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Tumor cells reside in a highly complex and heterogeneous tumor microenvironment (TME), which is composed of a myriad of genetically stable non-cancer cells, including fibroblasts, immune cells, endothelial cells, and epithelial cells, and a tumor-specific extracellular matrix (ECM). Cancer-associated fibroblasts (CAFs), as an abundant and active stromal cell population in the TME, function as the signaling center and remodeling machine to aid the creation of a desmoplastic tumor niche. Although there is no denial that the TME and CAFs may have anti-tumor effects as well, a great deal of findings reported in recent years have convincingly revealed the tumor-promoting effects of CAFs and CAF-derived ECM proteins, enzymes, chemical factors and other downstream effectors. While there is growing enthusiasm for the development of CAF-targeting therapies, a better understanding of the complexities of CAF-ECM and CAF-cancer cell interactions is necessary before novel therapeutic strategies targeting the malignant tumor \"soil\" can be successfully implemented in the clinic.

The purpose of this study is to provide an increased understanding of the molecular mechanisms responsible for mammalian polyamine transport, a process that has been a long-standing ‘black box’ for the polyamine field. Here, we describe how ATP13A3, a P-type ATPase, functions as a polyamine transporter in response to different polyamine stimuli and polyamine-targeted therapies in highly proliferating pancreatic cancer cells. We assessed the expression, cellular localization and the response of the human ATP13A3 protein to polyamine treatments in different pancreatic cancer cell lines using Western blot and immunofluorescence microscopy. Using CRISPR mutagenesis and radiolabeled polyamine uptake assays, we investigated the role of ATP13A3 protein in polyamine transport. Highly metastatic cancer cells with high polyamine import express higher levels of the full-length ATP13A3 compared to cells with slow proliferation and low import activity. Highlighting its role in polyamine trafficking, the localization of ATP13A3 is altered in the presence of polyamine stimuli and polyamine-targeted therapies in these cells. Using CRISPR mutagenesis, we demonstrate that the first membrane-associated domain of this protein is critical and indispensable for its function as a spermidine and spermine transporter in cells. Further analysis of existing databases revealed that pancreatic cancer patients with high expression of ATP13A3 have decreased overall survival consistent with the role of intracellular polyamines in supporting tumor growth. Our studies shed light on the mysterious polyamine transport process in human cells and clearly establishes ATP13A3 as an intrinsic component of the spermidine and spermine transport system in humans.

MicroRNA-mediated post-transcriptional regulation plays key roles in stem cell self-renewal and tumorigenesis. However, the in vivo functions of specific microRNAs in controlling mammary stem cell (MaSC) activity and breast cancer formation remain poorly understood. Here we show that miR-31 is highly expressed in MaSC-enriched mammary basal cell population and in mammary tumors, and is regulated by NF-κB signaling. We demonstrate that miR-31 promotes mammary epithelial proliferation and MaSC expansion at the expense of differentiation in vivo. Loss of miR-31 compromises mammary tumor growth, reduces the number of cancer stem cells, as well as decreases tumor-initiating ability and metastasis to the lung, supporting its pro-oncogenic function. MiR-31 modulates multiple signaling pathways, including Prlr/Stat5, TGFβ and Wnt/β-catenin. Particularly, it activates Wnt/β-catenin signaling by directly targeting Wnt antagonists, including Dkk1 . Importantly, Dkk1 overexpression partially rescues miR31 -induced mammary defects. Together, these findings identify miR-31 as the key regulator of MaSC activity and breast tumorigenesis. MicroRNAs play an important role in stem cell fate and tumorigenesis. In this work, the authors show that miR-31 controls mammary stem cell self-renewal and tumorigenesis by simultaneously activating Wnt/β-catenin and repressing TGFβ signaling pathways.

Prostate cancer (PCa) progression relies on androgen receptor (AR) function, making AR a top candidate for PCa therapy. However, development of drug resistance is common, which eventually leads to development of castration‐resistant PCa. This warrants a better understanding of the pathophysiology of PCa that facilitates the aberrant activation of key signaling pathways including AR. MicroRNAs (miRNAs) function as regulators of cancer progression as they modulate various cellular processes. Here, we demonstrate a multidimensional function of miR‐30e through the regulation of genes involved in various signaling pathways. We noted loss of miR‐30e expression in prostate tumors, which, when restored, led to cell cycle arrest, induction of apoptosis, improved drug sensitivity of PCa cells and reduced tumor progression in xenograft models. We show that experimental upregulation of miR‐30e reduces expression of mRNAs including AR, FBXO45, SRSF7 and MYBL2 and a novel long noncoding RNA (lncRNA) HELLPAR, which are involved in cell cycle, apoptosis and ubiquitination, and the effects could be rescued by inhibition of miR‐30e expression. RNA immunoprecipitation analysis confirmed direct interactions between miR‐30e and its RNA targets. We noted a newly identified reciprocal relationship between miR‐30e and HELLPAR, as inhibition of HELLPAR improved stabilization of miR‐30e. Transcriptome profiling and quantitative real‐time PCR (qRT‐PCR) validation of miR‐30e‐expressing PCa cells showed differential expression of genes involved in cell cycle progression, apoptosis and ubiquitination, which supports our in vitro study. This study demonstrates an integrated function of miR‐30e on dysregulation of miRNA/lncRNA/mRNA axes that may have diagnostic and therapeutic significance in aggressive PCa. This study describes a tumor suppressor role of microRNA miR‐30e in prostate cancer (PCa), mediated by modulation of AR signaling, cell cycle, apoptosis and ubiquitination pathways. This is achieved by regulating direct mRNA effectors (AR, FBXO45, SRSF7, and MYBL2), indirect mRNA effectors, and a novel long noncoding RNA (lncRNA) HELLPAR. The function of miR‐30e impacts PCa progression through a microRNA‐mRNA‐lncRNA regulatory network.

A major contributing factor to the failure of cell-based human hair follicle (HF) engineering is our inability to cultivate highly specialized, inductive mesenchymal fibroblasts, which reside in a unique niche at the HF base, called the dermal papilla (DP). We and other groups have discovered a unique DP fibroblast subpopulation that can be identified by the cell surface marker CD133. However, the biological difference between CD133-positive (CD133+) and CD133-negative (CD133-) DP cells remains unknown. Using a newly developed double fluorescent transgenic mouse strain, we isolated CD133 + and CD133- DP cells from mouse anagen HFs. In monolayer culture, both DP populations gradually lost expression of the anagen DP signature gene, versican. When maintained in three-dimensional spheroid culture, versican expression was restored in both CD133 + and CD133- DP cells. Importantly, CD133 + DP spheroids appeared more compact, showed stronger alkaline phosphatase staining (AP), and expressed higher levels of DP signature genes. In in vivo skin reconstitution assays, mice grafted with CD133 + DP spheroids grew more hairs in healed wounds than those grafted with CD133- DP spheroids. The data underscore the importance of CD133 + DP cells as a driver of HF formation, which may present a unique opportunity to improve the use of human DP cells in tissue-engineered skin substitutes (TESS).

MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.

Background FGD4 (Frabin) is an F-actin binding protein with GTP/GDP exchange activity specific for CDC42. It is involved in reorganization of the actin cytoskeleton, which requires both actin binding and CDC42 activating function of FGD4. Expression of FGD4 is altered in patients with heterogeneous hereditary motor and sensory neuropathies as a result of demyelination of peripheral nerves. Methods In this study, we examined the expression of FGD4 in prostate cancer specimens using immunohistochemistry and studied the function of FGD4 in maintaining cell phenotype, behavior and drug sensitivity using overexpression and siRNA-based silencing approaches. We used Mann-Whitney test for comparative analysis of FGD4 expression. Results Our results show that the expression of FGD4 is upregulated in cancerous prostates compared to the luminal cells in benign prostatic hyperplasia, although the basal cells showed high staining intensities. We noted a gradual increase in the staining intensity of FGD4 with increasing aggressiveness of the disease. Inhibition of expression of FGD4 using siRNAs showed reduced proliferation and cell cycle arrest in G2/M phase of androgen dependent LNCaP-104S and androgen refractory PC-3 cells. Inhibition of FGD4 also resulted in reduced cell migration and CDC42 activities in PC-3 cells whereas, ectopic expression of FGD4 induced cell migration, altered expression of mesenchymal and epithelial markers and activation of CDC42/PAK signaling pathway. Reduced expression of FGD4 improved sensitivity of LNCaP-104S cells to the anti-androgen drug Casodex and PC-3 cells to the microtubule stabilizing drug docetaxel. Conclusions Our data demonstrate a tumor promoting and a cell migratory function of FGD4 in prostate cancer cells and that inhibition of FGD4 expression enhances the response for both androgen-dependent and independent prostate cancer cells towards currently used prostate cancer drugs.

MicroRNAs have continued to attract enormous interest in the scientific community ever since their discovery. Their allure stems from their unique role in posttranscriptional gene expression control as well as their potential application as therapeutic targets in various disease pathologies. While much is known concerning their general biological function, such as their interaction with RNA-induced silencing complexes, many important questions still remain unanswered, especially regarding their functions in the skin. In this review, we summarize our current knowledge of the role of microRNAs in the skin in order to shine new light on our understanding of cutaneous biology and emphasize the significance of these small, single-stranded RNA molecules in the largest organ of the human body. Key events in epidermal and hair follicle biology, including differentiation, proliferation, and pigmentation, all involve microRNAs. We explore the role of microRNAs in several cutaneous processes, such as appendage formation, wound-healing, epithelial-mesenchymal transition, carcinogenesis, immune response, and aging. In addition, we discuss current trends in research and offer suggestions for future studies.

Stem cells cycle through active and quiescent states. Large populations of stem cells in an organ may cycle randomly or in a coordinated manner. Although stem cell cycling within single hair follicles has been studied, less is known about regenerative behavior in a hair follicle population. By combining predictive mathematical modeling with in vivo studies in mice and rabbits, we show that a follicle progresses through cycling stages by continuous integration of inputs from intrinsic follicular and extrinsic environmental signals based on universal patterning principles. Signaling from the WNT/bone morphogenetic protein activator/inhibitor pair is coopted to mediate interactions among follicles in the population. This regenerative strategy is robust and versatile because relative activator/inhibitor strengths can be modulated easily, adapting the organism to different physiological and evolutionary needs.

Dicer initiates RNA interference by generating small RNAs involved in various silencing pathways. Dicer participates in centromeric silencing, but its role in the epigenetic regulation of other chromatin domains has not been explored. Here we show that Dicer1 deficiency in Mus musculus leads to decreased DNA methylation, concomitant with increased telomere recombination and telomere elongation. These DNA-methylation defects correlate with decreased expression of Dnmt1, Dnmt3a and Dnmt3b DNA methyltransferases (Dnmts), and methylation levels can be recovered by their overexpression. We identify the retinoblastoma-like 2 protein (Rbl2) as responsible for decreased Dnmt expression in Dicer1 -null cells, suggesting the existence of Dicer-dependent small RNAs that target Rbl2. We identify the miR-290 cluster as being downregulated in Dicer1 -deficient cells and show that it silences Rbl2 , thereby controlling Dnmt expression. These results identify a pathway by which miR-290 directly regulates Rbl2-dependent Dnmt expression, indirectly affecting telomere-length homeostasis.