MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Matrigel, a mouse tumor extracellular matrix protein mixture, is an indispensable component of most organoid tissue culture. However, it has limited the utility of organoids for drug development and regenerative medicine due to its tumor-derived origin, batch-to-batch variation, high cost, and safety issues. Here, we demonstrate that gastrointestinal tissue-derived extracellular matrix hydrogels are suitable substitutes for Matrigel in gastrointestinal organoid culture. We found that the development and function of gastric or intestinal organoids grown in tissue extracellular matrix hydrogels are comparable or often superior to those in Matrigel. In addition, gastrointestinal extracellular matrix hydrogels enabled long-term subculture and transplantation of organoids by providing gastrointestinal tissue-mimetic microenvironments. Tissue-specific and age-related extracellular matrix profiles that affect organoid development were also elucidated through proteomic analysis. Together, our results suggest that extracellular matrix hydrogels derived from decellularized gastrointestinal tissues are effective alternatives to the current gold standard, Matrigel, and produce organoids suitable for gastrointestinal disease modeling, drug development, and tissue regeneration. 

/pdf/tissue-extracellular-matrix-hydrogels-as-alternatives-to-2khubfuv.pdf

Tissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids

Mitochondria undergo fission and fusion continually for survival through the course of cellular adaption processes in response to changes in the surrounding environment. Dysregulated mitochondrial dynamics has been reported in various diseases including cancer. Under hypoxic conditions (<1% O2), the relationship between mitochondrial dynamics and sensitivity to cisplatin (CDDP) was examined in ovarian cancer cells. We found that hypoxia promoted mitochondrial fission and CDDP resistance in ovarian cancer cells. Hypoxia-induced reactive oxygen species (ROS) caused an increase in mitochondrial fission, a response abolished by free radical scavenging with N-acetylcysteine (NAC) and Trolox. Also, treatment of hydrogen peroxide (H2O2) decreased inhibitory p-Drp1 (Ser637) content and increased mitochondrial fission. Suppression of mitochondrial fission enhanced the CDDP sensitivity of hypoxic ovarian cancer cells. Lastly, in tumor spheroids from malignant ascites or tissues of patients with advanced-stage ovarian cancer, pretreatment with Mdivi-1 increased the CDDP sensitivity. Taken together, our results implicate that hypoxia-induced ROS trigger mitochondrial fission and CDDP resistance through downregulation of p-Drp1 (Ser637) and Mfn1 in ovarian cancer cells. Inhibition of Drp1 by Mdivi-1 treatment or si-Drp1 transfection increased CDDP sensitivity of ovarian cancer cells under hypoxia. Therefore, mitochondrial dynamics of cancer cells adapting to the hypoxic tumor microenvironment could be a potential target for anticancer therapy.

Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells.

Extracellular matrix-based cancer targeting.

Cell-surface heparan sulfate proteoglycans as multifunctional integrators of signaling in cancer.

In colon cancer, downregulation of the transmembrane heparan sulfate proteoglycan syndecan-1 (Sdc-1) is associated with increased invasiveness, metastasis, and dedifferentiation. As Sdc-1 modulates signaling pathways relevant to stem cell function, we tested the hypothesis that it may regulate a tumor-initiating cell phenotype. Sdc-1 small-interfering RNA knockdown in the human colon cancer cell lines Caco2 and HT-29 resulted in an increased side population (SP), enhanced aldehyde dehydrogenase 1 activity, and higher expression of CD133, LGR5, EPCAM, NANOG, SRY (sex-determining region Y)-box 2, KLF2, and TCF4/TCF7L2. Sdc-1 knockdown enhanced sphere formation, cell viability, Matrigel invasiveness, and epithelial-to-mesenchymal transition-related gene expression. Sdc-1-depleted HT-29 xenograft growth was increased compared to controls. Decreased Sdc-1 expression was associated with an increased activation of β1-integrins, focal adhesion kinase (FAK), and wingless-type (Wnt) signaling. Pharmacological FAK and Wnt inhibition blocked the enhanced stem cell phenotype and invasive growth. Sequential flow cytometric SP enrichment substantially enhanced the stem cell phenotype of Sdc-1-depleted cells, which showed increased resistance to doxorubicin chemotherapy and irradiation. In conclusion, Sdc-1 depletion cooperatively enhances activation of integrins and FAK, which then generates signals for increased invasiveness and cancer stem cell properties. Our findings may provide a novel concept to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence. DATABASES: The GEO accession number of the Affymetrix transcriptomic screening is GSE58751.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.15356

The heparan sulfate proteoglycan syndecan-1 regulates colon cancer stem cell function via a focal adhesion kinase—Wnt signaling axis

Recent studies suggest that human tumors are generated from cancer cells with stem cell (SC) properties. Spontaneously occurring cancers in dogs contain a diversity of cells that like for human tumors suggest that certain canine tumors are also generated from cancer stem cells (CSCs). CSCs, like normal SCs, have the capacity for self-renewal as mammospheres in suspension cultures. To understand how cells with SC properties contribute to canine mammary gland tumor development and progression, comparative analysis between normal SCs and CSCs, obtained from the same individual, is essential. We have utilized the property of sphere formation to develop culture conditions for propagating stem/progenitor cells from canine normal and tumor tissue. We show that cells from dissociated mammospheres retain sphere reformation capacity for several serial passages and have the capacity to generate organoid structures ex situ. Utilizing various culture conditions for passaging SCs and CSCs, fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) were found to positively or negatively regulate mammosphere regeneration, organoid formation, and multi-lineage differentiation potential. The response of FGF2 and EGF on SCs and CSCs was different, with increased FGF2 and EGF self-renewal promoted in SCs and repressed in CSCs. Our protocol for propagating SCs from normal and tumor canine breast tissue will provide new opportunities in comparative mammary gland stem cell analysis between species and anticancer treatment and therapies for dogs. J. Cell. Biochem. 118: 570-584, 2017. © 2016 Wiley Periodicals, Inc.

FGF2 and EGF Are Required for Self-Renewal and Organoid Formation of Canine Normal and Tumor Breast Stem Cells.

MicroRNAs (miRNAs) are a class of small RNAs (18–22 nt) that post transcriptionally regulate gene expression by binding to complementary sequences on target mRNAs, resulting in translational repression or target degradation and gene silencing. As aberrant expression of miRNAs is implicated in important diseases including cancer miRNA-based therapies are under intensive investigation. We optimized strategies to stably or conditionally generate miRNA inhibitors for a continuous block of miRNA activity that allows for probing miRNA function in long-term cell culture experiments, cancer xenografts, 3D tissue models and for in vivo studies with transgenic organisms.

/pdf/a-versatile-tool-for-stable-inhibition-of-microrna-activity-3lkguw5xbb.pdf

A Versatile Tool for Stable Inhibition of microRNA Activity

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The heparan sulfate proteoglycan syndecan-1 regulates colon cancer stem cell function via a focal adhesion kinase—Wnt signaling axis

FGF2 and EGF Are Required for Self-Renewal and Organoid Formation of Canine Normal and Tumor Breast Stem Cells.

A Versatile Tool for Stable Inhibition of microRNA Activity