…In one study evaluating patients with high versus low ALDH1 expression pre- and post-surgery, colorectal cancer patients undergoing neoadjuvant chemoradiotherapy who expressed high levels of ALDH1 had greater rates of local failure and recurrence (28). Expression of ALDH1 in HNSCC and colorectal cancer is associated with increased nodal and distant metastasis, worse OS, and is mediated through TWIST1 and SNAI1 expression (29, 30). These findings highlight the concern that chemoradiotherapy can induce ALDH1 (and BMI1 ) expression which is a poor prognostic factor.…”

Aminopeptidase A initiates tumorigenesis and enhances tumor cell stemness via TWIST1 upregulation in colorectal cancer

“…Further, the number of primary- and secondary-seeded spheroid cells in APA-knocked down HT29 cells decreased significantly (Figure 3C middle and right and Figure 3D). ALDH1 activity has been reported as a reliable index of CRC stem cells [21], and ALDH1 expression in CRC is strongly associated with and dependent on TWIST expression [22]. Our flow cytometry data show that CD44 + and ALDH + cell populations significantly declined in APA-knocked down HT29 cells (Figure 3E and Figure 3F), suggesting that CSC-like characteristics are enhanced by APA expression.…”