Regulation of cancer metastasis by cell-free miRNAs

Alečković, Maša; Kang, Yibin

doi:10.1016/j.bbcan.2014.10.005

Cited by 71 publications

(69 citation statements)

References 313 publications

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“…In fact, several studies have reported the use of circulating miRNAs as biomarkers to predict tumor progression and the presence of bone metastases. [51][52][53][54] Furthermore, highly expressed circulating miRNAs from cancer patients have been reported to return to a normal level after tumor resection, 55,56 suggesting that the level of circulating miRNAs reflects the disease state of the patient to some extent and could be used as a pharmacodynamic marker. Moreover, cell-free and exosomal miRNAs are of particular interest owing to their pleiotropic roles in modulating many physiological and pathological processes, including cancer metastasis.…”

Section: Bone-derived Mirnas In Bone Metastasismentioning

confidence: 99%

“…carriers, such as HDL or LDL, or packaged into microvesicles such as exosomes (30-100 nm) or larger microparticles (100-1000 nm). 51 The presence of their protein-or lipid-based carriers or their encapsulation into vesicles confer circulating miRNAs remarkable stability under a variety of harsh environmental conditions. 50,51 As such, secreted miRNAs represent important potential biomarkers for diagnosis and prognosis that can be detected by noninvasive means in a reliable and reproducible manner.…”

Section: Bone-derived Mirnas In Bone Metastasismentioning

confidence: 99%

“…51 The presence of their protein-or lipid-based carriers or their encapsulation into vesicles confer circulating miRNAs remarkable stability under a variety of harsh environmental conditions. 50,51 As such, secreted miRNAs represent important potential biomarkers for diagnosis and prognosis that can be detected by noninvasive means in a reliable and reproducible manner. In fact, several studies have reported the use of circulating miRNAs as biomarkers to predict tumor progression and the presence of bone metastases.…”

Section: Bone-derived Mirnas In Bone Metastasismentioning

confidence: 99%

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Bone marrow stroma-derived miRNAs as regulators, biomarkers and therapeutic targets of bone metastasis

Alečković

Kang

2015

BoneKEy Reports

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MicroRNAs (miRNAs) are short, endogenous RNA molecules that have essential roles in regulating gene expression. They control numerous physiological and cellular processes, including normal bone organogenesis and homeostasis, by enhancing or inhibiting bone marrow cell growth, differentiation, functional activity and crosstalk of the multiple cell types within the bone. Hence, elucidating miRNA targets in bone marrow stromal cells has revealed novel regulations during bone development and maintenance. Moreover, recent studies have detailed the capacity for bone stromal miRNAs to influence bone metastasis from a number of primary carcinomas by interfering with bone homeostasis or by directly influencing metastatic tumor cells. Owing to the current lack of good diagnostic biomarkers of bone metastases, such changes in bone stromal miRNA expression in the presence of metastatic lesions may become useful biomarkers, and may even serve as therapeutic targets. In particular, cell-free and exosomal miRNAs shed from bone stromal cells into circulation may be developed into novel biomarkers that can be routinely measured in easily accessible samples. Taken together, these findings reveal the significant role of bone marrow stroma-derived miRNAs in the regulation of bone homeostasis and bone metastasis. Biogenesis and Function of miRNAsMicroRNAs (miRNAs) are a large family of noncoding B22-nucleotide-long RNA molecules that negatively regulate gene expression. 1 It is estimated that miRNAs regulate about 50% of all protein-coding genes. 2 They repress gene expression through complementary binding to sites in the 3 0 -untranslated region (UTR) of target mRNAs. 3,4 miRNA-mediated inhibition occurs either by mRNA degradation or translational silencing. Cleavage of target mRNAs occurs when the miRNA and the target mRNA exhibit perfect complementarity. 3 Conversely, miRNA-mRNA pairings with imperfect complementarity result in translational inhibition in the absence of target cleavage. 3,5 Thus, even in the absence of perfect binding, the association between an miRNA and a target 3 0 -UTR still results in the suppression of a target protein. Owing to the relatively short length of the seed sequence that binds to the 3 0 -UTR (5-7 nucleotides), each miRNA can potentially recognize hundreds of mRNAs and is thus a powerful molecular manager that can control several gene regulatory networks simultaneously.miRNA genes are typically transcribed into stem-loop structures from intra-or intergenic regions by RNA polymerase II and undergo sequential cleavage steps to produce mature miRNAs. 2 In the nucleus, newly transcribed pri-miRNAs (primary miRNAs) are cleaved by a complex formed by the RNase III enzyme Drosha and the double-stranded RNA-binding protein Pasha (or DGCR8) to produce precursor miRNAs. These precursor miRNAs are about 70-100 nucleotides long. 6 They are exported from the nucleus by Exportin 5 and the Ran-GTP cofactor, 7 where they undergo a second cleavage by the endoribonuclease Dicer to produce a double-stranded, B18-2...

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Section: Bone-derived Mirnas In Bone Metastasismentioning

confidence: 99%

Section: Bone-derived Mirnas In Bone Metastasismentioning

confidence: 99%

Section: Bone-derived Mirnas In Bone Metastasismentioning

confidence: 99%

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Bone marrow stroma-derived miRNAs as regulators, biomarkers and therapeutic targets of bone metastasis

Alečković

Kang

2015

BoneKEy Reports

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“…Exosomes are small membrane vesicles that are known to contain miRNAs, proteins, mRNAs, noncoding RNAs (ncRNA), lipids, proteins, and cellular constituents (Thery et al 2009). Emerging studies have shown that exosomes are essential for cell-to-cell communication throughout the body and play an important role in dissemination of disease (Alečković and Kang 2015), host-pathogen interactions (Schorey et al 2014), and regenerative medicine (De Jong et al 2014). Yang and colleagues (2014) have recently described the detection of tumor cell-specific mRNA in salivary exosome-like microvesicles of a novel human lung cancer xeongraft mouse model.…”

Section: The Neonatal Salivary Transcriptomementioning

confidence: 99%

The Neonatal Salivary Transcriptome

Maron

2015

Cold Spring Harb Perspect Med

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“…Binding of miRNAs to their target mRNAs along with the RISC complex mediates inhibition of translation initiation (5). miRNA involvement in cancer development and metastasis is the subject of intense research (6)(7)(8)(9)(10).…”

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A Repertoire of MicroRNAs Regulates Cancer Cell Starvation by Targeting Phospholipase D in a Feedback Loop That Operates Maximally in Cancer Cells

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Elkhadragy

Gómez‐Cambronero

2016

Molecular and Cellular Biology

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bWe report a negative feedback loop between the signaling protein phospholipase D (PLD), phosphatidic acid (PA), and a specific set of microRNAs (miRNAs) during nutrient starvation of breast cancer cells. We show that PLD expression is increased in four breast cancer cell lines and that hypoxia, cell overcrowding, and nutrient starvation for 3 to 6 h increase expression even further. However, after prolonged (>12-h) starvation, PLD levels return to basal or lower levels. The mechanism for this is as follows. First, during initial starvation, an elevated PA (the product of PLD enzymatic activity) activates mTOR and S6K, known to inhibit apoptosis, and enhances cell migration especially in post-epithelial-to-mesenchymal transition (post-EMT) cancer cells. Second, continued PA production in later starvation induces expression of PLD-targeting microRNA 203 (miR-203), miR-887, miR-3619-5p, and miR-182, which reduce PLD translation. We provide direct evidence for a feedback loop, whereby PLD induction upon starvation leads to PA, which induces expression of miRNAs, which in turn inhibits PLD2 translation. The physiological relevance for breast cancer cells is that as PA can activate cell invasion, then, due to the negative feedback, it can deprive mTOR and S6K of their natural activator. It can further prevent inhibition of apoptosis and allow cells to survive nutrient deprivation, which normal cells cannot do.M icroRNAs (miRNAs) are short molecules of noncoding RNA, ϳ22 nucleotides in length, and have crucial roles in the regulation of many cellular processes, including development, proliferation, differentiation, apoptosis, and stress response (1, 2). Mature miRNA molecules associate with the Argonaute (Ago1 and Ago2) proteins and the RNA-induced silencing complex (RISC) (3, 4). Active miRNAs regulate expression of their target genes via association of an ϳ7-nucleotide-long stretch seed region with a complementary sequence in the target mRNA located in the 3= untranslated region (UTR). Binding of miRNAs to their target mRNAs along with the RISC complex mediates inhibition of translation initiation (5). miRNA involvement in cancer development and metastasis is the subject of intense research (6-10).Phospholipase D (PLD) has been implicated in cellular signals that suppress apoptosis and contribute to cancer cell survival (11-13). Through cell signaling, elevated PLD activity leads to activation of mammalian target of rapamycin (mTOR), a survival signal often hyperactivated in cancer (14, 15). Elevated PLD activity also subdued the tumor suppressors p53 and protein phosphatase 2A (12). Zheng et al. published a model for enhanced survival and migration signals in the developing tumor (16). In a developing tumor mass, cells inside the mass were subjected to hypoxia and nutrient and growth factor deprivation. It is proposed that cells that respond to stress by elevating PLD protein levels will survive presumably by gaining the ability to migrate. However, very little is known about PLD regulation at gene and protein leve...

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Regulation of cancer metastasis by cell-free miRNAs

Cited by 71 publications

References 313 publications

Bone marrow stroma-derived miRNAs as regulators, biomarkers and therapeutic targets of bone metastasis

Bone marrow stroma-derived miRNAs as regulators, biomarkers and therapeutic targets of bone metastasis

The Neonatal Salivary Transcriptome

A Repertoire of MicroRNAs Regulates Cancer Cell Starvation by Targeting Phospholipase D in a Feedback Loop That Operates Maximally in Cancer Cells

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