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The high mobility group protein 2 (HMGA2) regulates gene expression by binding to AT-rich regions of DNA. Akin to other DNA architectural proteins, HMGA2 is highly expressed in embryonic stem cells during embryogenesis, while its expression is more limited at later stages of development and in adulthood. Importantly, HMGA2 is re-expressed in nearly all human malignancies, where it promotes tumorigenesis by multiple mechanisms. HMGA2 increases cancer cell proliferation by promoting cell cycle entry and inhibition of apoptosis. In addition, HMGA2 influences different DNA repair mechanisms and promotes epithelial-to-mesenchymal transition by activating signaling via the MAPK/ERK, TGFβ/Smad, PI3K/AKT/mTOR, NFkB, and STAT3 pathways. Moreover, HMGA2 supports a cancer stem cell phenotype and renders cancer cells resistant to chemotherapeutic agents. In this review, we discuss these oncogenic roles of HMGA2 in different types of cancers and propose that HMGA2 may be used for cancer diagnostic, prognostic, and therapeutic purposes.

Lung cancer is one of the most common cancers and its incidence is rising around the world. Various studies suggest that miR-330 acts as a tumor-suppressor microRNA (miRNA) in different types of cancers, but precisely how has remained unclear. In this study, we investigate miR-330 expression in lung cancer patient samples, as well as in vitro, by studying how normalization of miR-330 expression affects lung cancer cellular phenotypes such as viability, apoptosis, proliferation, and migration. We establish that low miR-330 expression predicts poor lung cancer prognosis. Stable restoration of reduced miR-330 expression in lung cancer cells reduces cell viability, increases the fraction of apoptotic cells, causes G2/M cell cycle arrest, and inhibits cell migration. These findings are substantiated by increased mRNA and protein expression of markers for apoptosis via the intrinsic pathway, such as caspase 9, and decreased mRNA and protein expression of markers for cell migration, such as vimentin, C-X-C chemokine receptor type 4, and matrix metalloproteinase 9. We showed that reduced miR-330 expression predicts poor lung cancer survival and that stable restoration of miR-330 expression in lung cancer cells has a broad range of tumor-suppressive effects. This indicates that miR-330 is a promising candidate for miRNA replacement therapy for lung cancer patients., (© 2020 Wiley Periodicals LLC.)

Glioblastoma multiform (GBM) as the most frequent and lethal brain tumor is defined by aggressive invasiveness and considerable resistance to chemotherapy. The molecular mechanisms underlying GBM tumorigenesis still needs to be further investigated. Considering that, the current study was aimed to investigate the function of miR-181a in human glioblastoma cells in combination with carmustine. U373 cell line with the low expression levels of miR-181a was selected for functional investigations. MTT assay was used to determine cell viability and Annexin V/PI and DAPI staining were employed to evaluate apoptosis induction. Also, cell migration and cell cycle progression were investigated using wound healing test and flow cytometry, respectively. qRT-PCR was used for the quantification of gene expression. MTT assay results revealed that miR-181a replacement increased the sensitivity of U373 cells to low doses of carmustine. Moreover, miR-181a was shown to increase the sub G1 cell cycle arrest and apoptosis induction by carmustine via regulating the expression of related genes including caspase-9, Bcl-2, and SIRT1. Furthermore, this miRNA combined with carmustine suppressed cell migration via downregulation of MMP-2 and Bach1 and reduced the clonogenic ability of U373 cells. Additionally, miR-181a-mediated downregulation of AKT1 implied that this miRNA could inhibit cell proliferation by modulating PI3K/AKT signaling pathway. In conclusion, the findings of this study suggest that miR-181a replacement, regarding its tumor-suppressive effects and sensitization of glioblastoma cells to carmustine, could be considered as a potential therapeutic strategy to improve the efficiency of glioblastoma chemotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Melanoma skin cancer is one of the main causes of male cancer-related deaths worldwide. It has been suggested that miR-330-5p can act as a tumor suppressor in various types of cancers. So, in this study, we replaced miR-330 in melanoma cancer cells by vector-based miR-330 to evaluate the effects of this microRNA on the growth and migration inhibition of melanoma cancer cells, and to determine the molecular mechanisms underlying its action. By using the MTT assay, the IC 50 of Geneticin antibiotic was obtained as 460 µg/mL. The results of the qRT-PCR showed the increased expression level of miR-330 and decreased expression levels of MMP-9, CXCR4, Vimentin, melanoma cell adhesion molecule, AKT1, and E2F1 messenger RNA in A375 transfected cells. The cytotoxicity assay results demonstrated the inhibition of cancer cells proliferation. Furthermore, the wound healing test results showed a migration reduction of transfected cells with miR-330 compared with nontransfected ones. In addition, 4',6-diamidino-2-phenylindoleLB: Luria-Bertani (DAPI) staining revealed the significant nucleus fragmentation in miR-330 replaced cells, which correspond to apoptosis induction in replaced cells. The results showed that increase in miR-330 expression level could significantly inhibit the tumor cell growth and the migration of melanoma cancer cells., (© 2019 Wiley Periodicals, Inc.)

miR-143 is a tumor suppressor miRNA which its downregulation is frequently reported in colorectal cancer (CRC). This miRNA is a negative regulator of K-RAS, c-MYC, BCL-2, and MMP-9 genes which are engaged in tumor growth and metastasis. In the present study, miR-143 restoration was performed by transfection of the pCMV-miR-143 vector into the SW-480 CRC cells. Subsequently, alterations in proliferative and migratory potential of the cells were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and wound-healing assays, respectively. Moreover, to detect apoptosis incidence in the transfected cells, 4',6-diamidino-2-phenylindole (DAPI) staining was used. Furthermore, mRNA levels of c-MYC, K-RAS, MMP-9, and BCL-2, as potential targets of miR-143, were assessed by quantitative Real-Time PCR (qRT-PCR). Also the expression levels of c-MYC, K-RAS, and MMP-9 proteins were investigated by the western blot analysis. Finally, the ratio of BAX to BCL-2 expression, as a potential marker of the response to apoptosis stimuli, was compared between the control and test groups. Furthermore, the trypan blue test was performed to determine the cell viability in cell suspension. According to the results, a decreased viability and migratory potential was observed for the miR-143 receiving cells. The DAPI staining also confirmed the occurrence of apoptosis. Moreover, BCL-2, K-RAS, MMP-9, and c-MYC mRNAs were significantly downregulated in the miR-143 grafted cells. The BAX/BCL-2 ratio also indicated a notable increase in the cells with miR-143 overexpression. In brief, miR-143 replacement could be considered as an effective strategy for the management of CRC and attenuating its invasive features., (© 2019 Wiley Periodicals, Inc.)

Background: Lung cancer is the main cause of cancer death in males and females worldwide. Reduced expression of miR-145 has been reported in many types of cancers. In this study, we transfected miR-145 into lung cancer cells by vector-based miR-145, and investigated the effects of this intervention on growth and migration inhibition of cancer cells as well on the expression of targeted genes., Methods: IC50 of Geneticin (G418) antibiotic was measured using MTT test in NSCLC cell lines. miR-145 was transfected into lung cancer cells by jetPEI. qRT-PCR was used to evaluate the transcript level of the miR-145 and expression for KRAS, MMP-9, vimentin, caspase-3, caspase-8 and caspase-9 genes in A549 cells. MTT assay was used to evaluate the proliferation inhibition of cancer cells. Wound healing assay was used to check the migration status of transfected lung cancer cells. The apoptosis induction was assessed by DAPI staining assay., Results: The MTT assay showed that the IC50 of Genticin was 494.1 μg/ml. The results of the qRT-PCR showed increased expression level of miR-145 and downregulation of KRAS, MMP-9, and vimentin expression in A549 transfected cells compared with the control group. The MTT assay results demonstrated inhibition of cancer cell proliferation after miR-145 replacement. Wound healing assay results revealed that migration was reduced upon miR-145 transfection. The transfected cell displayed increased apoptosis rate by inducing caspase-3 and caspase-9 mRNA expression., Conclusion: The results of this study showed that increased miR-145 expression exerted a critical role in subsiding the growth, survival, and migration of lung cancer cell line., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: MiR-152 has been reported as a tumor suppressor microRNA that is downregulated in a number of cancers, including colorectal cancer (CRC). A recent study suggested that miR-152 could be one of the key regulators of CRC. The aim of this study is to investigate the role of miR-152 in CRC and its mechanisms., Methods: The pCMV-GPF-miR-152 vector was transfected into SW-480 and HCT-116 CRC cells via JetPEI transfection reagent. The stable miR-152-expressed cells were selected for the further experiment. To evaluate the effect of miR-152 on cell proliferation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed. Also, the effect of miR-152 on the survival of CRC cells was analyzed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. The inhibitory effect of miR-152 on migration was assessed by wound healing scratch assay. Then, the proteins expression levels of protein kinase B (AKT), phosphorylated AKT (p-AKT), extracellular signal-regulated kinase (ERK), and phosphorylated ERK (p-ERK) were measured by the western blot analysis method., Results: The result of MTT assay represented miR-152 could inhibit cell proliferation. The TUNEL assay showed miR-152 could induce apoptosis in CRC cells. The wound healing scratch assay showed that miR-152 replacement repressed cell migration in CRC cell lines compared to control groups. The result of protein expression by western blot analysis demonstrated that miR-152 could reduce AKT-p-AKT, and ERK-p-ERK ratio compared to control cells., Conclusion: Our results show that miR-152 has new anticancer and antimetastatic effect in CRC tissue. The current study showed that miR-152 could be a novel therapeutic small molecule to suppress CRC cell proliferation, survival, and migration by suppressing AKT-ERK signaling pathways., (© 2018 Wiley Periodicals, Inc.)

Introduction: Breast adenocarcinoma is the second common cancer in women the incidence of which is increasing in many countries, especially in developing companies. In this study, miRNA143 has been replaced by vector based microRNA-143 in breast adenocarcinoma cells (MDA-MB-468) and its anti-cancer effects on breast adenocarcinoma cells have been evaluated., Methods: The pCMV-MIR-143 vector was transfected into MDA-MB-468 cells via JetPEI transfection reagent. The transfected cells were selected by IC50 concentration of Geneticin antibiotic (G418) after a 2-week treatment. To evaluate the effect of miR-143 on the inhibition of migration, scratch wound healing assay was performed. Then, the expression level of miR-143, Kras, Vimentin, CXCR4, MMP9 and E-Cadherin were measured by the qRT-PCR method., Results: Results of MTT and wound healing assays showed that miR-143 inhibited cell growth and cell migration in miR-143 induced cell line compared with control group. The result of gene expression showed that miR-143 reduced Kras, Vimentin, CXCR4 and MMP9 expression, and increased E-Cadherin expression in miR-143 replaced cells compared to control cells., Conclusion: The results showed that miRNA-143 plays an important role in cell growth and migration during breast cancer development and metastasis and it can be a candidate as a therapeutic molecule in microRNA replacement therapy of breast adenocarcinoma., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: MiR‐152 has been reported as a tumor suppressor microRNA that is downregulated in a number of cancers, including colorectal cancer (CRC). A recent study suggested that miR‐152 could be one of the key regulators of CRC. The aim of this study is to investigate the role of miR‐152 in CRC and its mechanisms. Methods: The pCMV‐GPF‐miR‐152 vector was transfected into SW‐480 and HCT‐116 CRC cells via JetPEI transfection reagent. The stable miR‐152‐expressed cells were selected for the further experiment. To evaluate the effect of miR‐152 on cell proliferation, 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay was performed. Also, the effect of miR‐152 on the survival of CRC cells was analyzed using terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) assay. The inhibitory effect of miR‐152 on migration was assessed by wound healing scratch assay. Then, the proteins expression levels of protein kinase B (AKT), phosphorylated AKT (p‐AKT), extracellular signal–regulated kinase (ERK), and phosphorylated ERK (p‐ERK) were measured by the western blot analysis method. Results: The result of MTT assay represented miR‐152 could inhibit cell proliferation. The TUNEL assay showed miR‐152 could induce apoptosis in CRC cells. The wound healing scratch assay showed that miR‐152 replacement repressed cell migration in CRC cell lines compared to control groups. The result of protein expression by western blot analysis demonstrated that miR‐152 could reduce AKT–p‐AKT, and ERK–p‐ERK ratio compared to control cells. Conclusion: Our results show that miR‐152 has new anticancer and antimetastatic effect in CRC tissue. The current study showed that miR‐152 could be a novel therapeutic small molecule to suppress CRC cell proliferation, survival, and migration by suppressing AKT–ERK signaling pathways. miR‐152 has been reported as a tumor suppressor microRNA that is downregulated in a number of cancers. Our results show that miR‐152 has new anticancer and antimetastatic effect in colorectal cancer (CRC) tissue. The current study showed that miR‐152 could be a novel therapeutic small molecule to suppress CRC cell proliferation, survival, and migration by suppressing protein kinase B–extracellular signal–regulated kinase signaling pathways. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic adenocarcinoma has a high prevalence all over the world. Most of the therapeutic approaches failed as a result of tumor invasion and rapid metastasis. Several natural plants have been shown to have promising therapeutic effects. Thus, the aim of this study was to investigate the cytotoxic activity of Eryngium billardieri against PANC-1 cancer cell lines. Methods: Dimethylthiazole diphenyltetrazolium bromide assay (MTT assay) and flow cytometry were used to assess the cytotoxicity of E. billardieri extracts against PANC-1 cancer cell lines. Quantitative Polymerase Chain Reaction (qPCR) was conducted to investigate the expression levels of Bcl2- associated X protein (BAX) and cyclin D1. Results: The results of the MTT assay showed that E. billardieri extracts had cytotoxic effects on PANC- 1 cancer cell lines. Moreover, the findings from the gene expression confirmed the over expression of Bax, and under expression of cyclin D1 following treatment with dichloromethane (DCM) and n-hexane (n- hex) extracts in cancer cells (P < 0.05). Interestingly, the flow cytometry results showed that DCM and n- hex extracts of E. billardieri induced apoptosis in PANC- 1 cancer cell lines. Conclusion: The results of this study demonstrated that DCM and n- hex extracts of E. billardieri significantly induce apoptosis by increasing Bax and decreasing cyclin D1 mRNA expression. Therefore, E. billardieri may be regarded as a novel approach for treatment of pancreatic cancer as a result of its promising apoptotic and cytotoxic properties. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer grows and spreads faster compared to other types of invasive breast cancer and has limited treatment options and subsequently worse prognosis. High mobility group A 2 (HMGA2) protein is widely expressed in undifferentiated cells including cancer cells. HMGA2 is a DNA binding protein involved in DNA architecture and the functional regulation of DNA. It was reported that HMGA2 is aberrantly regulated malignant signaling in different types of cancers. In this study, we aim to reveal the role of HMGA2 in TNBC biology and demonstrate a link between HMGA2-mediated cancer phenotypes and the regulation of NF-kB/IL-6/STAT3 signaling. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that exhibits a high proliferation rate and early metastasis leading to a poor prognosis. HMGA2 is a DNA binding transcriptional regulator implicated in tumorigenesis. Here, we demonstrate that the HMGA2 promoter is demethylated in TNBC tumors, leading to increased expression of HMGA2 at both mRNA and protein levels. Importantly, high HMGA2 levels in TNBC tumors are correlated with poor prognosis. To detail the role of HMGA2 in TNBC development and progression, we studied its effect on core cancer phenotypes. Stable knockdown of HMGA2 in TNBC cells revealed that HMGA2 may support cell proliferation, cell migration and invasion. In addition, HMGA2 knockdown decreased cancer stem cell (CSC) features. Importantly, we found that silencing HMGA2 inhibited NF-kB signaling and lead to decreased expression of the downstream molecules IL-6 and IL-8 and reduced STAT3 pathway activation. Our results demonstrate that HMGA2 supports cancer hallmarks in TNBC and may represent a promising target for TNBC treatment. [ABSTRACT FROM AUTHOR]

Gastric cancer is responsible for approximately one million annual deaths worldwide. Recently, the important roles of miRNAs as vital factors in malignancy processes such as metastasis have identified. They involve in the regulation of different biological procedures such as proliferation, invasion, metastasis and cell survival. MiR-146a has an aberrant expression in different tumors and has different expressions in the gastric cancer cell lines. This microRNA can act as a tumor suppressor and/or oncogene in gastric cancer related cases. Most of the studies have confirmed that miR-146a is downregulated in human gastric cancer cell lines and tissues, significantly and that it has tumor suppressor effects in gastric cancers. On the other hand, the role of miR-146a as an oncogene has been studied in an in-vitro experiment and results showed that over- an expression of miR-146a in gastric cancer tissues inhibits apoptosis and improves cell proliferation of gastric cancer cell. MiR-146a also has been a candidate for diagnosis and prognosis in gastric cancer cases. In this review, we focus on the important roles of miR-146a in tumor genesis of gastric tissues, emphasizing on the involvement of this microRNA in diagnosis, prognosis, chemotherapy response and finally, potential therapeutic applications as an anticancer agent in inhibition of gastric cancer cell metastasis and invasion. [ABSTRACT FROM AUTHOR]