Abstract
The transcriptional factor Forkhead box k1 (FOXK1) is a member of the FOX family. The abnormal expression of FOXK1 may have an important role in tumour development. Our previous studies showed that four-and-a-half LIM protein 2 (FHL2) is a critical inducer of the epithelial-to-mesenchymal transition (EMT) and invasion. However, the molecular mechanism by which FOXK1 synergizes with FHL2 tumour proliferation, EMT and metastasis is not well defined. We evaluated that messenger RNA (mRNA) and protein expression levels by quantitative RT–PCR, western blot, immunofluorescence and immunohistochemistry (IHC) assays. The migration and invasive abilities of colorectal cancer (CRC) cells were evaluated using short hairpin RNA (shRNA)-mediated inhibition in vitro and in vivo. We showed that FOXK1 expression was upregulated in CRC compared with matched normal tissues. FOXK1 physically interacts with FHL2 in CRC. Moreover, higher expression levels of the two proteins were significantly associated with differentiation, lymph node metastasis, AJCC stage and poorer prognosis. Furthermore, the overexpression of FOXK1 in CRC cells is associated with EMT, invasion and metastasis. However, the siRNA-mediated repression of FHL2 in FOXK1-overexpressing cells reversed EMT and both the proliferative and metastatic phenotypes in vitro and in vivo. These data identified that the co-expression of FOXK1 and FHL2 enhances cell proliferation and metastasis through the induction of EMT. Thus, FOXK1 and FHL2 may serve as putative targets in the combined therapy of CRC.
Highlights
The Drosophila transcription factor forkhead and subsequent mammalian orthologues of the forkhead DNA-binding domain were discovered over two decades ago.[1]
Forkhead box k1 (FOXK1) physically interacts with four-and-a-half LIM protein 2 (FHL2) in colorectal cancer (CRC) Because FHL2 has been previously implicated in cancer cell growth and metastasis,[22,24] we investigated whether a correlation exists between FHL2 and FOXK1 expression in CRC
The overexpression of FOXK1 resulted in a significant loss of epithelial marker E-cadherin, whereas the downregulation of FHL2 in FOXK1-overexpressed cells caused an increase in E-cadherin (Figure 6f). These results clearly indicated that the FOXK1– FHL2 axis has an important role in development and metastasis during CRC
Summary
The Drosophila transcription factor forkhead and subsequent mammalian orthologues of the forkhead DNA-binding domain were discovered over two decades ago.[1] Forkhead transcription factors encode a subgroup of helix-turn-helix proteins.[2] The arrangement of loops connecting the strands that flank one of the three helices gives rise to a butterfly-like appearance (these proteins are termed ‘winged-helix’ transcription factors).[3] Through the transcriptional control of gene expression, many FOX protein members have important roles in the embryonic development,[4] organogenesis and the regulation of a variety of physiological processes, such as cell cycle progression,[5] cell survival[6] and immune responses.[7] the dysregulation of the functions, subcellular localization and expression of FOX transcription factors leads to the development and progression of diseases, especially cancer.[8,9] For example, in the FOX family proteins, FOXM1 has been reported in several malignant tumours, including those of the breast,[10] liver,[11] pancreas,[12] ovarian,[13] lung[14] and colon.[15]
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