DCLK1 integrates induction of TRIB3, EMT, drug resistance and poor prognosis in colorectal cancer

Makino, Shinji; Takahashi, Hidekazu; Okuzaki, Daisuke; Miyoshi, Norikatsu; Haraguchi, Naotsugu; Hata, Taishi; Matsuda, Chu; Yamamoto, Hideya; Mizushima, Tsunekazu; Mori, Masaki; Doki, Yuichiro

doi:10.1093/carcin/bgaa016

Cited by 11 publications

(20 citation statements)

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“…Our data showed a strong reduction in EMT gene markers expression and an impaired in cell migration after DCLK1 inhibition ( Fig.S5 and S6). Consistent with these results, several research teams have demonstrated an important role of DCLK1 in the progression of different gastroenterological tumours (35)(36)(37)(38).…”

Section: Accepted Articlesupporting

confidence: 75%

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DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma

et al. 2021

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Background & Aims: Cholangiocarcinoma (CCA) is a very aggressive cancer showing high cancer stem cells (CSCs) presence. Doublecortin-like kinase1 (DCLK1) has been demonstrated as a CSC marker in different gastroenterological solid tumours. Our aim was to evaluate in vitro the expression and the biological function of DCLK1 in intrahepatic CCA (iCCA) and perihilar CCA (pCCA). Approach & Results: Specimens surgically resected of human CCA were enzymatically digested, submitted to immunosorting for specific CSC markers (LGR5, CD90, EpCAM, CD133, CD13) and primary cell cultures were prepared. DCLK1 expression was analysed in CCA cell cultures by real-time quantitative polymerase chain reaction (RT-qPCR), Western Blot and immunofluorescence. Functional studies have been performed by evaluating the effects of selective DCLK1 inhibitor (LRRK2-IN-1) on cell proliferation (MTS-Assay, cell population doubling time), apoptosis and colony formation capacity. DCLK1 was investigated in situ by immunohistochemistry and RT-qPCR. DCLK1 serum concentration was analysed by enzyme-linked immunosorbent assay (ELISA). We describe DCLK1 in CCA with an increased gene and protein DCLK1 expression in pCCA LGR5+ and in iCCA CD133+ cells compared to unsorted cells. LRRK2-IN-1 showed an anti-proliferative effect in dose-dependent manner. LRRK2-IN-1 markedly impaired cell proliferation, induced apoptosis, decreased colony formation capacity and colony size in both iCCA and pCCA compared to untreated cells. In situ analysis confirm that DCLK1 is present only in tumours, but not Accepted Article This article is protected by copyright. All rights reserved in healthy tissue. Interestingly, DCLK1 was detected in the human serum samples of iCCA (high), pCCA (high), HCC (low) and cirrhotic (low) patients, but it was almost undetectable in healthy controls. Conclusion: DCLK1 characterizes a specific CSC-subpopulation of iCCA CD133+ and pCCA LGR5+ and its inhibition exerts anti-neoplastic effects in primary CCA cell cultures. Human DCLK1 serum might represent a serum biomarker for the early CCA diagnosis.

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Section: Accepted Articlesupporting

confidence: 75%

“…Consistent with these results, several research teams have demonstrated an important role of DCLK1 in the progression of different gastroenterological tumors. ( 35‐38 )…”

Section: Discussionmentioning

confidence: 99%

DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma

et al. 2021

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“…These results suggest involvement of the processes regulated by KLF6 in response to BTZ treatment and bridging of those process may result in a treatment resistant phenotype. Apart from this top hit, a number of genes shown to be involved in proliferation of cancer cells were statistically significantly associated with BTZ induced methylation changes, including: ARHGAP26 38 , TBX2 39 , 40 , MAML3 41 , DCLK1 42 , 43 . The “GO cellular components” (Fig.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound

Łuczkowska

Sokołowska

Taryma-Leśniak

et al. 2021

Sci Rep

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The anticancer activity of bortezomib (BTZ) has been increasingly studied in a number of indications and promising results for the use of this treatment have been shown in neuroblastoma. As BTZ treatment is usually administered in cycles, the development of resistance and side effects in patients undergoing therapy with BTZ remains a major challenge for the clinical usage of this compound. Common resistance development also means that certain cells are able to survive BTZ treatment and bypass molecular mechanisms that render BTZ anticancer activity. We studied the methylome of neuroblastoma cells that survived BTZ treatment. Our results indicate that BTZ induces pronounced genome wide methylation changes in cells which recovered from the treatment. Functional analyses of identified methylation changes demonstrated they were involved in key cancer pathology pathways. These changes may allow the cells to bypass the primary anticancer activity of BTZ and develop a treatment resistant and proliferative phenotype. To study whether cells surviving BTZ treatment acquire a proliferative phenotype, we repeatedly treated cells which recovered from the first round of BTZ treatment. The repetitive treatment led to induction of the extraordinary proliferative potential of the cells, that increased with subsequent treatments. As we did not observe similar effects in cells that survived treatment with lenalidomide, and non-treated cells cultured under the same experimental conditions, this phenomenon seems to be BTZ specific. Overall, our results indicate that methylation changes may play major role in the development of BTZ resistance.

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“…DCLK1 (+ 60.2-fold) has been reported to be associated with chemoresistance to cisplatin in non-small cell lung cancer cells and targeting DCLK1 by miR539 led to increased sensitivity to cisplatin (Deng et al 2018). DCLK1 has also been associated with drug resistance in colorectal cancer, pancreatic cancer, and kidney cancer (Ge et al 2018;Makino et al 2020;Qu et al 2019). LBH (+ 31.9-fold) has been reported as a potential marker for hepatocellular carcinoma, as its overexpression was associated with poor prognosis (Chen et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion

et al. 2021

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TP53 (p53) is a pivotal player in tumor suppression with fifty percent of all invasive tumors displaying mutations in the TP53 gene. In the present study, we characterized colon cancer cells (HCT116 p53 −/−) with TP53 deletion, a sub-line derived from HCT116-p53 +/+ cells. RNA sequencing and network analyses were performed to identify novel drug resistance mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). Numerous genes were overexpressed in HCT116 p53 −/− cells: RND3/RhoE (235.6-fold up-regulated), DCLK1 (60.2-fold up-regulated), LBH (31.9-fold up-regulated), MYB (28.9-fold up-regulated), TACSTD2 (110.1-fold down-regulated), NRIP1 (81.5-fold down-regulated) and HLA-DMB (69.7-fold down-regulated) are among the identified genes with potential influence on multidrug resistance (MDR) and they are associated with cancer progression and tumorigenesis, according to previously published studies. Probably due to TP53 deletion, disturbances in DNA repair and apoptosis are leading to aberrancies in cellular and organismal organization, ultimately increasing tumorigenesis and cancer progression potential. With NFκB, PI3K and HSP70, being at the center of merged protein network, and TH1-2 pathways, being among the influenced pathways, it can be speculated that the inflammatory pathway contributes to a resistance phenotype together with cell cycle regulation and heat-shock response. HCT116-p53 −/− cells have more chromosomal aberrations, gains and losses in copy numbers than HCT116-p53 +/+ cells. In conclusion, numerous genomic aberrations, which might be associated with yet unknown drug resistance mechanisms, were identified. This may have important implications for future treatment strategies.

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DCLK1 integrates induction of TRIB3, EMT, drug resistance and poor prognosis in colorectal cancer

Cited by 11 publications

References 0 publications

DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma

DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma

Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound

Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion

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