Podocalyxin-Like Protein 1 Regulates TAZ Signaling and Stemness Properties in Colon Cancer

Abstract

Colon cancer is the third most common cancer in the world and the second most common cause of cancer-related mortality. Molecular biomarkers for colon cancer have undergone vigorous discovery and validation. Recent studies reported that overexpression of podocalyxin-like protein 1 (PODXL) is associated with distant metastasis and poor prognosis across several types of malignancies. Its role and underlying molecular mechanism, however, are not yet fully understood. In the present study, we revealed that the Hippo transducer, the transcriptional coactivator with PDZ-binding motif (TAZ), acts as a downstream mediator of PODXL in colon cancer. Inhibition of PODXL resulted in the suppression of TAZ signaling and the downregulation of Hippo downstream genes. Moreover, PODXL plays a critical role in cancer stemness, invasiveness, and sensitivity to chemotherapies in colon cancer HCT15 cells. Notably, expression of PODXL showed a positive correlation with stem-like and epithelial-mesenchymal transition (EMT) core signatures, and was associated with poor survival outcomes in patients with colon cancer. These findings provide novel insights into the molecular mechanism of PODXL-mediated tumorigenesis in colon cancer.

Emerging Role of Podocalyxin in the Progression of Mature B-Cell Non-Hodgkin Lymphoma

“…Similarly, PODXL silencing in HCT15 colon cancer cells and in SGC-7901 and AGS gastric cancer cells led to a reduction of EMT-associated markers [51,54]. Moreover, the analysis of mRNA expression levels in patients with colon cancer using GSE17536 datasets revealed a positive correlation of PODXL expression with the mesenchymal markers vimentin, N-cadherin, TWIST2, SLUG, and ZEB1 and a negative correlation with the epithelial marker E-cadherin [54]. In a study performed in HMLER human mammary epithelial cells, activation of EMT program by Dox-inducible expression of the EMT transcription factors Snail or ZEB1 resulted in increased mRNA PODXL levels, indicating that PODXL is induced during EMT process [81].…”

“…Accordingly, forced expression of PODXL in A549 cells promoted changes characteristic of EMT through a process dependent on the activation of PI3K/AKT signaling pathway [87]. Similarly, PODXL silencing in HCT15 colon cancer cells and in SGC-7901 and AGS gastric cancer cells led to a reduction of EMT-associated markers [51,54]. Moreover, the analysis of mRNA expression levels in patients with colon cancer using GSE17536 datasets revealed a positive correlation of PODXL expression with the mesenchymal markers vimentin, N-cadherin, TWIST2, SLUG, and ZEB1 and a negative correlation with the epithelial marker E-cadherin [54].…”

“…On the other hand, PODXL overexpression in MCF-7 breast cancer cell line stimulated invadopodia formation and activation, through the induction of Rac1/Cdc42/cortactin signaling [82]. The migratory and invasive properties promoted by PODXL has also been demonstrated in vitro in colorectal cancer (HCT116, LOVO and HCT15), gastric cancer (SGC-7901, AGS, BGC823, and MGC803), malignant testicular tumor (NT2), oral squamous cell carcinoma (SAS), lung adenocarcinoma (A549), and glioblastoma multiforme (LN-299 and U-118) cell lines [32,46,51,54,[75][76][77][78]87]. Besides, silencing of PODXL in both NAMEC8R and the highly metastatic MDA-MB-231 4175 breast cancer cells decreased extravasation in vitro, an effect which was totally reversed by overexpressing wild type PODXL [81].…”

“…PODXL in SGC-7901 and AGS gastric cancer cells also enhanced primary tumor growth in nude mice [51]. In HCT15 colorectal cells, knockdown of PODXL reduced the expression of TAZ protein, its downstream targets survivin, connective tissue growth factor (CTGF), CYR61 and cyclinD1, and stem-cell-related genes, as well as tumorsphere formation, indicating that PODXL plays a crucial role in self-renewal of colon cancer cells [54].…”

PODXL Might Be a New Prognostic Biomarker in Various Cancers: A Meta-analysis and Sequential Verification with TCGA Datasets

“…Some latest studies showed that PODXL promoted the gelsolin-actin interaction in cell protrusions to enhance the motility and invasiveness [26], and some showed that the PODXL-ezrin signaling axis could rearrange the dynamic cytoskeleton for transendothelial migration [43]. PODXL also took part in the NF-kB, PI3K/AKT, Hippo and MAPK/ERK signaling pathway, and facilitated tumor progression by increasing cell proliferation, migration and invasion as well as suppressing apoptosis [21,44,45].…”