Gap Junction–Mediated Import of MicroRNA from Bone Marrow Stromal Cells Can Elicit Cell Cycle Quiescence in Breast Cancer Cells

Lim, Philip K.; Bliss, Sarah A.; Patel, Shyam A.; Taborga, Marcelo; Dave, Meneka A.; Gregory, Larissa A.; Greco, Steven J.; Bryan, Margarette; Patel, Prem; Rameshwar, Pranela

doi:10.1158/0008-5472.can-10-2372

Cited by 383 publications

(317 citation statements)

References 44 publications

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“…It is well established that gap junctions contribute to cell homeostasis by allowing the intercellular exchange of essential growth regulators, including ions, nucleotides, sugars, small peptides, RNAs (Kardamia et al, 2007;Vinken et al, 2011), and microRNAs (Lim et al, 2011). Cx26 expression is virtually absent in the normal adult airway epithelium (Chanson, Koval, 2013).…”

Section: Discussionmentioning

confidence: 99%

Cx26 regulates proliferation of repairing basal airway epithelial cells

Crespin

Bacchetta

Saab

et al. 2014

The International Journal of Biochemistry & Cell Biology

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The recovery of an intact epithelium following injury is critical for restoration of lung homeostasis, a process that may be altered in cystic fibrosis (CF). In response to injury, progenitor cells in the undamaged areas migrate, proliferate and re-differentiate to regenerate an intact airway epithelium. The mechanisms regulating this regenerative response are, however, not well understood. In a model of circular wound injury of well-differentiated human airway epithelial cell (HAEC) cultures, we identified the gap junction protein Cx26 as an important regulator of cell proliferation. We report that induction of Cx26 in repairing HAECs is associated with cell proliferation. We also show that Cx26 is expressed in a population of CK14-positive basal-like cells. Cx26 silencing in immortalized cell lines using siRNA and in primary HAECs using lentiviral-transduced shRNA enhanced Ki67-labeling index and Ki67 mRNA, indicating that Cx26 acts a negative regulator of HAEC proliferation.Cx26 silencing also markedly decreased the transcription of KLF4 in immortalized HAECs.We further show that CF HAECs exhibited deregulated expression of KLF4, Ki67 and Cx26 as well enhanced rate of wound closure in the early response to injury. These results point to an altered repair process of CF HAECs characterized by rapid but desynchronized initiation of HAEC activation and proliferation.

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Section: Discussionmentioning

confidence: 99%

Cx26 regulates proliferation of repairing basal airway epithelial cells

Crespin

Bacchetta

Saab

et al. 2014

The International Journal of Biochemistry & Cell Biology

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“…74 A separate study found that multiple miRNAs were transferred from bone marrow stromal cells to nearby breast cancer cells upon seeding to the bone. 75 MiR-127, miR-197, miR-222 and miR-223, all direct inhibitors of CXCL12, were shown to directly transfer from stromal cells into cancer cells via gap junctions or through secreted exosomes. The transfer of these miRNAs decreased cancer cell proliferation and could represent a mechanism for tumor quiescence within the bone microenvironment.…”

Section: Mirna Regulation Of Tumor-stromal Interactions During Bone Mmentioning

confidence: 99%

MicroRNAs as regulators of bone homeostasis and bone metastasis

Ell

Kang

2014

Bonekey Reports

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MicroRNAs (miRNAs) are short, endogenous RNAs that have essential roles in regulating gene expression through the disruption of target genes. The miRNA-induced suppression can occur through Argonaute-mediated cleavage of target mRNAs or by translational inhibition. System-wide studies have underscored the integral role that miRNAs play in regulating the expression of essential genes within bone marrow stromal cells. The miRNA expression has been shown to enhance or inhibit cell differentiation and activity, and elucidating miRNA targets within bone marrow cells has revealed novel regulations during normal bone development. Importantly, multiple studies have shown that miRNA misexpression mediates the progression of bone-related pathologies, including osteopetrosis and osteoporosis, as well as the development and progression of osteosarcoma. Furthermore, recent studies have detailed the capacity for miRNAs to influence bone metastasis from a number of primary carcinomas. Taken together, these findings reveal the significant clinical potential for miRNAs to regulate bone homeostasis, as well as to mediate bone-related pathologies.BoneKEy Reports 3, Article number: 549 (2014) | doi:10.1038/bonekey.2014.44 MiRNA Biogenesis and FunctionThe past decade has seen a torrent of novel research into the post-translational regulation of genes via microRNA-mediated suppression. The microRNAs (miRNAs) are a class of B22-nucleotide-long RNAs that repress gene expression through complementary binding to sites in the 3 0 -untranslated region (UTR) of target mRNAs. 1 Mature miRNAs are generated by the sequential cleavage of longer precursor transcripts, or pri-miRNAs, that are typically transcribed from intragenic or intergenic regions by RNA polymerase II. 2 The initial cleavage step, mediated by Drosha and the DGCR8 complex, occurs in the nucleus and produces a shortened (70-100 nucleotides) pre-miRNA hairpin. Pre-miRNAs are exported from the nucleus by Exportin 5, followed by a second cleavage by the ribonuclease Dicer that produces a double-stranded, B18-25-nucleotide-long mature miRNA. One miRNA strand will then combine with Argonaute (AGO2) proteins to produce an RNAinduced silencing complex, allowing for directed pairing with target mRNAs. 1

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“…Lately miRNA has also become implicated in signaling between stromal and epithelial cells and some recent reports [28,29] have provided evidence suggesting that traffic of miRNA subtypes between disseminated cancer cells and bone marrow stromal cells can influence whether the cancer cells establish metastatic colonies or remain in dormant state. If these findings are corroborated, it will show that non-proteinaceous molecules also convey signals between interacting cell populations in the tumor microenvironment, which can determine whether tumor cells can fulfill an already activated, intrinsic potential towards malignant behavior.…”

Section: Ii) Cancer Formation: Microscopic and Cellular Aspectsmentioning

confidence: 99%

Clinical and Biological Implications of the Tumor Microenvironment

Tarin¹

2012

Cancer Microenvironment

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In normal tissues and organs, the activities of the constituent cells are strictly restricted to the tasks assigned to them during development. In addition they (with the exception of leukocytes) remain inflexibly confined to their territorial domains by regulatory interactions with their neighbors. This creates specialized local micro-environments in which structure and function are orderly, stable and tightly controlled by feed-back loops, within interacting regulatory networks. This system has considerable ability to adapt to changing conditions. In contrast, the microenvironment in regions where tumors are forming and expanding is characterized by progressive loss of specialized or differentiated cellular functions, disorderly molecular signals, degeneration of microscopical organ structure. This, coupled with the traffic of cells into and out of the tumor, often culminating in local invasion and metastasis to other organs. The nature of these disturbed molecular and cellular interactions is, by definition, highly unstable and increasingly unpredictable as time passes. It also varies between different tumors, sometimes even leading to regression. However, systematic analysis of this dysfunction in the tumor microcosm, using multiple modern research techniques, has revealed that all actively growing primary and secondary neoplasms share an absolute dependency upon support from adjacent non-neoplastic cells of the host. This support, in turn, continuously depends upon dynamic interplay between tumor and host cell populations, via signaling molecules and surface receptors in the tumor microenvironment. Such interplay determines the fate of the growing neoplasm. Such information, described and evaluated in this article, provides important new insights into the etiology of carcinogenesis and how tumor growth, invasion and metastasis might be therapeutically arrested. The facts and concepts assembled below, regarding the cancer microenvironment, demonstrate how modern molecular findings reveal the impact of the wide range of cancer diseases upon the internal cellular, tissue and organ environments of the whole individual and how this applies to designing new work to improve human cancer diagnosis and treatment. The article discusses several specific types of experimentally-induced and clinically common cancers to derive principles useful for interpreting events in the tumor microenvironment, which apply to cancers in general and especially to human malignant disease.

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Gap Junction–Mediated Import of MicroRNA from Bone Marrow Stromal Cells Can Elicit Cell Cycle Quiescence in Breast Cancer Cells

Cited by 383 publications

References 44 publications

Cx26 regulates proliferation of repairing basal airway epithelial cells

Cx26 regulates proliferation of repairing basal airway epithelial cells

MicroRNAs as regulators of bone homeostasis and bone metastasis

Clinical and Biological Implications of the Tumor Microenvironment

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