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

Weygant N, Qu D, May R, Tierney RM, Berry WL, Zhao L, Agarwal S, Chandrakesan P, Chinthalapally HR, Murphy NT, Li JD, Sureban SM, Schlosser MJ, Tomasek JJ, Houchen CW - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.

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.

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DCLK1 protein is overexpressed in RCC tumor tissueA) DCLK1 protein is significantly increased in stage II-III tumors compared to normal or stage I tumors (p<0.002). B) Representative DCLK1 immunoreactivity for normal, stage I, stage II, and stage III tissue samples from low to high composite score. C) DCLK1 immunoreactivity is elevated in grade 1 and grade 2 tumors.
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Figure 3: DCLK1 protein is overexpressed in RCC tumor tissueA) DCLK1 protein is significantly increased in stage II-III tumors compared to normal or stage I tumors (p<0.002). B) Representative DCLK1 immunoreactivity for normal, stage I, stage II, and stage III tissue samples from low to high composite score. C) DCLK1 immunoreactivity is elevated in grade 1 and grade 2 tumors.

Mentions: To assess DCLK1 protein expression in RCC we performed immunohistochemistry using α-DCLK1 antibody on a commercially available tissue microarray. A chi-square test was performed to examine the relation between DCLK1 immunostaining and RCC diagnosis. The relation between these variables was significant, X2(1, n = 192) = 4.156, p <0.05, indicating that RCC tumors were significantly more likely to demonstrate DCLK1 immunostaining. Mean tumor expression of DCLK1 protein was 2 fold higher in tumors compared to normal kidney (data not shown). Moreover, stage II and III tumors demonstrated significantly increased DCLK1 protein expression compared to both normal kidney and stage I tumors (Fig 3A-B), and DCLK1 protein expression was also upregulated in grade I and II tumors (Fig 3C). Together, these data demonstrate that DCLK1 is epigenetically altered and significantly overexpressed in RCC, and dysregulation of DCLK1 methylation and mRNA expression are interrelated. Moreover, immunohistochemical staining confirms these findings for DCLK1 protein in patient tumors and demonstrates increased expression in mid-to-advanced stage disease.


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

Weygant N, Qu D, May R, Tierney RM, Berry WL, Zhao L, Agarwal S, Chandrakesan P, Chinthalapally HR, Murphy NT, Li JD, Sureban SM, Schlosser MJ, Tomasek JJ, Houchen CW - Oncotarget (2015)

DCLK1 protein is overexpressed in RCC tumor tissueA) DCLK1 protein is significantly increased in stage II-III tumors compared to normal or stage I tumors (p<0.002). B) Representative DCLK1 immunoreactivity for normal, stage I, stage II, and stage III tissue samples from low to high composite score. C) DCLK1 immunoreactivity is elevated in grade 1 and grade 2 tumors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385845&req=5

Figure 3: DCLK1 protein is overexpressed in RCC tumor tissueA) DCLK1 protein is significantly increased in stage II-III tumors compared to normal or stage I tumors (p<0.002). B) Representative DCLK1 immunoreactivity for normal, stage I, stage II, and stage III tissue samples from low to high composite score. C) DCLK1 immunoreactivity is elevated in grade 1 and grade 2 tumors.
Mentions: To assess DCLK1 protein expression in RCC we performed immunohistochemistry using α-DCLK1 antibody on a commercially available tissue microarray. A chi-square test was performed to examine the relation between DCLK1 immunostaining and RCC diagnosis. The relation between these variables was significant, X2(1, n = 192) = 4.156, p <0.05, indicating that RCC tumors were significantly more likely to demonstrate DCLK1 immunostaining. Mean tumor expression of DCLK1 protein was 2 fold higher in tumors compared to normal kidney (data not shown). Moreover, stage II and III tumors demonstrated significantly increased DCLK1 protein expression compared to both normal kidney and stage I tumors (Fig 3A-B), and DCLK1 protein expression was also upregulated in grade I and II tumors (Fig 3C). Together, these data demonstrate that DCLK1 is epigenetically altered and significantly overexpressed in RCC, and dysregulation of DCLK1 methylation and mRNA expression are interrelated. Moreover, immunohistochemical staining confirms these findings for DCLK1 protein in patient tumors and demonstrates increased expression in mid-to-advanced stage disease.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK.

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.

Show MeSH
Related in: MedlinePlus