Increased expression of DCLK1, a novel putative CSC maker, is associated with tumor aggressiveness and worse disease-specific survival in patients with bladder carcinomas

Shafiei, Somayeh B.; Kalantari, Elham; Zanjani, Leili Saeednejad; Abolhasani, Maryam; Lari, Mohammad Hossein Asadi; Madjd, Zahra

doi:10.1016/j.yexmp.2019.04.015

Cited by 20 publications

(29 citation statements)

References 55 publications

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“…In our previous works, oncopathological value of DCLK1 expression was evaluated in various cancers including colorectal, bladder, and gastric carcinomas; results of which were in line with other studies 17,19,23,[27][28][29][30] . In a comprehensive study on 472 bladder cancer cases, an increase was found in expression of DCLK1 (DCLK1-L/S) that associated with more aggressive tumors, advanced stages, and poorer DSS in the patients with bladder cancer 19 . Additionally, results of our previous study on local and circulating DCLK1 (DCLK1-L) in 58 fresh CRC tissues and their correspondent normal margins demonstrated signi cantly higher expression of DCLK1 in the patients with CRC having advanced-stage and higher tumor grade in both protein and mRNA expression levels 28 .…”

Section: Discussionsupporting

confidence: 83%

“…In parallel, the results of immune electron microscopy (IEM) have con rmed the presence of S-isoform in cytosol, mitochondrial, and cell membrane fractions of HCT-116 and COLO205-S-GFP cell lines, unlike L-isoform that was present mainly in cell membrane fractions of HEK293 cells only expressing L-isoform 10 . Other clinical studies used anti-DCLK1-L/S or anti DCLK1-L antibodies have also reported mainly cytoplasmic and membranous localization of DCLK1 in gastric, colorectal, and bladder carcinoma tissues 18,19,30,31 , meanwhile in the current study, nucleus localization of DCLK1-S was shown in tumor cells area.…”

Section: Discussionsupporting

confidence: 58%

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Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

Kalantari

Ghods

Zanjani

et al. 2021

Preprint

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Isoform-specific function of doublecortin-like kinase 1(DCLK1) has highlighted key role of the DCLK1-S (short isoform) in maintenance, progression, and invasion of tumor. Therefore, this study was designed to produce an anti-DCLK1-S polyclonal antibody in order to specifically evaluate expression pattern and clinical significance of DCLK1-S in a well-deﬁned tissue microarray (TMA) series of colorectal tissues including 348 colorectal cancer (CRC) and 51 adjacent normal tissues during a follow-up period of 108 months. Expression of DCLK1-S was significantly higher in CRC samples compared to adjacent normal samples (P < 0.001). Cytoplasmic expression of DCLK1-S was significantly higher in the tumors at advanced stage of the cancer and with poorer differentiation (P<0.001, P= 0.02). The patients with CRC whose tumors showed higher cytoplasmic expression of DCLK1-S had worse disease-specific survival (DSS) (log-rank test, P = 0.03) and 5-year DSS rates (P= 0.01). Additionally, an improved prognostic value was observed in the patients with CRC with high DCLK1-S expression vs. its moderate expression (HR: 2.70, 95% CI: 0.98-7.38; p =0.04) by multivariate analysis. Our findings strongly supported that high cytoplasmic expression of DCLK1-S compared to its moderate expression could be considered as an independent prognostic factor influencing DSS. Taken together, DCLK1-S can be a promising prognostic candidate and targeted-therapeutic indicator for effective treatment of CRC.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 58%

Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

Kalantari

Ghods

Zanjani

et al. 2021

Preprint

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“…In parallel, the results of immune electron microscopy (IEM) have con rmed the presence of S-isoform in cytosol, mitochondrial, and cell membrane fractions of HCT-116 and COLO205-S-GFP cell lines, unlike L-isoform that was present mainly in cell membrane fractions of HEK293 cells only expressing L-isoform [10]. Other clinical studies used anti-DCLK1-L/S or anti DCLK1-L antibodies have also reported mainly cytoplasmic and membranous localization of DCLK1 in gastric, colorectal, and bladder carcinoma tissues [18,19,33,43], meanwhile in the current study, nucleus localization of DCLK1-S was shown in tumor cells area.…”

Section: Discussionmentioning

confidence: 80%

“…In our previous research, expression pattern and prognostic signi cance of DCLK1 have been studied in colorectal, gastric, and bladder carcinomas [17][18][19][20][21] using available commercial anti-DCLK1 antibodies that can detect C-terminal domain of both DCLK1-L/S isoforms or only N-terminal end of DCLK1-L isoform, while role of the main isoform to overexpress DCLK1 has remained unknown. To the best of our knowledge, there is no commercial anti-DCLK1-S antibody, and also no study has been previously performed to investigate prognostic signi cance of DCLK1-S on tumor tissues, particularly in CRC by immunohistochemistry (IHC).…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

Kalantari

Ghods

Zanjani

et al. 2021

Preprint

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Background: Oncogenic role of doublecortin-like kinase 1 (DCLK1) as a putative cancer stem cell (CSC) marker has been clarified in colorectal cancer (CRC). Isoform-specific function of DCLK1 has highlighted key role of the DCLK1-S (short isoform) in tumor maintenance, progression, and invasion. Considering the lack of commercial anti-DCLK1-S antibody suitable for immunohistochemical (IHC) application, this study was conducted to produce and validate an anti-DCLK1-S polyclonal antibody in order to specifically evaluate expression pattern and clinical significance of short isoform of DCLK1 in colorectal cancer tissues.Methods: Rabbit immunization was performed against a synthetic peptide corresponding to the published six specific amino acid sequences of DCLK1-S, and production of antibody was evaluated by enzyme-linked immunosorbent assay (ELISA). After IHC assessment of the purified anti-DCLK1-S polyclonal antibody, it was used to undertake a definitive study for determining prognostic significance of DCLK1-S expression in a well-deﬁned tissue microarray (TMA) series including 348 CRC and 51 adjacent normal tissues with a follow-up period of 108 months. Results: Positive immunoreactivity of DCLK1-S was found in 84.2% of CRC samples. Cytoplasmic expression was the main localization of DCLK1-S compared to nuclear and membranous area of tumor cells. Expression of DCLK1-S in CRC samples was significantly higher compared to adjacent normal samples (P <0.001). A positive significant association was found between high cytoplasmic expression of DCLK1-S and advanced tumor, nodes, and metastases (TNM) stage (P<0.001) as well as the increased tumor differentiation (P= 0.02). Moreover, the patients with CRC whose tumors showed higher cytoplasmic expression of DCLK1-S had worse disease-specific survival (DSS) (log-rank test, P = 0.03) and 5-year DSS rate (P= 0.01). Additionally, the improved prognostic value was seen in the patients with CRC with high DCLK1-S expression versus moderate expression (HR: 2.70, 95% CI: 0.98-7.38; p =0.04) by multivariate analysis.Conclusions: Our findings strongly supported that DCLK1-S isoform may play a crucial role in invasion, tumor aggressive behavior, and worsened DSS of the patients with CRC. Importantly, high cytoplasmic expression of DCLK1-S compared to moderate expression could be considered as an independent prognostic factor influencing DSS. Taken together, DCLK1-S can be a candidate as a promising prognostic and targeted-therapeutic indicator for effective treatment of CRC.

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“…It has been reported that there was increased DCLK1 expression among a sample of Iranian BC cases in comparison with normal margins. Moreover, the DCLK1 overexpression was correlated with higher stage, grade, poor prognosis, low survival rate, and tumor aggressiveness (Shafiei et al, 2019). BMI1 (OMIM: 164831) is belonged to the polycomb group (PcG) proteins which are transcriptional suppressors (Orlando, 2003).…”

Section: Self‐renewalmentioning

confidence: 99%

Genetic and molecular biology of bladder cancer among Iranian patients

Mojarrad

Moghbeli

2020

Molec Gen & Gen Med

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Background Bladder cancer (BC) is the sixth common cancer among Iranians. Various risk factors such as smoking, body mass index, chronic infection, age, and genetic factors are associated with BC progression. Methods It has been shown that a significant ratio of patients have tumors with muscle bladder layer invasion and poor prognosis at the time of diagnosis. Therefore, the early detection of tumors is required to reduce the mortality rate of BC cases. Since there is a wide geographical incidence variation in BC in Iran, it seems that the ethnic and genetic factors can be the main risk factors among Iranian BC patients. Results For the first time, in present review we have summarized all of the reported genes among Iranian BC patients until now which were significantly associated with tumorigenesis. Moreover, we categorized all of the reported genes based on their cell and molecular functions to clarify the genetic and molecular biology of BC among Iranian population. Conclusion This review paves the way of determination of a population‐based genetic panel markers for the early detection of BC in this population.

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Increased expression of DCLK1, a novel putative CSC maker, is associated with tumor aggressiveness and worse disease-specific survival in patients with bladder carcinomas

Cited by 20 publications

References 55 publications

Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

Genetic and molecular biology of bladder cancer among Iranian patients

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