International Journal of Molecular Sciences

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12 pages, 2588 KiB

Open AccessArticle

Deregulation of the miR-19b/PPP2R5E Signaling Axis Shows High Functional Impact in Colorectal Cancer Cells

by Andrea Santos, Ion Cristóbal, Cristina Caramés, Melani Luque, Marta Sanz-Álvarez, Juan Madoz-Gúrpide, Federico Rojo and Jesús García-Foncillas

Int. J. Mol. Sci. 2023, 24(9), 7779; https://doi.org/10.3390/ijms24097779 - 24 Apr 2023

Cited by 2 | Viewed by 1248

Abstract

MicroRNA (miR)-19b is deregulated in colorectal cancer (CRC) and locally advanced rectal cancer (LARC), predicting worse outcome and disease progression in CRC patients, and acting as a promising prognostic marker of patient recurrence and pathological response to 5-fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy in LARC. [...] Read more.

MicroRNA (miR)-19b is deregulated in colorectal cancer (CRC) and locally advanced rectal cancer (LARC), predicting worse outcome and disease progression in CRC patients, and acting as a promising prognostic marker of patient recurrence and pathological response to 5-fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy in LARC. Moreover, there is a strong inverse correlation between miR-19b and PPP2R5E in LARC, and both predict the response to neoadjuvant therapy in LARC patients. However, the functional role of the miR-19b/PPP2R5E axis in CRC cells remains to be experimentally evaluated. Here, we confirm with luciferase assays that miR-19b is a direct negative regulator of PPP2R5E in CRC, which is concordant with the observed decreased PP2A activity levels after miR-19b overexpression. Furthermore, PPP2R5E downregulation plays a key role mediating miR-19b-induced oncogenic effects, increasing cell viability, colonosphere formation ability, and the migration of CRC cells. Lastly, we also confirm the role of miR-19b mediating 5-FU sensitivity of CRC cells through negative PPP2R5E regulation. Altogether, our findings demonstrate the functional relevance of the miR-19b/PPP2R5E signaling pathway in disease progression, and its potential therapeutic value determining the 5-FU response of CRC cells. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases 2.0)

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20 pages, 10219 KiB

Open AccessArticle

5-FU-miR-15a Inhibits Activation of Pancreatic Stellate Cells by Reducing YAP1 and BCL-2 Levels In Vitro

by Vanessa M. Diaz Almanzar, Kunal Shah, Joseph F. LaComb, Aisharja Mojumdar, Hetvi R. Patel, Jacky Cheung, Meiyi Tang, Jingfang Ju and Agnieszka B. Bialkowska

Int. J. Mol. Sci. 2023, 24(4), 3954; https://doi.org/10.3390/ijms24043954 - 16 Feb 2023

Cited by 6 | Viewed by 1999

Abstract

Chronic pancreatitis is characterized by chronic inflammation and fibrosis, processes heightened by activated pancreatic stellate cells (PSCs). Recent publications have demonstrated that miR-15a, which targets YAP1 and BCL-2, is significantly downregulated in patients with chronic pancreatitis compared to healthy controls. We have [...] Read more.

Chronic pancreatitis is characterized by chronic inflammation and fibrosis, processes heightened by activated pancreatic stellate cells (PSCs). Recent publications have demonstrated that miR-15a, which targets YAP1 and BCL-2, is significantly downregulated in patients with chronic pancreatitis compared to healthy controls. We have utilized a miRNA modification strategy to enhance the therapeutic efficacy of miR-15a by replacing uracil with 5-fluorouracil (5-FU). We demonstrated increased levels of YAP1 and BCL-2 (both targets of miR-15a) in pancreatic tissues obtained from Ptf1aCre^ERTM and Ptf1aCre^ERTM;LSL-Kras^G12D mice after chronic pancreatitis induction as compared to controls. In vitro studies showed that delivery of 5-FU-miR-15a significantly decreased viability, proliferation, and migration of PSCs over six days compared to 5-FU, TGFβ1, control miR, and miR-15a. In addition, treatment of PSCs with 5-FU-miR-15a in the context of TGFβ1 treatment exerted a more substantial effect than TGFβ1 alone or when combined with other miRs. Conditioned medium obtained from PSC cells treated with 5-FU-miR-15a significantly inhibits the invasion of pancreatic cancer cells compared to controls. Importantly, we demonstrated that treatment with 5-FU-miR-15a reduced the levels of YAP1 and BCL-2 observed in PSCs. Our results strongly suggest that ectopic delivery of miR mimetics is a promising therapeutic approach for pancreatic fibrosis and that 5-FU-miR-15a shows specific promise. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases 2.0)

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13 pages, 4103 KiB

Open AccessArticle

Dexamethasone Suppresses Palatal Cell Proliferation through miR-130a-3p

by Hiroki Yoshioka, Goo Jun, Akiko Suzuki and Junichi Iwata

Int. J. Mol. Sci. 2021, 22(22), 12453; https://doi.org/10.3390/ijms222212453 - 18 Nov 2021

Cited by 6 | Viewed by 2559

Abstract

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital birth defects. This study aims to identify novel pathogenic microRNAs associated with cleft palate (CP). Through data analyses of miRNA-sequencing for developing palatal shelves of C57BL/6J mice, we [...] Read more.

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital birth defects. This study aims to identify novel pathogenic microRNAs associated with cleft palate (CP). Through data analyses of miRNA-sequencing for developing palatal shelves of C57BL/6J mice, we found that miR-449a-3p, miR-449a-5p, miR-449b, miR-449c-3p, and miR-449c-5p were significantly upregulated, and that miR-19a-3p, miR-130a-3p, miR-301a-3p, and miR-486b-5p were significantly downregulated, at embryonic day E14.5 compared to E13.5. Among them, overexpression of the miR-449 family (miR-449a-3p, miR-449a-5p, miR-449b, miR-449c-3p, and miR-449c-5p) and miR-486b-5p resulted in reduced cell proliferation in primary mouse embryonic palatal mesenchymal (MEPM) cells and mouse cranial neural crest cell line O9-1. On the other hand, inhibitors of miR-130a-3p and miR-301a-3p significantly reduced cell proliferation in MEPM and O9-1 cells. Notably, we found that treatment with dexamethasone, a glucocorticoid known to induce CP in mice, suppressed miR-130a-3p expression in both MEPM and O9-1 cells. Moreover, a miR-130a-3p mimic could ameliorate the cell proliferation defect induced by dexamethasone through normalization of Slc24a2 expression. Taken together, our results suggest that miR-130-3p plays a crucial role in dexamethasone-induced CP in mice. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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14 pages, 3660 KiB

Open AccessCommunication

Targeting the Highly Expressed microRNA miR-146b with CRISPR/Cas9n Gene Editing System in Thyroid Cancer

by Daniel Casartelli de Santa-Inez, Cesar Seigi Fuziwara, Kelly Cristina Saito and Edna Teruko Kimura

Int. J. Mol. Sci. 2021, 22(15), 7992; https://doi.org/10.3390/ijms22157992 - 27 Jul 2021

Cited by 12 | Viewed by 3502

Abstract

Thyroid cancer is the most common endocrine malignancy, and the characterization of the genetic alterations in coding-genes that drive thyroid cancer are well consolidated in MAPK signaling. In the context of non-coding RNAs, microRNAs (miRNAs) are small non-coding RNAs that, when deregulated, cooperate [...] Read more.

Thyroid cancer is the most common endocrine malignancy, and the characterization of the genetic alterations in coding-genes that drive thyroid cancer are well consolidated in MAPK signaling. In the context of non-coding RNAs, microRNAs (miRNAs) are small non-coding RNAs that, when deregulated, cooperate to promote tumorigenesis by targeting mRNAs, many of which are proto-oncogenes and tumor suppressors. In thyroid cancer, miR-146b-5p is the most overexpressed miRNA associated with tumor aggressiveness and progression, while the antisense blocking of miR-146b-5p results in anti-tumoral effect. Therefore, inactivating miR-146b has been considered as a promising strategy in thyroid cancer therapy. Here, we applied the CRISPR/Cas9n editing system to target the MIR146B gene in an aggressive anaplastic thyroid cancer (ATC) cell line. For that, we designed two single-guide RNAs cloned into plasmids to direct Cas9 nickase (Cas9n) to the genomic region of the pre-mir-146b structure to target miR-146b-5p and miR-146b-3p sequences. In this plasmidial strategy, we cotransfected pSp-Cas9n-miR-146b-GuideA-puromycin and pSp-Cas9n-miR-146b-GuideB-GFP plasmids in KTC2 cells and selected the puromycin resistant + GFP positive clones (KTC2-Cl). As a result, we observed that the ATC cell line KTC2-Cl1 showed a 60% decrease in the expression of miR-146b-5p compared to the control, also showing reduced cell viability, migration, colony formation, and blockage of tumor development in immunocompromised mice. The analysis of the MIR146B edited sequence shows a 5 nt deletion in the miR-146b-5p region and a 1 nt deletion in the miR-146b-3p region in KTC2-Cl1. Thus, we developed an effective CRISPR/Cas9n system to edit the MIR146B miRNA gene and reduce miR-146b-5p expression which constitutes a potential molecular tool for the investigation of miRNAs function in thyroid cancer. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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13 pages, 1744 KiB

Open AccessArticle

miR-373-3p Regulates Invasion and Migration Abilities of Trophoblast Cells via Targeted CD44 and Radixin

by Hyun-Jung Lee, Seung Mook Lim, Hee Yeon Jang, Young Ran Kim, Joon-Seok Hong and Gi Jin Kim

Int. J. Mol. Sci. 2021, 22(12), 6260; https://doi.org/10.3390/ijms22126260 - 10 Jun 2021

Cited by 11 | Viewed by 2559

Abstract

Preterm labor (PTL) is one of the obstetric complications, and is known to be associated with abnormal maternal inflammatory response and intrauterine inflammation and/or infection. However, the expression of specific miRNAs associated with PTL is not clear. In this study, we performed combination [...] Read more.

Preterm labor (PTL) is one of the obstetric complications, and is known to be associated with abnormal maternal inflammatory response and intrauterine inflammation and/or infection. However, the expression of specific miRNAs associated with PTL is not clear. In this study, we performed combination analysis of miRNA array and gene array, and then selected one miRNA (miR-373-3p) and its putative target genes (CD44 and RDX) that exhibited large expression differences in term and PTL placentas with or without inflammation. Using qRT-PCR and luciferase assays, we confirmed that miR-373-3p directly targeted CD44 and RDX. Overexpression of miR-373-3p reduced the migration and invasion of trophoblast cells, while inhibition of miR-373-3p restored the migration and invasion abilities of trophoblast cells. Finally, we validated the expression of miR-373-3p and its target genes in clinical patients’ blood. miR-373-3p was increased in PTL patients’ blood, and was the most expressed in PTL patients’ blood with inflammation. In addition, by targeting the miR-373-3p, CD44 and RDX was decreased in PTL patients’ blood, and their expression were the lowest in PTL patients’ blood with inflammation. Taken together, these findings suggest that miR-373-3p and its target genes can be potential biomarkers for diagnosis of PTL. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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12 pages, 1047 KiB

Open AccessArticle

Mirna Expression in Glaucomatous and TGFβ2 Treated Lamina Cribrosa Cells

by Navita N. Lopez, Rajiv Rangan, Abbot F. Clark and Tara Tovar-Vidales

Int. J. Mol. Sci. 2021, 22(12), 6178; https://doi.org/10.3390/ijms22126178 - 8 Jun 2021

Cited by 3 | Viewed by 2457

Abstract

Glaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely [...] Read more.

Glaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing the profibrotic cytokine transforming growth factor-beta 2 (TGFβ2) and ECM proteins. Moreover, microRNAs (miRNAs or miR) regulate ECM gene expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to the remodeling of ONH. This study aimed to determine whether modulation of miRNAs alters the expression of ECM in human LC cells. Primary human normal and glaucoma LC cells were grown to confluency and treated with or without TGFβ2 for 24 h. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFβ2 treatment downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated collagen expression. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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19 pages, 4867 KiB

Open AccessArticle

MiR-15a-5p Confers Chemoresistance in Acute Myeloid Leukemia by Inhibiting Autophagy Induced by Daunorubicin

by Emeline Bollaert, Melissa Claus, Virginie Vandewalle, Sandrine Lenglez, Ahmed Essaghir, Jean-Baptiste Demoulin and Violaine Havelange

Int. J. Mol. Sci. 2021, 22(10), 5153; https://doi.org/10.3390/ijms22105153 - 13 May 2021

Cited by 17 | Viewed by 2752

Abstract

Anthracyclines remain a cornerstone of induction chemotherapy for acute myeloid leukemia (AML). Refractory or relapsed disease due to chemotherapy resistance is a major obstacle in AML management. MicroRNAs (miRNAs) have been observed to be involved in chemoresistance. We previously observed that miR-15a-5p was [...] Read more.

Anthracyclines remain a cornerstone of induction chemotherapy for acute myeloid leukemia (AML). Refractory or relapsed disease due to chemotherapy resistance is a major obstacle in AML management. MicroRNAs (miRNAs) have been observed to be involved in chemoresistance. We previously observed that miR-15a-5p was overexpressed in a subgroup of chemoresistant cytogenetically normal AML patients compared with chemosensitive patients treated with daunorubicin and cytarabine. MiR-15a-5p overexpression in AML cells reduced apoptosis induced by both drugs in vitro. This study aimed to elucidate the mechanisms by which miR-15a-5p contributes to daunorubicin resistance. We showed that daunorubicin induced autophagy in myeloid cell lines. The inhibition of autophagy reduced cell sensitivity to daunorubicin. The overexpression of miR-15a-5p decreased daunorubicin-induced autophagy. Conversely, the downregulation of miR-15a-5p increased daunorubicin-induced autophagy. We found that miR-15a-5p targeted four genes involved in autophagy, namely ATG9a, ATG14, GABARAPL1 and SMPD1. Daunorubicin increased the expression of these four genes, and miR-15a-5p counteracted this regulation. Inhibition experiments with the four target genes showed the functional effect of miR-15a-5p on autophagy. In summary, our results indicated that miR-15a-5p induces chemoresistance in AML cells through the abrogation of daunorubicin-induced autophagy, suggesting that miR-15a-5p could be a promising therapeutic target for chemoresistant AML patients. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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12 pages, 1416 KiB

Open AccessArticle

Phenytoin Inhibits Cell Proliferation through microRNA-196a-5p in Mouse Lip Mesenchymal Cells

by Hiroki Yoshioka, Sai Shankar Ramakrishnan, Akiko Suzuki and Junichi Iwata

Int. J. Mol. Sci. 2021, 22(4), 1746; https://doi.org/10.3390/ijms22041746 - 9 Feb 2021

Cited by 8 | Viewed by 2456

Abstract

Cleft lip (CL) is one of the most common birth defects. It is caused by either genetic mutations or environmental factors. Recent studies suggest that environmental factors influence the expression of noncoding RNAs [e.g., microRNA (miRNA)], which can regulate the expression of genes [...] Read more.

Cleft lip (CL) is one of the most common birth defects. It is caused by either genetic mutations or environmental factors. Recent studies suggest that environmental factors influence the expression of noncoding RNAs [e.g., microRNA (miRNA)], which can regulate the expression of genes crucial for cellular functions. In this study, we examined which miRNAs are associated with CL. Among 10 candidate miRNAs (miR-98-3p, miR-101a-3p, miR-101b-3p, miR-141-3p, miR-144-3p, miR-181a-5p, miR-196a-5p, miR-196b-5p, miR-200a-3p, and miR-710) identified through our bioinformatic analysis of CL-associated genes, overexpression of miR-181a-5p, miR-196a-5p, miR-196b-5p, and miR-710 inhibited cell proliferation through suppression of genes associated with CL in cultured mouse embryonic lip mesenchymal cells (MELM cells) and O9-1 cells, a mouse cranial neural crest cell line. In addition, we found that phenytoin, an inducer of CL, decreased cell proliferation through miR-196a-5p induction. Notably, treatment with a specific inhibitor for miR-196a-5p restored cell proliferation through normalization of expression of CL-associated genes in the cells treated with phenytoin. Taken together, our results suggest that phenytoin induces CL through miR-196a-5p induction, which suppresses the expression of CL-associated genes. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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21 pages, 4897 KiB

Open AccessArticle

MiR-21 Is Required for the Epithelial–Mesenchymal Transition in MDA-MB-231 Breast Cancer Cells

by Elif Damla Arisan, Ozge Rencuzogullari, Clara Cieza-Borrella, Francesc Miralles Arenas, Miriam Dwek, Sigrun Lange and Pinar Uysal-Onganer

Int. J. Mol. Sci. 2021, 22(4), 1557; https://doi.org/10.3390/ijms22041557 - 4 Feb 2021

Cited by 39 | Viewed by 5781

Abstract

Breast cancer (BCa) is one of the leading health problems among women. Although significant achievements have led to advanced therapeutic success with targeted therapy options, more efforts are required for different subtypes of tumors and according to genomic, transcriptomic, and proteomic alterations. This [...] Read more.

Breast cancer (BCa) is one of the leading health problems among women. Although significant achievements have led to advanced therapeutic success with targeted therapy options, more efforts are required for different subtypes of tumors and according to genomic, transcriptomic, and proteomic alterations. This study underlines the role of microRNA-21 (miR-21) in metastatic MDA-MB-231 breast cancer cells. Following the knockout of miR-21 from MDA-MB-231 cells, which have the highest miR-21 expression levels compared to MCF-7 and SK-BR-3 BCa cells, a decrease in epithelial-mesenchymal transition (EMT) via downregulation of mesenchymal markers was observed. Wnt-11 was a critical target for miR-21, and the Wnt-11 related signaling axis was altered in the stable miR-21 knockout cells. miR-21 expression was associated with a significant increase in mesenchymal markers in MDA-MB-231 BCa cells. Furthermore, the release of extracellular vesicles (EVs) was significantly reduced in the miR-21 KO cells, alongside a significant reduction in relative miR-21 export in EV cargo, compared with control cells. We conclude that miR-21 is a leading factor involved in mesenchymal transition in MDA-MB-231 BCa. Future therapeutic strategies could focus on its role in the treatment of metastatic breast cancer. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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19 pages, 2324 KiB

Open AccessArticle

LncRNA H19-Derived miR-675-5p Accelerates the Invasion of Extravillous Trophoblast Cells by Inhibiting GATA2 and Subsequently Activating Matrix Metalloproteinases

by Manabu Ogoyama, Akihide Ohkuchi, Hironori Takahashi, Dongwei Zhao, Shigeki Matsubara and Toshihiro Takizawa

Int. J. Mol. Sci. 2021, 22(3), 1237; https://doi.org/10.3390/ijms22031237 - 27 Jan 2021

Cited by 15 | Viewed by 2735

Abstract

The invasion of extravillous trophoblast (EVT) cells into the maternal decidua, which plays a crucial role in the establishment of a successful pregnancy, is highly orchestrated by a complex array of regulatory mechanisms. Non-coding RNAs (ncRNAs) that fine-tune gene expression at epigenetic, transcriptional, [...] Read more.

The invasion of extravillous trophoblast (EVT) cells into the maternal decidua, which plays a crucial role in the establishment of a successful pregnancy, is highly orchestrated by a complex array of regulatory mechanisms. Non-coding RNAs (ncRNAs) that fine-tune gene expression at epigenetic, transcriptional, and post-transcriptional levels are involved in the regulatory mechanisms of EVT cell invasion. However, little is known about the characteristic features of EVT-associated ncRNAs. To elucidate the gene expression profiles of both coding and non-coding transcripts (i.e., mRNAs, long non-coding RNAs (lncRNAs), and microRNAs (miRNAs)) expressed in EVT cells, we performed RNA sequencing analysis of EVT cells isolated from first-trimester placentae. RNA sequencing analysis demonstrated that the lncRNA H19 and its derived miRNA miR-675-5p were enriched in EVT cells. Although miR-675-5p acts as a placental/trophoblast growth suppressor, there is little information on the involvement of miR-675-5p in trophoblast cell invasion. Next, we evaluated a possible role of miR-675-5p in EVT cell invasion using the EVT cell lines HTR-8/SVneo and HChEpC1b; overexpression of miR-675-5p significantly promoted the invasion of both EVT cell lines. The transcription factor gene GATA2 was shown to be a target of miR-675-5p; moreover, small interfering RNA-mediated GATA2 knockdown significantly promoted cell invasion. Furthermore, we identified MMP13 and MMP14 as downstream effectors of miR-675-5p/GATA2-dependent EVT cell invasion. These findings suggest that miR-675-5p-mediated GATA2 inhibition accelerates EVT cell invasion by upregulating matrix metalloproteinases. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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9 pages, 1416 KiB

Open AccessArticle

From miRNA Target Gene Network to miRNA Function: miR-375 Might Regulate Apoptosis and Actin Dynamics in the Heart Muscle via Rho-GTPases-Dependent Pathways

by German Osmak, Ivan Kiselev, Natalia Baulina and Olga Favorova

Int. J. Mol. Sci. 2020, 21(24), 9670; https://doi.org/10.3390/ijms21249670 - 18 Dec 2020

Cited by 8 | Viewed by 1875

Abstract

MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, which are involved in the regulation of main biological processes, such as apoptosis or cell proliferation and differentiation, through sequence-specific interaction with target mRNAs. In this study, we propose a workflow for predicting [...] Read more.

MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, which are involved in the regulation of main biological processes, such as apoptosis or cell proliferation and differentiation, through sequence-specific interaction with target mRNAs. In this study, we propose a workflow for predicting miRNAs function by analyzing the structure of the network of their target genes. This workflow was applied to study the functional role of miR-375 in the heart muscle (myocardium), since this miRNA was previously shown to be associated with heart diseases, and data on its function in the myocardium are mostly unclear. We identified PIK3CA, RHOA, MAPK3, PAFAH1B1, CTNNB1, MYC, PRKCA, ERBB2, and CDC42 as key genes in the miR-375 regulated network and predicted the possible function of miR-375 in the heart muscle, consisting mainly in the regulation of the Rho-GTPases-dependent signaling pathways. We implemented our algorithm for miRNA function prediction into a Python module, which is available at GitHub. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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Review

Jump to: Research

25 pages, 2635 KiB

Open AccessReview

The Role of MicroRNAs in Pancreatitis Development and Progression

by Hetvi R. Patel, Vanessa M. Diaz Almanzar, Joseph F. LaComb, Jingfang Ju and Agnieszka B. Bialkowska

Int. J. Mol. Sci. 2023, 24(2), 1057; https://doi.org/10.3390/ijms24021057 - 5 Jan 2023

Cited by 6 | Viewed by 3348

Abstract

Pancreatitis (acute and chronic) is an inflammatory disease associated with significant morbidity, including a high rate of hospitalization and mortality. MicroRNAs (miRs) are essential post-transcriptional modulators of gene expression. They are crucial in many diseases’ development and progression. Recent studies have demonstrated aberrant [...] Read more.

Pancreatitis (acute and chronic) is an inflammatory disease associated with significant morbidity, including a high rate of hospitalization and mortality. MicroRNAs (miRs) are essential post-transcriptional modulators of gene expression. They are crucial in many diseases’ development and progression. Recent studies have demonstrated aberrant miRs expression patterns in pancreatic tissues obtained from patients experiencing acute and chronic pancreatitis compared to tissues from unaffected individuals. Increasing evidence showed that miRs regulate multiple aspects of pancreatic acinar biology, such as autophagy, mitophagy, and migration, impact local and systemic inflammation and, thus, are involved in the disease development and progression. Notably, multiple miRs act on pancreatic acinar cells and regulate the transduction of signals between pancreatic acinar cells, pancreatic stellate cells, and immune cells, and provide a complex interaction network between these cells. Importantly, recent studies from various animal models and patients’ data combined with advanced detection techniques support their importance in diagnosing and treating pancreatitis. In this review, we plan to provide an up-to-date summary of the role of miRs in the development and progression of pancreatitis. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases 2.0)

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23 pages, 1051 KiB

Open AccessReview

Cardiac Metabolism and MiRNA Interference

by Krishnamoorthi Sumaiya, Thiruvelselvan Ponnusamy, Kalimuthusamy Natarajaseenivasan and Santhanam Shanmughapriya

Int. J. Mol. Sci. 2023, 24(1), 50; https://doi.org/10.3390/ijms24010050 - 20 Dec 2022

Cited by 3 | Viewed by 2870

Abstract

The aberrant increase in cardio-metabolic diseases over the past couple of decades has drawn researchers’ attention to explore and unveil the novel mechanisms implicated in cardiometabolic diseases. Recent evidence disclosed that the derangement of cardiac energy substrate metabolism plays a predominant role in [...] Read more.

The aberrant increase in cardio-metabolic diseases over the past couple of decades has drawn researchers’ attention to explore and unveil the novel mechanisms implicated in cardiometabolic diseases. Recent evidence disclosed that the derangement of cardiac energy substrate metabolism plays a predominant role in the development and progression of chronic cardiometabolic diseases. Hence, in-depth comprehension of the novel molecular mechanisms behind impaired cardiac metabolism-mediated diseases is crucial to expand treatment strategies. The complex and dynamic pathways of cardiac metabolism are systematically controlled by the novel executor, microRNAs (miRNAs). miRNAs regulate target gene expression by either mRNA degradation or translational repression through base pairing between miRNA and the target transcript, precisely at the 3’ seed sequence and conserved heptametrical sequence in the 5’ end, respectively. Multiple miRNAs are involved throughout every cardiac energy substrate metabolism and play a differential role based on the variety of target transcripts. Novel theoretical strategies have even entered the clinical phase for treating cardiometabolic diseases, but experimental evidence remains inadequate. In this review, we identify the potent miRNAs, their direct target transcripts, and discuss the remodeling of cardiac metabolism to cast light on further clinical studies and further the expansion of novel therapeutic strategies. This review is categorized into four sections which encompass (i) a review of the fundamental mechanism of cardiac metabolism, (ii) a divulgence of the regulatory role of specific miRNAs on cardiac metabolic pathways, (iii) an understanding of the association between miRNA and impaired cardiac metabolism, and (iv) summary of available miRNA targeting therapeutic approaches. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases 2.0)

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23 pages, 1745 KiB

Open AccessReview

Breast Cancer-Delivered Exosomal miRNA as Liquid Biopsy Biomarkers for Metastasis Prediction: A Focus on Translational Research with Clinical Applicability

by Oana Baldasici, Valentina Pileczki, Daniel Cruceriu, Laura Ioana Gavrilas, Oana Tudoran, Loredana Balacescu, Laurian Vlase and Ovidiu Balacescu

Int. J. Mol. Sci. 2022, 23(16), 9371; https://doi.org/10.3390/ijms23169371 - 19 Aug 2022

Cited by 21 | Viewed by 3387

Abstract

Metastasis represents the most important cause of breast cancer-associated mortality. Even for early diagnosed stages, the risk of metastasis is significantly high and predicts a grim outcome for the patient. Nowadays, efforts are made for identifying blood-based biomarkers that could reliably distinguish patients [...] Read more.

Metastasis represents the most important cause of breast cancer-associated mortality. Even for early diagnosed stages, the risk of metastasis is significantly high and predicts a grim outcome for the patient. Nowadays, efforts are made for identifying blood-based biomarkers that could reliably distinguish patients with highly metastatic cancers in order to ensure a closer follow-up and a more personalized therapeutic method. Exosomes are nano vesicles secreted by cancer cells that can transport miRNAs, proteins, and other molecules and deliver them to recipient cells all over the body. Through this transfer, cancer cells modulate their microenvironment and facilitate the formation of the pre-metastatic niche, leading to sustained progression. Exosomal miRNAs have been extensively studied due to their promising potential as prognosis biomarkers for metastatic breast cancer. In this review, we tried to depict an overview of the existing literature regarding exosomal miRNAs that are already validated as potential biomarkers, and which could be immediately available for the clinic. Moreover, in the last section, we highlighted several miRNAs that have proven their function in preclinical studies and could be considered for clinical validation. Considering the lack of standard methods for evaluating exosomal miRNA, we also discussed the challenges and the technical aspects underlying this issue. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases 2.0)

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29 pages, 5084 KiB

Open AccessReview

The Expression of Non-Coding RNAs and Their Target Molecules in Rheumatoid Arthritis: A Molecular Basis for Rheumatoid Pathogenesis and Its Potential Clinical Applications

by Chang-Youh Tsai, Song-Chou Hsieh, Chih-Wei Liu, Cheng-Hsun Lu, Hsien-Tzung Liao, Ming-Han Chen, Ko-Jen Li, Cheng-Han Wu, Cheih-Yu Shen, Yu-Min Kuo and Chia-Li Yu

Int. J. Mol. Sci. 2021, 22(11), 5689; https://doi.org/10.3390/ijms22115689 - 26 May 2021

Cited by 18 | Viewed by 4466

Abstract

Rheumatoid arthritis (RA) is a typical autoimmune-mediated rheumatic disease presenting as a chronic synovitis in the joint. The chronic synovial inflammation is characterized by hyper-vascularity and extravasation of various immune-related cells to form lymphoid aggregates where an intimate cross-talk among innate and adaptive [...] Read more.

Rheumatoid arthritis (RA) is a typical autoimmune-mediated rheumatic disease presenting as a chronic synovitis in the joint. The chronic synovial inflammation is characterized by hyper-vascularity and extravasation of various immune-related cells to form lymphoid aggregates where an intimate cross-talk among innate and adaptive immune cells takes place. These interactions facilitate production of abundant proinflammatory cytokines, chemokines and growth factors for the proliferation/maturation/differentiation of B lymphocytes to become plasma cells. Finally, the autoantibodies against denatured immunoglobulin G (rheumatoid factors), EB virus nuclear antigens (EBNAs) and citrullinated protein (ACPAs) are produced to trigger the development of RA. Furthermore, it is documented that gene mutations, abnormal epigenetic regulation of peptidylarginine deiminase genes 2 and 4 (PADI2 and PADI4), and thereby the induced autoantibodies against PAD2 and PAD4 are implicated in ACPA production in RA patients. The aberrant expressions of non-coding RNAs (ncRNAs) including microRNAs (miRs) and long non-coding RNAs (lncRNAs) in the immune system undoubtedly derange the mRNA expressions of cytokines/chemokines/growth factors. In the present review, we will discuss in detail the expression of these ncRNAs and their target molecules participating in developing RA, and the potential biomarkers for the disease, its diagnosis, cardiovascular complications and therapeutic response. Finally, we propose some prospective investigations for unraveling the conundrums of rheumatoid pathogenesis. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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Open AccessReview

MicroRNAs as Modulators of Oral Tumorigenesis—A Focused Review

by Kumar Rishabh, Soham Khadilkar, Aviral Kumar, Ishu Kalra, Alan Prem Kumar and Ajaikumar B. Kunnumakkara

Int. J. Mol. Sci. 2021, 22(5), 2561; https://doi.org/10.3390/ijms22052561 - 4 Mar 2021

Cited by 44 | Viewed by 4202

Abstract

Oral cancers constitute the majority of head and neck tumors, with a relatively high incidence and poor survival rate in developing countries. While the five-year survival rates of the oral cancer patients have increased to 65%, the overall survival for advanced stages has [...] Read more.

Oral cancers constitute the majority of head and neck tumors, with a relatively high incidence and poor survival rate in developing countries. While the five-year survival rates of the oral cancer patients have increased to 65%, the overall survival for advanced stages has been at 27% for the past ten years, emphasizing the necessity for further understanding the etiology of the disease, diagnosis, and formulating possible novel treatment regimens. MicroRNAs (miRNAs), a family of small non-coding RNA, have emerged as master modulators of gene expression in various cellular and biological process. Aberrant expression of these dynamic molecules has been associated with many human diseases, including oral cancers. The deregulated miRNAs have been shown to control various oncogenic processes, including sustaining proliferative signaling, evading growth suppressors, resisting cell death activating invasion and metastasis, and inducing angiogenesis. Hence, the aberrant expression of miRNAs associated with oral cancers, makes them potential candidates for the investigation of functional markers, which will aid in the differential diagnosis, prognosis, and development of novel therapeutic regimens. This review presents a holistic insight into our understanding of the role of miRNAs in regulating various hallmarks of oral tumorigenesis. Full article

(This article belongs to the Special Issue MicroRNA Signaling in Human Diseases)

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