DOX-PLGA Nanoparticles Effectively Suppressed the Expression of Pro-Inflammatory Cytokines TNF-a, IL-6, iNOS, and IL-1ß in MCF-7 Breast Cancer Cell Line.

Background: Inflammation contributes to cancer pathobiology through different mechanisms. Higher levels of pro-inflammatory cytokines can lead to hyperinflammation and promote cancer development and metastasis. For cancer treatment, Doxorubicin (DOX) can be encapsulated into the poly-lactic-glycolic acid (PLGA) nanoparticles. This study aimed to investigate the impact of doxorubicin-loaded PLGA nanoparticles (DOX-PLGA NP) on the expression of pro-inflammatory genes TNF-α, IL-6, iNOS, and IL-1ß in the MCF-7 cells. Methods: The DOX-PLGA NP was prepared by loading doxorubicin into PLGA and characterized using dynamic light scattering (DLS) and atomic force microscopy (AFM). The cytotoxic effect of the nanoparticles was determined by the MTT assay, and their impacts on the expression of pro-inflammatory genes were assessed by qRT-PCR. Results: The encapsulation efficiency and loading capacity were 60±1.5 and 1.13±0.21 percent, respectively. The zeta potential and mean DOX-PLGA nanoparticle size were -18±0.550 mV and 172±55.6 nm, respectively. The 50% inhibitory concentration (IC50) of the DOX-PLGA NP on MCF-7 cell viability was 24.55 µg/mL after 72 hours of treatment. The qRT-PCR results revealed that the 20 µg/mL concentration of the DOX-PLGA NP significantly suppressed the expression of the pro-inflammatory genes TNF-α, IL-6, iNOS, and IL-1ß compared to DOX alone (20 µg/mL). Additionally, the suppression effect of DOX-PLGA NP on the expression of these pro-inflammatory genes was dose-dependent. Conclusions: These results show that DOX-PLGA NP efficiently suppressed the expression of pro-inflammatory genes. Furthermore, encapsulation of DOX into PLGA nanoparticles significantly improved the effectiveness of DOX in suppressing pro-inflammatory genes in MCF-7 breast cancer cells.

5-Fluorouracil-Loaded PLGA Declined Expression of Pro-Inflammatory Genes IL-9, IL-17A, IL-23 and IFN- y; in the HT-29 Colon Cancer Cell Line.

Background: Pro-inflammatory cytokines play critical roles in cancer pathobiology and have been considered potential targets for cancer management and therapy. Understanding the impact of cancer therapeutics such as 5-fluorouracil (5-FU) on their expression might shed light on development of novel combinational therapies. This study aimed to encapsulate 5-FU into PLGA and evaluate their effects on the expression of pro-inflammatory genes IL-9, IL-17-A, IL-23, and IFN-y; in the HT-29 cells. Methods: PLGA-5-FU NPs were constructed and characterized by Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM). The cytotoxicity was evaluated by MTT test and, the IC50 was identified. HT-29 cells were treated with different concentrations of the PLGA-5-FU NPs for 48 hours and, gene expression levels were analyzed by qRT-PCR. Results: DLS and AFM analysis revealed that the prepared PLGA-5-FU NPs were negatively charged spherical-shaped particles with a mean size of 215.9 ± 43.3 nm. PLGA-5-FU NPs impacted the viability of HT-29 cells in a dose- and time-dependent manner. The qRT-PCR results revealed a dose-dependent decrease in the expression of IL-9, IL-17A, IL-23 and IFN-y; genes, and their expressions were significantly different in both 10 and 20 µg/mL treated groups compared to the control. However, although the treatment of HT-29 cells with 20 µg/mL free 5-FU resulted in decreased expression of the studied genes, the differences were not statistically significant compared to the control group. Conclusion: PLGA-5-FU NPs significantly suppressed expression of the IL-9, IL-17A, IL-23 and IFN-y; genes, and the encapsulation of 5-FU into PLGA improved considerably impact of the 5-FU on the HT-29 cells.

A biochemical assessment of apoptosis-inducing impact of Salinomycin in combination with ciprofloxacin on human leukemia KG1-a stem-like cells in the presence and absence of insulin.

BACKGROUND: Acute Myeloid Leukemia (AML) is a fast-developing invading cancer that impacts the blood and bone marrow, marked by the rapid proliferation of abnormal white blood cells. Chemotherapeutic agents, a primary treatment for AML, encounter clinical limitations such as poor solubility and low bioavailability. Previous studies have highlighted antibiotics as effective in inducing cancer cell death and potentially preventing metastasis. Besides, insulin is known to activate the PI3K/Akt pathway, often disrupted in cancers, leading to enhanced cell survival and resistance to apoptosis. In light of the above-mentioned points, we examined the anti-cancer impact of antibiotics Ciprofloxacin (CP) and Salinomycin (SAL) and their combination on KG1-a cells in the presence and absence of insulin. METHODS: This was accomplished by exposing KG1-a cells to different doses of CP and SAL alone, in combination, and with or without insulin for 24-72 h. Cell viability was evaluated using the MTT assay. Besides, apoptotic effects were examined using Hoechst staining and Annexin-V/PI flow cytometry. The expression levels of Bax, p53, BIRC5, Akt, PTEN, and FOXO1 were analyzed through Real-Time PCR. RESULTS: CP and SAL demonstrated cytotoxic and notable pro-apoptotic impact on KG1-a cells by upregulating Bax and p53 and downregulating BIRC5, leading to G0/G1 cell cycle arrest and prevention of the PI3K-Akt signaling pathway. Our findings demonstrated that combination of CP and SAL promote apoptosis in the KG1-a cell line by down-regulating BIRC5 and Akt, as well as up-regulating Bax, p53, PTEN, and FOXO1. Additionally, the findings strongly indicated that insulin effectively mitigates apoptosis by enhancing Akt expression and reducing FOXO1 and PTEN gene expression in the cells treated with CP and SAL. CONCLUSION: Our findings showed that the combined treatment of CP and SAL exhibit a strong anti-cancer effect on leukemia KG1-a cells. Moreover, it was discovered that the PI3K-Akt signaling can be a promising target in leukemia treatment particularly in hyperinsulinemia condition.

Promoter of lncRNA MORT is aberrantly methylated in colorectal cancer.

Aberrant DNA methylation plays essential roles in the colorectal cancer (CRC) carcinogenesis and has been demonstrated as a promising marker for cancer early detection. In this project, methylation status of the MORT promoter was studied in CRC and their marginal tissues using qMSP assay. Furthermore, we investigated the molecular function of MORT in CRC progression using computational analysis. The results showed a high methylation level of MORT promoter in CRC tissues. By in silico analysis, we found that MORT downregulation could promote the proliferation of CRC cells via sponging of has-miR-574-5p and has-miR-31-5p, and alteration of their targets expression pattern such as MYOCD and FOXP2. In conclusion, based on our results, promoter hypermethylation of MORT might be considered as a potential biomarker for CRC detection.

Plasma Circulating Terminal Differentiation-Induced Non-Coding RNA Serves as a Biomarker in Breast Cancer.

Background: Breast cancer is identified as the most common malignancy and cause of cancer-related death worldwide. Compared with healthy controls, this study evaluated the expression level and diagnostic power of lncRNA plasma TINCR in breast cancer patients. Materials and Methods: Fifty-eight women diagnosed with invasive ductal carcinoma and fifty healthy age- matched controls were included in the study. TRIzol® LS regent was used to isolate the total RNA from the whole plasma. Total RNA was converted to cDNA using Prime ScriptTM RT reagent kit and the expression levels of TINCR were quantified by qRT-PCR. Results: Low levels of TINCR lncRNA were observed in the plasma of breast cancer patients compared with control subjects. Plasma TINCR level was also positively correlated with the diagnostic age of breast cancer patients. Conclusion: A low level of plasma TINCR could discriminate breast cancer patients from healthy control subjects.

Minocycline induced apoptosis and suppressed expression of matrix metalloproteinases 2 and 9 in the breast cancer MCF-7 cells.

BACKGROUND: In women, breast cancer is the second most frequent type of cancer. Looking for new and effective cancer-specific therapies with little to no adverse effects on healthy cells is critical. OBJECTIVE: Minocycline, a second-generation tetracycline, has shown anticancer effects by targeting multiple pathways in various cancers. This study aimed to determine minocycline effects on the cell proliferation, apoptosis, and invasion of the human MCF-7 cells. METHODS: MTT assay was used to evaluate the cytotoxicity of minocycline on the cells. Flow cytometry was performed to investigate the induction of apoptosis and the cell cycle progression. The expression levels of apoptotic and migration proteins and genes were assessed by western blotting and qRT-PCR. The scratch test was performed to evaluate the anti-migration effect of the drug. RESULTS: The results indicated that the IC50 value of minocycline for MCF-7 cells was 36.10 µM. Minocycline treatment caused sub-G1 cell accumulation, indicating a significant apoptotic effect on the MCF-7 cells. Annexin-V/PI staining revealed a significant rise in early and late apoptotic cell percentages. Minocycline up-regulated Bax and Caspase-3 expression and down-regulated Bcl-2 and Pro-Cas3. The scratch test revealed significant anti-migration effects for minocycline. Furthermore, it caused down-regulation of MMP-2 and MMP-9 in a concentration-dependent method. CONCLUSION: These findings further confirmed the anticancer effect of minocycline and highlighted that minocycline maybe considered as potential therapeutic agent for breast cancer treatment.

Minocycline as a prospective therapeutic agent for cancer and non-cancer diseases: a scoping review.

Minocycline is an FDA-approved secondary-generation tetracycline antibiotic. It is a synthetic antibiotic having many biological effects, such as antioxidant, anti-inflammatory, anti-cancer, and neuroprotective functions. This study discusses the pharmacological mechanisms of preventive and therapeutic effects of minocycline. Specifically, it provides a comprehensive overview of the molecular pathways by which minocycline acts on the different cancers, including ovarian, breast, glioma, colorectal, liver, pancreatic, lung, prostate, melanoma, head and neck, leukemia, and non-cancer diseases such as Alzheimer's disease, Parkinson, schizophrenia, multiple sclerosis, Huntington, polycystic ovary syndrome, and coronavirus disease 19. Minocycline may be a potential medication for these disorders due to its strong blood-brain barrier penetrance. It is also widely accepted as a specific medication, has a well-known side-effect characteristic, is reasonably priced, making it appropriate for continuous use in managing diseases, and has been demonstrated as an oral approach because it is effectively absorbed and accomplished almost all of the body's parts.

Insights into the radiotherapy-induced deferentially expressed RNAs in colorectal cancer management.

Radiotherapy (RT) has been commonly applied to treat advanced local cancers. In radiation therapy, high doses of radiation are utilized to trigger cell death. Radiation often leads to DNA double-strand breakages (DSB), which causes the activation of downstream genes including those for non-coding RNAs (ncRNA) such as long non-coding and RNAsmicro RNAs. The consequence of RT significantly relies on the radiosensitivity of cancer cells, which is affected by multiple factors, including some proteins and cellular processes. Activation of these genes can cause cell cytotoxicity and indirectly damages the cells. Recent studies have shown that non-coding RNAs can play as radiosensitivity or radioinhibitory regulators in cancers by mechanisms such as cell cycle arrest or affecting the DNA damage repair systems. ncRNAs are also known to function as tumor suppressor genes or oncogenes in colorectal cancer and therefore are considered potential diagnostic biomarkers in disease detection. For example, the investigations have shown that miR-29a and miR-224 can be informative biomarkers for early detection or screening of CRC via a noninvasive method such as liquid biopsy. Here, we discuss ncRNAs involved in the radioresistance and radiosensitivity of CRC and highlight their predictive clinical value in response to RT. Accordingly, this review represents a principal guide in the context of three major types of ncRNAs with potential roles in the pathway of radiosensitivity and radioresistance, including miRNAs, lncRNAs, and circRNAs which can be considered a precious archivement in organizing additional studies and broadening views in this area. Our findings can also assist radiotherapists in predicting CRC patients' response and, therefore, prognosis to radiation therapy, although, to achieve our goals in the clinic, we certainly need further studies.

Dual impacts of mesenchymal stem cell-derived exosomes on cancer cells: unravelling complex interactions.

Mesenchymal stem cells (MSCs) are multipotent, self-renewing stromal cells found in a variety of adult tissues. MSCs possess a remarkable ability to migrate towards tumor sites, known as homing. This homing process is mediated by various factors, including chemokines, growth factors, and extracellular matrix components present in the tumor microenvironment. MSCs release extracellular vesicles known as exosomes (MSC-Exos), which have been suggested to serve a key role in mediating a wide variety of MSC activities. Through cell-cell communication, MSC-Exos have been shown to alter recipient cell phenotype or function and play as a novel cell-free alternative for MSC-based cell therapy. However, MSC recruitment to tumors allows for their interaction with cancer cells and subsequent regulation of tumor behavior. MSC-Exos act as tumor niche modulators via transferring exosomal contents, such as specific proteins or genetic materials, to the nearby cancer cells, leading to either promotion or suppression of tumorigenesis, angiogenesis, and metastasis, depending on the specific microenvironmental cues and recipient cell characteristics. Consequently, there is still a debate about the precise relationship between tumor cells and MSC-Exos, and it is unclear how MSC-Exos impacts tumor cells. Although the dysregulation of miRNAs is caused by the progression of cancer, they also play a direct role in either promoting or inhibiting tumor growth as they act as either oncogenes or tumor suppressors. The utilization of MSC-Exos may prove to be an effective method for restoring miRNA as a means of treating cancer. This review aimed to present the existing understanding of the impact that MSC-Exos could have on cancer. To begin with, we presented a brief explanation of exosomes, MSCs, and MSC-Exos. Following this, we delved into the impact of MSC-Exos on cancer growth, EMT, metastasis, angiogenesis, resistance to chemotherapy and radiotherapy, and modulation of the immune system. Opposing effects of mesenchymal stem cells-derived exosomes on cancer cells.

GLUL gene knockdown and restricted glucose level show synergistic inhibitory effect on the luminal subtype breast cancer MCF7 cells' proliferation and metastasis.

The glutamine synthetase path is one of the most important metabolic pathways in luminal breast cancer cells, which plays a critical role in supplying glutamine as an intermediate in the biosynthesis of amino acids and nucleotides. On the other hand, glycolysis and its dominant substrate, glucose, are the most critical players in cancer metabolism. Accordingly, targeting these two critical paths might be more efficient in luminal-type breast cancer treatment. MCF7 cells were cultivated in media containing 4.5, 2, and 1 g/L glucose to study its effects on GLUL (Glutamate Ammonia Ligase) expression. Followingly, high and low glucose cell cultures were transfected with 220 pM of siGLUL and incubated for 48 h at 37 ºC. The cell cycle progression and apoptosis were monitored and assessed by flow cytometry. Expression of GLUL, known as glutamine synthetase, was evaluated in mRNA and protein levels by qRT-PCR and western blotting, respectively. To examine the migration and invasion capacity of studied cells exploited from wound healing assay and subsequent expression studies of glutathione-S-transferase Mu3 (GSTM3) and alfa-enolase (ENO1). Expression of GLUL significantly decreased in cells cultured at lower glucose levels compared to those at higher glucose levels. siRNA-mediated knockdown of GLUL expression in low glucose cultures significantly reduced growth, proliferation, migration, and invasion of the MCF7 cells and enhanced their apoptosis compared to the controls. Based on the results, GLUL suppression down-regulated GSTM3, a main detoxifying enzyme, and up-regulated Bax. According to the role of glycolysis as a ROS suppressor, decreased amounts of glucose could be associated with increased ROS; it can be considered an efficient involved mechanism in this study. Also, increased expression of Bax could be attributable to mTOR/AKT inhibition following GLUL repression. In conclusion, utilizing GLUL and glycolysis inhibitors might be a more effective strategy in luminal-type breast cancer therapy. See also Figure 1(Fig. 1).

NRF2 Suppression Enhances the Susceptibility of Pancreatic Cancer Cells, Miapaca-2 to Paclitaxel.

Pancreatic cancer is one of the most deadly diseases, with a very high metastasis and low survival rate. High levels of NRF2 have been detected in numerous malignancies, including head, neck, lung, and colon cancers, promoting the expansion and survival of cancer cells and chemical resistance to stressful conditions and affecting the response to treatment. To evaluate the possibility that modulation of NRF2 expression could be effective in treating pancreatic cancer cells, we explored the effect of knockdown of the NRF2 gene by NRF2-specific siRNA and its influence in combination with paclitaxel on pancreatic cancer cells. Miapaca-2 cell line, due to the high expression of the NRF2 gene, was selected for this study. Then, Miapaca-2 cells in different groups were treated with NRF2 siRNA and paclitaxel separately and in combination. After that, cell viability was measured by MTT assay and apoptosis induction by Annexin V-FITC/PI staining test. Cell cycle and autophagy were examined by flow cytometry, and cell migration was assessed by wound-healing assay. Finally, the expression of genes involved in apoptosis, Bax, Caspase-3, Caspase-9, and genes related to migration pathway, MMP-2, and MMP-9 in different groups were measured using qRT-PCR. Combined use of NRF2-specific siRNA with paclitaxel significantly reduced NRF2 gene expression in pancreatic cancer cells. NRF2 siRNA transfection significantly reduced cell viability. In addition, paclitaxel combination therapy with NRF2 siRNA strengthens the anti-tumor effects, such as inhibiting cell migration and provoking apoptosis, and autophagy and the cell cycle arrest in the G2 phase. NRF2 suppression augmented the expression of Bax, Caspase-3, and Caspase-9 genes and lowered the expression of Bcl-2, MMP-2, and MMP-9 genes, which play crucial roles in the pathways of apoptosis and cell migration, respectively. NRF2 siRNA enhances the susceptibility of Miapaca-2 cells to paclitaxel in pancreatic cancer cells. Thereby, suppressing NRF2 in combination with paclitaxel can be a new and efficacious treatment approach in treating pancreatic cancer.

The siRNA-mediated knockdown of SNHG4 efficiently induced pro-apoptotic signaling and suppressed metastasis in SW1116 colorectal cancer cell line.

BACKGROUND: Long non-coding RNAs are broadly dysregulated in disease conditions, especially cancer, and are associated with tumor initiation, invasion, and overall survival. This study aimed to elucidate the expression level of Small Nucleolar RNA Host Gene 4 (SNHG4) lncRNA in colorectal cancer (CRC) and its effect on cell cycle progression, invasion, and death. METHODS AND RESULTS: We evaluated the expression level of SNHG4 in clinical samples, including CRC tissues, adenomatous colorectal polyps (ACP), and their marginals. SNHG4-silenced SW1116 cells were used to evaluate the cell viability, cycle arrest, invasion, and apoptosis using MTT assay, scratching, flow cytometry, and immunoblotting. We also predicted molecular networks related to the SNHG4 involvement in CRC development. Results showed that SNHG4 expresses in cancerous tissues significantly higher than in polyps and marginals. This overexpression discriminated CRC from marginals and ACP with a suitable prognostic potential. Silencing of SNHG4 arrested the cell cycle at S and G2 phases and promoted early apoptosis in SW1116. It affected the active form of MMP2 and prevented cell invasion. Sponging of miRNAs which promotes the choline metabolism is the probable mechanism of SNHG4 involvement in CRC. CONCLUSIONS: In conclusion, SNHG4 promotes CRC by dysregulating apoptosis and cell migration, and shows significant prognostic potential for CRC.

Effects of KISS1 structural polymorphism on the risk of polycystic ovary syndrome and reproductive hormones in Iraqi women who take metformin.

OBJECTIVE: To identify the effects of metformin and kisspeptin structural polymorphism on the risk of polycystic ovary syndrome (PCOS) in Iraqi women. METHODS: Samples were collected at the family planning center of Al-Hassan Teaching Hospital (infertility clinic), Iraq. Hormonal and hematological parameters were measured. Kisspeptin structural polymorphisms were analyzed by polymerase chain reaction using a conventional thermal cycler and Phyre2 predictions. Kisspeptin concentrations were assessed by an enzyme-linked immunosorbent assay. RESULTS: Follicle-stimulating hormone (FSH) was the only sex hormone that changed in women with PCOS after metformin treatment. FSH concentrations were significantly increased after therapy compared with before therapy (9.39 ± 2.1 vs 5.13 ± 1.53 IU/L). We found that a single nucleotide polymorphism substituting G to C was related to PCOS. The kisspeptin structural polymorphism showed that the C allele was related to low FSH concentrations after treatment (6.92 ± 2.2 IU/L to 5.34 ± 1.58 IU/L). Kisspeptin concentrations were significantly lower after metformin treatment than before metformin treatment (395.44 ± 67.83 vs 273.18 ± 42.98 ng/mL). CONCLUSION: A variation in the KISS1 gene or its protein structure may be involved in the development of PCOS. The response to metformin may be used as an indicator and could contribute to the early diagnosis and medical therapy of PCOS.

The Assessment of Cytotoxicity, Apoptosis Inducing Activity and Molecular Docking of a new Ciprofloxacin Derivative in Human Leukemic Cells.

The fluoroquinolone class of antibiotics includes derivatives of the drug ciprofloxacin. These substances have recently been advocated for the treatment of cancer. In the current study, we examined the cytotoxicity and apoptosis-inducing potential of a novel synthetic ciprofloxacin derivative in the human myeloid leukemia KG1-a cell line. With an IC50 of 25µM, this ciprofloxacin derivative, 7-(4-(2-(benzhydryloxy)-2-oxoethyl) piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4 dihydroquinoline-3- carboxylic acid (4-BHPCP), was an active drug. Through Hoechst 33,258 staining and Annexin V/PI double staining experiments, the apoptotic activity of the 4-BHPCP was assessed morphologically. Real-time quantitative PCR was used to assess changes in the expression level of certain apoptosis-related genes, including Bcl-2, Bax, and Survivin (qRT PCR). The results of the qRT PCR analysis demonstrated that 4-BHPCP promotes apoptosis in the KG1-a cell line by down-regulating Survivin and Bcl2, up-regulating Bax, and increasing the Bax/Bcl2 transcripts in a time-dependent manner. These results imply that this novel chemical may be a promising therapy option for acute myeloid leukemia.

Silencing tumor-intrinsic HHLA2 potentiates the anti-tumoral effect of paclitaxel on MG63 cells: Another side of immune checkpoint.

BACKGROUND: Osteosarcoma is common type of bone cancer; however, the prognosis of patients with metastatic osteosarcoma is poor. As a new inhibitory immune checkpoint molecule, HHLA2 is upregulated in osteosarcoma. Herein, we studied the significance of tumor-intrinsic HHLA2 in MG-63 growth. Also, we examined the influence of combined therapy of HHLA2 knockdown with paclitaxel on the apoptosis, cell cycle, migration, and stemness of MG-63 cells. METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was performed to study the half-maximal inhibitory concentration (IC50) of paclitaxel and the cytotoxicity of HHLA2-small interfering RNA (siRNA) on MG-63 cells. The apoptosis and cell cycle were analyzed using flow cytometry. The wound-healing and colony formation assays were conducted to investigate the effect of paclitaxel and HHLA2 knockdown on the migration and stemness of MG-63 cells, respectively. QRT-PCR was used to determine the Bax, caspase-3, and Bcl-2 mRNA expression levels. RESULTS: HHLA2 silencing has enhanced the chemosensitivity of MG-63 cells to paclitaxel. Besides, HHLA2 knockdown has increased the paclitaxel-induced cytotoxic effect on MG-63 cells. In terms of stimulating apoptosis, decreasing clonogenicity, halting the cell cycle at the sub G1 phase, and inhibiting migration, tumor-intrinsic HHLA2 silencing has increased these anti-tumor effects of paclitaxel on MG-63 cells. Besides, HHLA2 knockdown has potentiated paclitaxel-mediated Bcl-2 downregulation and paclitaxel-mediated caspase-3 and Bax upregulation in MG-63 cells. CONCLUSION: Tumor-intrinsic HHLA2 knockdown increases the anti-tumoral effect of paclitaxel on MG-63 cells and enhances the chemosensitivity of MG-63 cells to paclitaxel.

MSC-Derived exosomes suppress colorectal cancer cell proliferation and metastasis via miR-100/mTOR/miR-143 pathway.

Exosomes derived from mesenchymal stem cells (MSCs) are mostly responsible for the therapeutic effects of MSCs. To show the therapeutic effects of the human bone marrow MSC-derived exosomes (MSC-Exos) on colorectal cancer (CRC) and explore the molecular cross-talks between them, CRC cells were treated with the MSC-Exos. We found that MSC-Exos were enriched with miR-100 and miR-143, which effectively downregulated mTOR, Cyclin D1, K-RAS, HK2 while upregulated p-27 expression. All these effects were reversed by concurrent treatment with MSC-Exos and antagomiR-100, confirming that they were caused by exosomal transfer of miR-100 into recipient CRC cells. Moreover, exosomal miR-100 promoted endogenous miR-143 expression. The flow cytometry, MTT and trypan blue assays revealed that MSC-Exos could efficiently suppress proliferation and induce apoptosis of the CRC cells. Furthermore, wound healing, transwell migration and invasion assays confirmed their inhibitory effects on the migration and invasiveness of SW480 cells. We further confirmed these effects by analyzing the expression levels of epithelial to mesenchymal transition (EMT) factors and metastasis-related genes. Results showed that MSC-Exos significantly suppressed the expression of MMP2 and MMP9 (metastasis-related genes), SNAIL and TWIST (EMT-inducing transcription factors), Vimentin and N-cadherin (mesenchymal cell markers), whereas E-cadherin (epithelial cell marker) was remarkably up-regulated. Collectively, our data indicated that MSC-Exos could suppress proliferation, migration, invasion and metastasis while inducing the apoptosis of the CRC cells via miR-100/mTOR/miR-143 axis. Our findings highlight that MSC-Exo treatment as well as miR-100 restoration might be considered as potential therapeutic strategies for CRC.

Expression profiling of cancer-related long non-coding RNAs revealed upregulation and biomarker potential of HAR1B and JPX in colorectal cancer.

BACKGROUND: Aberrant expressions of long non-coding RNAs promote cancer development including colorectal cancer. Expression profiling of cancer-related lncRNAs may introduce new deregulated lncRNAs that might be recruited as novel platforms in diagnosis and therapy of CRC. METHODS AND RESULTS: In this study, we exploited the SBI Human LncProfiler qPCR Array to examine the expression pattern of 90 cancer-related lncRNAs in CRC samples. Among deregulated lncRNAs, HAR1B, JPX, and KRASP1- which were showed a significantly higher expression profile in aggressive CRC tumors- were selected for more validation. We found that HAR1B and JPX expression profiles may discriminate between adjacent, adenomatous colorectal polyps, and colorectal cancer samples. The area under the curve of near 0.7 and a sensitivity/specificity of more than 70.80%, respectively, claim a suitable cancer prognostic potential for these two lncRNAs, JPX and HAR1B. Further analysis revealed that HAR1B and JPX may contribute to CRC pathobiology through affecting the FOXO, ErbB, and Wnt/ß-catenin signaling pathways. CONCLUSIONS: Upregulated JPX and HAR1B lncRNAs may contribute to colorectal cancer pathobiology by affecting multiple cancer-related signaling pathways. They also potentially discriminate between CRC tumors, marginals, and adenomatous colorectal polyps.

Molecular evidences on anti-inflammatory, anticancer, and memory-boosting effects of frankincense.

Chemical diversity of natural products with drug-like features has attracted much attention from medicine to develop more safe and effective drugs. Their anti-inflammatory, antitumor, analgesic, and other therapeutic properties are sometimes more successful than chemical drugs in controlling disease due to fewer drug resistance and side effects and being more tolerable in a long time. Frankincense, the oleo gum resin extracted from the Boswellia species, contains some of these chemicals. The anti-inflammatory effect of its main ingredient, boswellic acid, has been traditionally used to treat many diseases, mainly those target memory functions. In this review, we have accumulated research evidence from the beneficial effect of Frankincense consumption in memory improvement and the prevention of inflammation and cancer. Besides, we have discussed the molecular pathways mediating the therapeutic effects of this natural supplement.

Expression of HOTAIR and MEG3 are negatively associated with H. pylori positive status in gastric cancer patients.

BACKGROUND: Chronic infection with Helicobacter pylori is one of the main causes of gastric cancer (GC). Besides, lncRNAs play crucial roles in cancer pathobiology including GC. Here we aimed to investigate the expression of MEG3 and HOTAIR in gastric cancer tissues and evaluate their association with the H. pylori status. MATERIALS AND METHODS: One hundred samples were obtained. Total RNA was extracted, cDNA was synthesized and expression of MEG3 and HOTAIR was assessed using qRT-PCR. Association of their expression with H. pylori status and other clinicopathological characteristics were investigated. Furthermore, sensitivity and specificity of the MEG3 and HOTAIR expression levels for discrimination of the tumor and non-tumor samples were evaluated by Receiver operating characteristic (ROC) curve analysis. RESULTS: We observed upregulation of HOTAIR but downregulation of MEG3 in tumor compared to the non-tumor tissues. We also found a significant negative association between their expression levels and H. pylori positive status. However, only the expression level of HOTAIR was significantly associated with the size and stage of the tumor (P < 0.05). The ROC curve analysis revealed that the expression levels of MEG3 and HOTAIR might discriminate GC tumor and non-tumor tissues. CONCLUSIONS: In conclusion, this study revealed a negative association between H. pylori infection and expression of MEG3 and HOTAIR. The results suggested that the expression level of these lncRNAs might be considered as potential biomarkers for GC.

Aberrant expression of lncRNAs SNHG6, TRPM2-AS1, MIR4435-2HG, and hypomethylation of TRPM2-AS1 promoter in colorectal cancer.

Accumulating evidence has indicated that deregulation of lncRNAs plays essential roles in colorectal cancer (CRC) carcinogenesis. The goal of this study was to analyze the expression of lncRNAs in colorectal cancer and their association with clinicopathological variables. Bioinformatics analysis of published CRC microarray data was performed to identify the important lncRNAs. The expression levels of candidate genes were assessed in the human colon cancer/normal cell lines, CRC, adenomatous colorectal polyps, and their marginal tissues by qRT-PCR. Moreover, the methylation status of the TRPM2-AS1 promoter was studied using qMSP assay. Furthermore, we investigated the molecular mechanisms of these lncRNAs in CRC progression using in silico analysis. Microarray analysis revealed that lncRNAs SNHG6, MIR4435-2HG, and TRPM2-AS1 were upregulated in CRC. These results were validated in colon cell lines. Moreover, qRT-PCR showed that the expression levels of SNHG6 and TRPM2-AS1 were upregulated in the colorectal tumor tissues compared with their paired tissues. Nonetheless, there was no significant increase in MIR4435-2HG expression in CRC samples. Furthermore, we observed a significant hypomethylation of TRPM2-AS1 promoter and its activation in CRC tissues. By in silico analysis, we found that the lncRNAs upregulation could promote proliferation and drug resistance of colorectal cancer cells via miRNAs sponging and modulation of their targets expression. In conclusion, based on our results upregulation of SNHG6 and TRPM2-AS1, and hypomethylation of TRPM2-AS1 promoter might be considered as potential diagnostic biomarkers for CRC initiation and development.