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Charles B Nguyen, Courtney W Houchen, Naushad Ali
Liver diseases are the fourth leading cause of mortality among adults in the United States. Patients with chronic liver diseases such as viral hepatitis, fibrosis, and cirrhosis have significantly higher risks of developing hepatocellular carcinoma (HCC). With a dismal five-year survival rate of 11%, HCC is the third most common cause of cancer-related deaths worldwide. Regardless of the underlying cause, late presentation and a lack of effective therapy are the major impediments for successful treatment of HCC...
September 30, 2016: Experimental Biology and Medicine
Joni Leppänen, Olli Helminen, Heikki Huhta, Joonas H Kauppila, Ilkka Miinalainen, Veli-Pekka Ronkainen, Juha Saarnio, Petri P Lehenkari, Tuomo J Karttunen
Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated kinase. In murine intestine, DCLK1 marks tuft cells with characteristic microvilli, features of neuroendocrine cells and also quiescent stem cell-like properties. The occurrence and pathological role of DCLK1-positive cells in human intestinal mucosa is unknown. We analysed DCLK1 expression in healthy duodenal, jejunal and colorectal mucosa samples (n = 35), and in duodenal specimens from patients with coeliac disease (n = 20). The samples were immunohistochemically double-stained with DCLK1, and synaptophysin, chromogranin A and Ki-67...
November 2016: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
Hironori Koga, Yu Ikezono, Takuji Torimura
No abstract text is available yet for this article.
2016: Stem Cell Investigation
Onisha Patel, Weiwen Dai, Mareike Mentzel, Michael D W Griffin, Juliette Serindoux, Yoann Gay, Stefanie Fischer, Shoukat Sterle, Ashleigh Kropp, Christopher J Burns, Matthias Ernst, Michael Buchert, Isabelle S Lucet
Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that belongs to the family of microtubule-associated proteins. Originally identified for its role in neurogenesis, DCLK1 has recently been shown to regulate biological processes outside of the CNS. DCLK1 is among the 15 most common putative driver genes for gastric cancers and is highly mutated across various other human cancers. However, our present understanding of how DCLK1 dysfunction leads to tumorigenesis is limited. Here, we provide evidence that DCLK1 kinase activity negatively regulates microtubule polymerization...
September 6, 2016: Structure
Matthew P Hanley, Krishna Kadaveru, Christine Perret, Charles Giardina, Daniel W Rosenberg
The role of folate one-carbon metabolism in colorectal cancer development is controversial, with nutritional intervention studies producing conflicting results. It has been reported that Apc(Min/+) mice maintained on a diet deficient in the methyl donors folic acid, methionine, choline, and vitamin B12, and supplemented with homocysteine, show a greater than 95% reduction in intestinal tumor development. The present study extends these findings and shows that tumor protection afforded by dietary methyl donor deficiency (MDD) is long-lasting...
October 2016: Cancer Prevention Research
Tianbo Gao, Min Wang, Lingling Xu, Tao Wen, Jian Liu, Guangyu An
PURPOSE: Metastasis is a primary cause of colorectal cancer (CRC)-related death, and cancer stem cells (CSCs) are thought to be majorly responsible for initiating metastatic behaviors. Doublecortin-like kinase 1 (DCLK1) was recently discovered to be a marker for gastrointestinal CSCs. Here, we aimed to explore whether DCLK1 is associated with CRC metastasis through clinical and in vitro investigations. METHODS: The expression levels of DCLK1 mRNA and protein in human CRC tissues were analyzed through quantitative RT-PCR and immunohistochemistry staining, respectively...
October 2016: Journal of Cancer Research and Clinical Oncology
Hiroyuki Koizumi, Hiromi Fujioka, Kazuya Togashi, James Thompson, John R Yates, Joseph G Gleeson, Kazuo Emoto
Doublecortin-like kinase 1 (DCLK1) is a member of the neuronal microtubule-associated doublecortin (DCX) family and functions in multiple stages of neural development including radial migration and axon growth of cortical neurons. DCLK1 is suggested to play the roles in part through its protein kinase activity, yet the kinase substrates of DCLK1 remain largely unknown. Here we have identified MAP7D1 (microtubule-associated protein 7 domain containing 1) as a novel substrate of DCLK1 by using proteomic analysis...
August 9, 2016: Developmental Neurobiology
Lorenz Kadletz, Klaus Aumayr, Gregor Heiduschka, Sven Schneider, Elisabeth Enzenhofer, Claudia Lill
Salivary gland carcinomas are a rare malignancy. Therefore, little is known about biomarkers and cancer stem cells in salivary gland malignancies. Double cortin-like kinase 1 (DCLK1) is a promising therapeutic target and cancer stem cell marker, predominantly investigated in pancreatic and colorectal cancer. The purpose of this study was to investigate the expression of DCLK1 in major and minor salivary gland carcinomas and its influence on survival. We examined a total of 80 patients with major or minor salivary gland cancer in this retrospective study...
July 28, 2016: European Archives of Oto-rhino-laryngology
C Benedikt Westphalen, Michael Quante, Timothy C Wang
Doublecortin like kinase protein 1 (Dclk1) is a microtubule-associated protein with C-terminal serine/threonine kinase domain. Originally designated Doublecortin and CaM kinase-like 1 protein (Dcamkl1) or KIAA0369, Dclk1 was first described as a marker for radial glia cells in the context of microtubule polymerization and neuronal migration, possibly contributing to early neurogenesis. Additionally, Dclk1 was proposed as a marker of quiescent gastrointestinal and pancreatic stem cells, but in recent years has been recognized as a marker for tuft cells in the gastrointestinal tract...
July 26, 2016: Small GTPases
Kishan Bellamkonda, Naveen Kumar Chandrashekar, Janina Osman, Benson Chellakkan Selvanesan, Sayeh Savari, Anita Sjölander
BACKGROUND: Colorectal cancer is one of the most common types of cancers worldwide. Recent studies have identified cancer-initiating cells (CICs) as a subgroup of replication-competent cells in the development of colorectal cancer. Although it is understood that an inflammation-rich tumor microenvironment presumably supports CIC functions, the contributory factors are not very well defined. The present study advances our understanding of the role of the eicosanoids leukotriene D4 (LTD4) and prostaglandin E2 (PGE2) in the tumorigenic ability of CICs and investigates the consequential changes occurring in the tumor environment that might support tumor growth...
2016: BMC Cancer
P Chandrakesan, J Panneerselvam, D Qu, N Weygant, R May, M S Bronze, C W Houchen
The identification of functionally relevant subpopulations of therapy-resistant cancer cells is a challenge. These cells, intrinsically resistant to conventional therapy, can cause recurrence. Evidence has suggested that therapy-resistant cancer cells are likely epithelial-mesenchymal transition (EMT) cells and/or stem-like cells called cancer stem cells (CSCs). EMT, a normal embryological process that converts epithelial cells into mesenchymal cells, is frequently activated during cancer development and progression...
April 2016: Journal of Carcinogenesis & Mutagenesis
C Benedikt Westphalen, Yoshihiro Takemoto, Takayuki Tanaka, Marina Macchini, Zhengyu Jiang, Bernhard W Renz, Xiaowei Chen, Steffen Ormanns, Karan Nagar, Yagnesh Tailor, Randal May, Youngjin Cho, Samuel Asfaha, Daniel L Worthley, Yoku Hayakawa, Aleksandra M Urbanska, Michael Quante, Maximilian Reichert, Joshua Broyde, Prem S Subramaniam, Helen Remotti, Gloria H Su, Anil K Rustgi, Richard A Friedman, Barry Honig, Andrea Califano, Courtney W Houchen, Kenneth P Olive, Timothy C Wang
The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation...
April 7, 2016: Cell Stem Cell
Wenyao Wang, Hongfei Zhang, Lichao Wang, Shaojun Zhang, Miao Tang
microRNAs (miRNAs) play key regulatory roles in various biological processes. In this study, we aimed to determine the expression and biological roles of miR-613 in hepatocellular carcinoma (HCC). Compared with non-cancerous liver tissues, miR-613 was significantly downregulated in HCC tissues. Ectopic expression of miR-613 significantly suppressed the proliferation and invasion of Hep3B and SMMC-7721 HCC cells. Bioinformatic and luciferase reporter analysis identified doublecortin-like kinase 1 (DCLK1) as a direct target of miR-613...
May 13, 2016: Biochemical and Biophysical Research Communications
Martine P Roudier, Brian R Winters, Ilsa Coleman, Hung-Ming Lam, Xiaotun Zhang, Roger Coleman, Lisly Chéry, Lawrence D True, Celestia S Higano, Bruce Montgomery, Paul H Lange, Linda A Snyder, Shiv Srivastava, Eva Corey, Robert L Vessella, Peter S Nelson, Aykut Üren, Colm Morrissey
BACKGROUND: The TMPRSS2-ERG gene fusion is detected in approximately half of primary prostate cancers (PCa) yet the prognostic significance remains unclear. We hypothesized that ERG promotes the expression of common genes in primary PCa and metastatic castration-resistant PCa (CRPC), with the objective of identifying ERG-associated pathways, which may promote the transition from primary PCa to CRPC. METHODS: We constructed tissue microarrays (TMA) from 127 radical prostatectomy specimens, 20 LuCaP patient-derived xenografts (PDX), and 152 CRPC metastases obtained immediately at time of death...
June 2016: Prostate
Xiaoqin Fu, Kristy J Brown, Sree Rayavarapu, Kanneboyina Nagaraju, Judy S Liu
Mutations in microtubule subunits and microtubule-associated proteins are the causes of many neurological disorders. These human conditions are usually associated with axonal tract defects or degeneration. The molecular mechanisms of these axonal dysfunction are still largely unknown. Conventional methods may not yield a complete analysis of downstream molecules related to axonal dysfunctions. Therefore, we devised a simple unbiased method to screen molecular motors and axonal molecules, which might be involved in axonal defects...
2016: Methods in Cell Biology
Ishfaq Ahmed, Badal C Roy, Dharmalingam Subramaniam, Showkat Ahmad Ganie, Deep Kwatra, Dan Dixon, Shrikant Anant, Mohammad Afzal Zargar, Shahid Umar
Phytochemicals modulate key cellular signaling pathways and have proven anticancer effects. Alcea rosea(AR; Hollyhock) is an ornamental plant with known anti-inflammatory properties. This study explored its role as an anticancer agent. The AR seed extract (AR extract) inhibited proliferation and colony formation in a dose- and time-dependent manner and promoted apoptosis as was evidenced by cleavage of PARP and increased expression of Bax accompanying reduced levels of BCL-xl protein in HCT116 and SW480 cells, respectively...
April 2016: Carcinogenesis
Hiromitsu Ito, Shinji Tanaka, Yoshimitsu Akiyama, Shu Shimada, Rama Adikrisna, Satoshi Matsumura, Arihiro Aihara, Yusuke Mitsunori, Daisuke Ban, Takanori Ochiai, Atsushi Kudo, Shigeki Arii, Shoji Yamaoka, Minoru Tanabe
Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model...
2016: PloS One
Joanna Lipka, Lukas C Kapitein, Jacek Jaworski, Casper C Hoogenraad
In neurons, the polarized distribution of vesicles and other cellular materials is established through molecular motors that steer selective transport between axons and dendrites. It is currently unclear whether interactions between kinesin motors and microtubule-binding proteins can steer polarized transport. By screening all 45 kinesin family members, we systematically addressed which kinesin motors can translocate cargo in living cells and drive polarized transport in hippocampal neurons. While the majority of kinesin motors transport cargo selectively into axons, we identified five members of the kinesin-3 (KIF1) and kinesin-4 (KIF21) subfamily that can also target dendrites...
February 1, 2016: EMBO Journal
Masazumi Sakaguchi, Shigeo Hisamori, Nobu Oshima, Fumiaki Sato, Yohei Shimono, Yoshiharu Sakai
UNLABELLED: miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused on miRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colon CSCs (EpCAM⁺/CD44⁺/CD66a⁻) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1(DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs...
April 2016: Molecular Cancer Research: MCR
Agnieszka Pastuła, Moritz Middelhoff, Anna Brandtner, Moritz Tobiasch, Bettina Höhl, Andreas H Nuber, Ihsan Ekin Demir, Steffi Neupert, Patrick Kollmann, Gemma Mazzuoli-Weber, Michael Quante
The gastrointestinal epithelium is characterized by a high turnover of cells and intestinal stem cells predominantly reside at the bottom of crypts and their progeny serve to maintain normal intestinal homeostasis. Accumulating evidence demonstrates the pivotal role of a niche surrounding intestinal stem cells in crypts, which consists of cellular and soluble components and creates an environment constantly influencing the fate of stem cells. Here we describe different 3D culture systems to culture gastrointestinal epithelium that should enable us to study the stem cell niche in vitro in the future: organoid culture and multilayered systems such as organotypic cell culture and culture of intestinal tissue fragments ex vivo...
2016: Stem Cells International
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