DCLK1 is a broadly dysregulated target against epithelial-mesenchymal transition, focal adhesion, and stemness in clear cell renal carcinoma

Abstract

Renal clear cell carcinoma (RCC) is the most common type of kidney cancer and the 8th most common cancer overall in the US. RCC survival rates drop precipitously with regional and distant spread and recent studies have demonstrated that RCC presents an epithelial-mesenchymal transition (EMT) phenotype linked to increased recurrence and decreased survival. EMT is a key characteristic of tumor stem cells (TSCs) along with chemo-resistance and radio-resistance, which are also phenotypic of RCC. Targeting these factors is key to increasing the survival of RCC patients. Doublecortin-like kinase 1 (DCLK1) marks TSCs in pancreatic and colorectal cancer and regulates EMT and stemness. Analysis of the Cancer Genome Atlas' RCC dataset revealed that DCLK1 is overexpressed and dysregulated on the mRNA and epigenetic level in more than 93% of RCC tumors relative to adjacent normal tissue. Immunohistochemistry using α-DCLK1 antibody confirmed overexpression and demonstrated a major increase in immunoreactivity in stage II-III tumors compared to normal kidney and stage I tumors. Small-interfering RNA (siRNA) mediated knockdown of DCLK1 resulted in decreased expression of EMT and pluripotency factors and significantly reduced invasion, migration, focal adhesion, drug-resistance, and clonogenic capacity. These findings suggest that DCLK1 is a novel, overexpressed factor in RCC progression that may be targeted to suppress EMT, metastasis, and stemness in early-stage and advanced RCC to increase patient survival. Moreover, the possibility that DCLK1 may mark a population of tumor stem-like cells in RCC should be further investigated in light of these findings.

Induction of Epithelial-Mesenchymal Transition via Activation of Epidermal Growth Factor Receptor Contributes to Sunitinib Resistance in Human Renal Cell Carcinoma Cell Lines

“…Several cancers have been shown to possess an EMT phenotype that is linked with resistance to conventional chemotherapies (Hollier et al, 2009;Keitel et al, 2014;Weygant et al, 2015). In our study, the expression of fibronectin and vimentin and nuclear translocation of b-catenin were increased in 786-O cells treated with sunitinib.…”

“…Several recent studies showed that cells that have undergone epithelial-mesenchymal transition (EMT) are relatively resistant to conventional chemotherapies (Hollier et al, 2009;Keitel et al, 2014;Weygant et al, 2015). Sánchez-Tilló demonstrated that the expression of E-cadherin is associated with a high sensitivity to the epidermal growth factor receptor (EGFR) inhibitor gefitinib (Witta et al, 2006;Sánchez-Tilló et al, 2011).…”

Expression of lactate dehydrogenase C correlates with poor prognosis in renal cell carcinoma

“…35,36 EMT is also correlated with an advanced recurrence risk and poor overall survival in patients with RCC. 37 Moreover, our data demonstrated that LDHC could upregulate the expression of MMP-9. This protein was a member of the family of zinc-dependent endopeptidases, the central role of which was the degradation and remodelling of the extracellular matrix, leading to tumour invasion and metastasis.…”

Functional implication of Dclk1 and Dclk1-expressing cells in cancer

“…Again, siRNA-mediated knockdown of Dclk1 led to a significant inhibition of tumor cell proliferation, focal adhesion, invasion and clonogenic growth. 18 However, some of the strongest data on tumor growth can be found in models of pancreatic cancer. Sureban and colleagues extended our knowledge on Dclk1 function in cancer through a series of well-designed experiments in mouse models of pancreatic cancer and pancreatic cancer cell lines.…”