LncRNAs-Regulated High Expression of LAMC2 Reveals a Prognostic and Immunological Value in Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is one of the most hazardous cancers in digestive system, and the prognosis is notoriously bad. Increasing evidences indicate that Laminin Subunit Gamma 2 (LAMC2) is critical for the initiation and the growth of various sorts of human cancers. However, the involved molecular pathways of LAMC2 in PAAD are still poorly understood. In this study, prediction programs and databases were employed to conduct pan-cancer analysis. Multiple variations of human malignancies showed increased LAMC2 expression, which was positively correlated to a poor prognosis in PAAD. Moreover, LAMC2 was positively correlated with the biomarkers of immune cells including CD19, CD163, and NOS2 in PAAD. The lncRNA C5orf66 /PTPRG-AS1- miR-128-3p -LAMC2 axis was identified to be a potential upstream regulatory pathway of LAMC2 in PAAD. Furthermore, LAMC2 upregulation in PAAD was associated with PD-L1 expression, indicating promoting carcinoma immune cell infiltration. Our study elucidated prognostic and immunological values of LAMC2 in PAAD, providing a promise target for PAAD treatment.

A Ratiometric Gene-Switch System for miRNA Sensing and Gene Regulation.

microRNAs (miRNAs) are a class of non-coding, small RNAs that play an important role in diverse biological processes and diseases. By regulating the expression of eukaryotic genes post-transcriptionally in a sequence-specific manner, miRNAs are widely used to design synthetic RNA switches. However, most of the RNA switches are often dependent on the corresponding ligand molecules, whose specificity and concentration would affect the efficiency of synthetic RNA circuits. Here, a fused transcriptional repressor Gal4BD-Rluc based gene-switch system Gal-miR for miRNA visualization and gene regulation is described. By placing a luciferase downstream gene under the control of endogenous miRNA machinery, the Gal-miR system makes the conversion of miRNA-mediated gene silencing into a ratiometric bioluminescent signal, which quantitatively reflected miRNA-206 activity during myogenic differentiation. Moreover, it demonstrates that this gene-switch system can effectively inhibit breast cancer cell viability, migration and invasion under the control of specific miRNAs by replacing the downstream gene with melittin functional gene. The study proposes a powerful modular genetic design for achieving precise control of transgene expression in a miRNA responsive way, as well as visualizing the dynamics of miRNA activity.

Characteristics and risk factors for advanced lung cancer with pulmonary embolism: A cross-sectional, case-control study.

OBJECTIVES: Pulmonary embolism (PE) is a life-threatening complication that can occur in patients with lung cancer. In this study, we aimed to identify risk factors and examine the clinical characteristics of advanced lung cancer patients with PE. METHODS: We conducted a retrospective review of patients admitted to our two hospitals between January 2020 and June 2022. The case group consisted of patients with lung cancer and PE, and a closely matched control group was included to identify risk factors. Statistical analysis was conducted using R language. RESULTS: A total of 4957 patients were reviewed, and 162 patients (comprising 54 cases and 108 controls) were included in this study. The prevalence of lung cancer with PE in the study population was 1.08%. The majority of patients were male, and the most common histological subtype was adenocarcinoma (67%), followed by squamous cell carcinoma, small cell carcinoma, and poorly differentiated non-small cell lung cancer. The majority of patients had a high performance status (PS) score, with 50% experiencing respiratory failure (mainly hypoxia) and 33% with deep vein thrombosis (DVT). Forty-eight percent of patients were diagnosed with concurrent PE. Further analysis showed that PE was an independent predictor of poor survival, and a PS score of >1 was an independent risk factor for PE in patients with lung cancer. CONCLUSION: Our study provides valuable insights into the epidemiology and prognosis of PE in lung cancer patients and suggests that a poor ECOG PS, which has not been previously reported, is an independent risk factor for PE.

Exploration of pyroptosis-associated prognostic gene signature and lncRNA regulatory network in ovarian cancer.

Ovarian cancer (OC), is a tumor that poses a serious threat to women's health due to its high mortality rate and bleak prognosis. Pyroptosis, a type of programmed cell death, is important for determining the prognosis of a patient's prognosis for cancer and may represent a novel target for treatment. However, research into how prognosis is impacted by pyroptosis-related genes (PRGs) is poorly understood. In this study, a prognostic model was created using bioinformatic analysis of PRGs in OC. In OC, we discovered 18 pyroptosis regulators that were either up- or down-regulated. By analyzing prognoses, we developed a 9-genes based prognostic model. Each OC patient received a risk score that could be used to categorize them into two subgroups: those with high risk and/or low chance of survival and those with low risk and/or high chance of survival. Functional enrichment and immunoinfiltration analysis indicated that low expression of immune pathways in high-risk group may account for the decrease of survival possibility. In Multivariable cox regression studies, age, clinical stage and the prognostic model were discovered to be independent factors impacting the prognosis for OC. To forecast OC patient survival, a predictive nomogram was developed. Furthermore, we found a correlation between predictive PRGs and clinical stage, indicating that AIM2, CASP3, ZBP1 and CASP8 may play a role in the growth of tumor in OC. After detailed and complete bioinformatics analysis, the lncRNA RP11-186B7.4/hsa-miR-449a/CASP8/AIM2/ZBP1 regulatory axis was identified in OC. Our study may provide a novel approach for prognostic biomarkers and therapeutic targets of OC.

POLRMT over-expression is linked to WNT/beta-catenin signaling, immune infiltration, and unfavorable outcomes in lung adenocarcinoma patients.

BACKGROUND: Mitochondrial RNA polymerase (POLRMT) is essential for the expression of mitochondrial genes. In recent studies, POLRMT expression promoted non-small cell cancer cell proliferation in cell lines and xenografts. The present study investigated the impact of POLRMT expression and function on lung adenocarcinoma (LUAD) patients. METHOD: Multi-omics data (genomics, transcriptomics, and proteomics) from publicly available databases were used to assess the role of POLRMT expression and function in LUAD. These findings were further verified using cancer tissues from clinical samples. RESULTS: POLRMT was over-expressed in LUADs, with mutation frequencies ranging from 1.30% to 5.71%. Over-expression of POLRMT was associated with an abnormal clinicopathological condition resulting in a decreased lifespan. Furthermore, gene sets enrich analysis revealed that POLRMT expression was linked to WNT/beta-catenin signaling; the expression of downstream target genes was positively correlated with POLRMT expression. Also, POLRMT expression was positively correlated with immunosuppressive genes, thereby affecting immune infiltration. CONCLUSION: POLRMT is over-expressed in LUAD, thereby impacting patient survival. It is also involved in WNT/beta-catenin signaling and may affect tumor infiltration.

Recycling Spent Lithium-Ion Batteries Using Waste Benzene-Containing Plastics: Synergetic Thermal Reduction and Benzene Decomposition.

Spent lithium-ion batteries (LIBs) and benzene-containing polymers (BCPs) are two major pollutants that cause serious environmental burdens. Herein, spent LIBs and BCPs are copyrolyzed in a sealed reactor to generate Li2CO3, metals, and/or metal oxides without emitting toxic benzene-based gases. The use of a closed reactor allows the sufficient reduction reaction between the BCP-derived polycyclic aromatic hydrocarbon (PAH) gases and lithium transition metal oxides, achieving the Li recovery efficiencies of 98.3, 99.9, and 97.5% for LiCoO2, LiMn2O4, and LiNi0.6Co0.2Mn0.2O2, respectively. More importantly, the thermal decomposition of PAHs (e.g., phenol and benzene) is further catalyzed by the in situ generated Co, Ni, and MnO2 particles, which forms metal/carbon composites and thus prevent the emissions of toxic gases. Overall, the copyrolysis in a closed system paves a green way to synergistically recycle spent LIBs and handle waste BCPs.

Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia.

Transient receptor potential vanilloid 1 (TRPV1) ion channel is a classic analgesic target, but antagonists of TRPV1 failed in clinical trials due to their side effects like hyperthermia. Here we rationally engineer a peptide s-RhTx as a positive allosteric modulator (PAM) of TRPV1. Patch-clamp recordings demonstrate s-RhTx selectively potentiated TRPV1 activation. s-RhTx also slows down capsaicin-induced desensitization of TRPV1 in the presence of calcium to cause more calcium influx in TRPV1-expressing cells. In addition, our thermodynamic mutant cycle analysis shows that E652 in TRPV1 outer pore specifically interacts with R12 and K22 in s-RhTx. Furthermore, we demonstrate in vivo that s-RhTx exhibits long-lasting analgesic effects in noxious heat hyperalgesia and CFA-induced chronic inflammatory pain by promoting the reversible degeneration of intra-epidermal nerve fiber (IENF) expressing TRPV1 channels in mice, while their body temperature remains unaffected. Our results suggest s-RhTx is an analgesic agent as a PAM of TRPV1.

Dysregulation of Pseudogenes/lncRNA-Hsa-miR-1-3p-PAICS Pathway Promotes the Development of NSCLC.

Objective: Non-small cell lung cancer (NSCLC) explains about 80 percent of whole lung cancers, and its 5-year survival rate is impoverished, as when people are first diagnosed, 68% of whom are identified at a dangerous stage. The molecular mechanisms of NSCLC are still being explored. Methods: GSE18842 and GSE19804 were exerted to scan for diversely expressed genes (DEGs) in NSCLC, and then we used GEPIA for the validation of DEGs expression. The prognostic values were determined through Kaplan-Meier analysis. Three target prediction databases indicated potential microRNAs (miRNAs), while miRNet predicted hsa-miR-1-3p's upstream long non-coding RNAs (lncRNAs) and pseudogenes. UALCAN was utilized to identify the co-expressed genes of PAICS, while enrichment analysis on them was managed with Enrichr. Results: We initially found that the gene expression level of cyclin B1 (CCNB1), cyclin-dependent kinases1 (CDK1), and phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) had a notable increase in NSCLC. We predicted 6, 10, and 7 microRNAs to target CCNB1, CDK1, and PAICS, respectively. Among miRNA-mRNA (microRNA-messenger RNA) pairs, we deduced that the hsa-miR-1-PAICS axis was the most potential one to inhibit the occurrence of NSCLC. We also noted that the hsa-miR-1-3p-PAICS axis participated in regulating the process of mitosis with mechanical functions. Moreover, we identified 5 pseudogenes and 33 long non-coding RNAs (lncRNAs) that might inhibit the hsa-miR-1-3p-PAICS axis in NSCLC. Conclusions: The pseudogene/lncRNA-hsa-miR-1-3p-PAICS is very important in NSCLC on the basis of this study, thus providing us with effective treatments and promising biomarkers for the diagnosis of NSCLC.

Optimized Reconstruction Procedure of Photoacoustic Imaging for Reflection Artifacts Reduction.

Photoacoustic (PA) imaging technology is of some value in medical diagnoses such as breast cancer detection, vasculature imaging, and surgery navigating. While as most imaging objects are bounded, the received RF signals consist of the direct-arrived signals (DAS) from the PA sources and the boundary-reflected signals (BRS). The undesired BRS will severely impair the quality during the image reconstruction. They will bring in many artifacts and confuse the actual shape and location of the PA sources. We improved the reconstruction procedure by removing the BRS before the regular reconstruction process to suppress those artifacts. To verify our proposed method, we compared the results of the conventional and optimized procedures experimentally. In terms of qualitative observation, the reconstructed images by the optimized procedure illustrate fewer artifacts and more accurate shapes of the PA sources. To quantitatively evaluate the traditional and the optimized imaging procedure, we calculated the Distribution Relative Error (DRE) between each experiment result and its standard drawing of the phantoms. For both phantoms and the ex-vivo sample, the DREs of reconstruction result by the optimized reconstruction procedure decrease significantly. The results suggest that the optimized reconstruction process can effectively suppress the reflection artifacts and improve the shape accuracy of the PA sources.

Single and combined 1064 nm Q-switched Nd: YAG laser therapy in melasma: A meta-analysis.

PURPOSE: This article attempted to describe the efficacy and safety of 1064QNYL in combination with other treatments for refractory melasma. METHODS: Two researchers independently retrieved randomized controlled trials (RCTs) according to inclusion and exclusion criteria. Primary outcome was evaluated with MASI and mMASI scores in control group and experiment group. The secondary outcome was evaluated with MI scores. We calculated 95% CI of standardized mean difference (SMD) and heterogeneity of the included literature by Higgins I2 test, and assessed publication bias by Funnel plots, Egger's, and Begg's tests. RESULTS: A total of 12 articles including 322 subjects were analyzed. Experiment group was treated with 1064QNYL combined with single treatment (e.g., PDL, IPL, RF, and TA). Control group was treated with 1064QNYL alone. A greater reduction of Melasma Area and Severity Index (MASI)/modified Melasma Area and Severity Index (mMASI) scores were shown in experiment group than that in control group at the end of the treatment (SMD, -0.37; 95% CI -0.70 to -0.04, p = 0.03, I2  = 33%). The SMD of MI scores further supported this conclusion by -0.32 (95% CI -0.63 to -0.02, p = 0.04, I2  = 27%). As for adverse events (AEs), combined treatment gave rise to more mild burning, stinging, and erythema that resolved spontaneously. Several studies reported focal purpura, punctate leukoderma, hyperpigmentation, hypopigmentation, and so on. CONCLUSION: Combined 1064QNYL treatment was better than single laser treatment, with the highest short-term benefit and long-term follow-up to maintain the effect in favor of combined treatment.

Intermediate risk pulmonary embolism concomitant with or without lung cancer: a wide spectrum of features.

OBJECTIVES: We aimed to investigate the differences in clinical features between pulmonary embolism (PE) patients concomitant with lung cancer and without lung cancer (LC) and gain further understanding of the impact of lung cancer on pulmonary embolism. METHODS: This retrospective study sampled 114 patients diagnosed with pulmonary embolism from January 2017 to April 2021 in the First Affiliated Hospital of Soochow University. The patients were categorized into the LC group (n = 22) or non-LC group (n = 92). Myocardial injury, coagulation and blood cell parameters, along with imaging findings, were analyzed for the two groups. The primary outcome measure was the 90-day mortality. RESULTS: Of the 114 patients with pulmonary embolism in the present study, the 90 intermediate-risk patients were enrolled for further investigations. Compared to the non-LC group, patients in the LC group had milder myocardial injury, more severe coagulation function disorder, a higher incidence of central PE and a smaller change in diameter of the main pulmonary artery. We found that the occurrence of pericardial effusion created the risk of lung cancer in patients with pulmonary embolism, but there was no increase in the 90-day mortality for non-LC group versus LC group. CONCLUSION: Intermediate risk PE patients concomitant with lung cancer seem to be more likely to present specific clinical features, accordingly, clinicians must pay great attention to PE patients concomitant with lung cancer and implement effective treatments to simultaneously manage the two conditions.

High Expression of MicroRNA-200a/b Indicates Potential Diagnostic and Prognostic Biomarkers in Epithelial Ovarian Cancer.

Objective: To detect the expression levels of microRNA-200a/b (miR-200a/b) in tumor tissues and serum of patients with epithelial ovarian cancer (EOC) and to explore its clinical significance. Methods: A retrospective selection of 30 cases of benign ovarian disease or healthy physical examination (control group) and 55 cases of EOC patients. Real-time quantitative PCR was used to detect the expression level of miR-200a/b in tumor tissues and serum, and the miR-200a/b expresses relevance in the two types of samples were evaluated at the same time. Receiver operating characteristic curve (ROC) and Kaplan-Meier survival analysis were used to evaluate the diagnostic value of miR-200a/b expression and its influence on prognosis, respectively. Results: The serum and tissue miR-200a/b expression levels in EOC patients were higher than those in the control group (P < 0.001), and there was a significant positive correlation between serum and tissue miR-200a/b expression (R 2 = 0.9419, P < 0.001 and R 2 = 0.9605, P < 0.001). ROC analysis showed that the expression of serum miR-200a/b can distinguish EOC patients from the control group. In addition, there were significant differences in the TNM stage, tumor differentiation, and lymph node metastasis between the miR-200a/b high- and low-expression groups (P < 0.05). Kaplan-Meier survival analysis found that the overall survival and disease-free survival of patients with high miR-200a/b expression were shorter than those of patients with low miR-200a/b expression (P < 0.05). Conclusion: Upregulation of miR-200a/b expression is a common molecular event in EOC patients, and miR-200a/b can be used as a noninvasive biomarker for the diagnosis and prognosis of EOC.

Empathetic nursing with mindful cognitive therapy for fatigue, depression, and negative emotions in leukemia patients undergoing long-term chemotherapy.

BACKGROUND: Leukemia is a broad term for blood cell cancer. Leukemia is divided into acute or chronic, depending on cell differentiation. Leukemia patients are prone to adverse reactions during chemotherapy, such as anxiety, depression, and even suicide, affecting prognosis. As a nursing model developed by three well-known cognitive psychologists, empathetic nursing with mindfulness cognitive therapy (ENMCT) can effectively reduce anxiety and depression and improve the quality of life in patients with chronic disease. AIM: To explore the effect of ENMCT on cancer-induced fatigue, hope level, and negative emotions in patients with long-term leukemia chemotherapy. METHODS: A total of 103 patients with long-term leukemia chemotherapy diagnosed and treated in our hospital from July 2017 to October 2019 were enrolled and randomly assigned to observation and control groups using the random number table approach. Fifty-one patients in the control group received routine nursing, while 52 patients in the observation group received empathic nursing with mindfulness cognitive therapy. After three months of nursing care, cancer-induced fatigue was measured with the Piper Fatigue Scale (PFS), hope level with the Herth Hope Index (HHI), and negative emotion with the Hamilton Anxiety Scale (HAMA)/Hamilton Depression Scale (HAMD). Self-management (Chinese Strategies Used by People to Promote Health) was also recorded. RESULTS: The observation group's total scores in behavior, cognition, emotion, feeling, and PFS were lower than the control group after the intervention (P < 0.05). Keeping close contact with others, the attitude of taking positive actions, the attitude toward reality and future, and the total HHI score were higher in the observation group than the control group (P < 0.05). The observation group's HAMA and HAMD scores were lower than the control group (P < 0.05). The observation group's positive attitude, self-decision, and self-relief scores were greater than the control group (P < 0.05). CONCLUSION: Empathetic nursing with cognitive mindfulness therapy is beneficial in improving cancer-related fatigue, negative emotions, expectation level, and self-management ability in patients with long-term leukemia chemotherapy.

Establishment and Comprehensive Analysis of Underlying microRNA-mRNA Interactive Networks in Ovarian Cancer.

Background: The rate of ovarian cancer (OC) is one of the highest in women's reproductive systems. An improperly expressed microRNA (miRNA) has been discovered to have a vital role in the pathophysiology of OC. However, more research into OC's miRNA-message RNA (mRNA) gene interaction network is required. Methods: Firstly, the microarray data sets GSE25405 and GSE119055 from the GEO (Gene Expression Omnibus) database were downloaded and then analyzed with the GEO2R tool aiming at identifying DEMs (differential expressed miRNAs) between ovarian malignant tissue and ovarian normal tissue. The whole consistently changed miRNAs were then screened out to be candidate DEMs. For estimating underlying upstream transcription factors, FunRich was employed. miRNet was utilized to determine putative DEMs' downstream target genes. The R program was then used to do the GO annotation as well as the analysis of KEGG pathway enrichment for target genes. The PPI (protein-protein interaction), as well as the DEM-hub gene networks, were created by the Cytoscape software and STRING database. Finally, we chose the GSE74448 dataset to test the precision of hub gene expressions. Results: We have screened out six (five upregulated and one downregulated) DEMs. The majority of upregulated and downregulated DEMs are likely regulated by SP1 (specificity protein 1). SP4 (s protein 4), POU2F1 (POU class 2 homeobox 1), MEF2A (myocyte-specific enhancer factor 2A), ARID3A (AT-rich interaction domain 3A), and EGR1 (early growth response 1) can regulate upregulated and downregulated DEMs. We have found 807 target genes (656 upregulated and 151 downregulated DEM), being generally enriched in focal adhesion and proteoglycans in cancer, gastric cancer, hepatocellular carcinoma, as well as breast cancer. The majority of hub genes are projected to be controlled by hsa-miR-429, hsa-miR-140-5p, hsa-miR-199a-5p, and hsa-miR-199a-3p after the DEM-hub gene network was built. VEGFA (vascular endothelial growth factor A), EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), and HIF1A (hypoxia inducible factor 1 subunit alpha) expressions are consistent with the GSE74448 dataset in the first 18 hub genes. Conclusion: We have built an underlying miRNA-mRNA interacting network in OC, giving us unparalleled insight into the disease's diagnosis and treatment.

The role of FOLFIRINOX in metastatic pancreatic cancer: a meta-analysis.

BACKGROUND: The prognosis of pancreatic cancer (PC) is extremely poor, and most patients with metastatic PC still receive palliative care. Here, we report the efficacy and safety of FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, 5-fluorouracil) in the treatment of metastatic PC. METHODS: We searched PubMed, Web of Science, EBSCO, and Cochrane library databases for articles that described efficacy and safety of FOLFIRINOX in patients with metastatic PC, from January 1996 to July 2020. The primary outcomes targeted included overall survival (OS) and progression-free survival (PFS). RESULTS: We found that FOLFIRINOX could directly improve OS rate of patients with metastatic PC (HR 0.76, 95% Cl 0.67-0.86, p<0.001) but had no benefit on PFS. Results from subgroup analyses showed that FOLFIRINOX had superior benefits than monochemotherapy (HR 0.59, 95% Cl 0.52-0.67, p<0.001), followed by FOLFIRINOX versus combination chemotherapy (HR 0.76, 95% Cl 0.61-0.95, p<0.001). The result of FOLFIRINOX versus nab-paclitaxel + gemcitabine had no benefit (HR 0.91, 95% Cl 0.82-1.02, p>0.05). The main adverse events (AEs) targeted hematological toxicity and the gastrointestinal system, and included febrile neutropenia, a reduction in white blood cells and appetite, as well as diarrhea. CONCLUSION: These findings indicated that FOLFIRINOX has potential benefits for the prognosis of patients with metastatic PC. Furthermore, there is no difference between the regimen of FOLFIRINOX and nab-paclitaxel + gemcitabine in this study. The application of FOLFIRINOX should be according to the actual situation of the patients and the experience of the doctors.

Identification and characterization of a subpopulation of CD133+ cancer stem-like cells derived from SK-UT-1 cells.

BACKGROUND: Uterine leiomyosarcoma (ULMS) is a malignant tumor found in the smooth muscle lining the walls of the uterus. Cancer stem cells (CSCs) are responsible for metastasis, drug resistance, and relapse of cancer, resulting in treatment failure. However, little is known about CSCs and their associated-markers in ULMS. We aimed to characterize and identify a subpopulation of CD133+ cancer stem-like cells derived from SK-UT-1 cell line. METHODS: SK-UT-1 cells were sphere-forming cultured in vitro. We also sorted the CD133+ cells derived from SK-UT-1 cell line by immunomagnetic beads. CD133+ subpopulation and apoptotic cells were detected by flow cytometry. Self-renewal and anchorage-independent growth capabilities were examined using sphere and colony formation assays. The tumorigenicity of the fourth-passage spheres and parental SK-UT-1 cells was used by mouse xenograft model in vivo. Cell proliferation ability and sensitivity to doxorubicin (DXR) were assessed by CCK-8 assay. Cell migration and invasion were tested by wound healing assay or Transwell migration and invasion assays. Expressions of CSC-related marker were analyzed by Western blotting. RESULTS: The fourth-passage spheres were defined as a CD133+ cell population, which was accompanied by increase of sphere and colony forming rate, migration and invasion abilities, as well as drug-resistant properties in vitro. Moreover, the fourth-passage spheres showed a stronger tumorigenic potential in vivo. CD133+ cell population sorted from SK-UT-1 line showed an increased ability in sphere and colony formation, proliferation, migration, invasion, resistance to apoptosis after treatment with doxorubicin (DXR) compared with CD133- cell population. The expression levels of CSCs-related markers (e.g., CD44, ALDH1,BMI1, and Nanog), were significantly elevated in CD133+ cells compared with those in CD133- cells. CONCLUSIONS: Collectively, our findings indicated that CD133 may be a significant marker for cancer stem-like cells, and it may be a potential therapeutic target for human ULMS.

The mRNA of TCTP functions as a sponge to maintain homeostasis of TCTP protein levels in hepatocellular carcinoma.

Translationally controlled tumor protein (TCTP) is a highly conserved protein that accumulated in the tumorigenesis of various malignancies. Despite the important role of TCTP protein in tumor progression, the precise function and underlying mechanistic regulation of TCTP mRNA in hepatocellular carcinoma (HCC) remain unclear. In this study, we found that TCTP protein was overexpressed in HCC patients but TCTP mRNA expression levels were reversed. TCTP knockout HCC cells exhibited attenuated abilities of proliferation, migration, and invasion. The knockdown of TCTP by siRNA effectively reduced TCTP mRNA levels but not protein levels in HCC cells. Moreover, although the constitutive knockdown of TCTP inhibited almost 80% of TCTP protein expression levels in tumors of wildtype transgenic mice (TCTP KD/WT), partial restoration of TCTP protein expression was observed in the tumors of heterozygous TCTP mice (TCTP KD/TCTP±). The blockage of mRNA synthesis with ActD stimulated TCTP protein expression in HCC cells. In contrast, combined treatment with ActD and CHX or MG132 treatment alone did not lead to the TCTP protein accumulation in cells. Furthermore, following the introduction of exogenous TCTP in cells and orthotopic HCC tumor models, the endogenous TCTP protein did not change with the recombinational TCTP expression and kept a rather stable level. Dual-luciferase assays revealed that the coding sequence of TCTP mRNA functions as a sponge to regulate the TCTP protein expression. Collectively, our results indicated that the TCTP mRNA and protein formed a closed regulatory circuit and works as a buffering system to keep the homeostasis of TCTP protein levels in HCC.

Targeting miRNAs by natural products: A new way for cancer therapy.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through mRNA degradation or translation inhibition. MiRNAs play important roles in a variety of biological processes, and dysregulation of miRNA expression is highly associated with cancer development. Individual miRNA regulates multiple gene expressions, enabling them to regulate multiple cellular signaling pathways simultaneously. Hence, miRNAs could be served as cancer biomarkers for diagnosis and prognosis, and also therapeutic targets. Recently, more and more evidences showed that natural products such as paclitaxel, curcumin, resveratrol, genistein or epigallocatechin-3-gallate exert their anti-proliferative and/or pro-apoptotic effects through regulating one or more miRNAs, leading to the inhibition of cancer cell growth, induction of apoptosis or enhancement of conventional cancer therapeutic efficacy. Herein, we outlined the recent advances in the regulation of miRNAs expression by the natural products and highlight the importance of these natural drugs as a potential strategy in cancer treatment. This review will help us better understand how natural products modulate miRNAs and contribute to the development of effective and safe natural drugs for therapeutic purposes.

p53-dependent upregulation of miR-16-2 by sanguinarine induces cell cycle arrest and apoptosis in hepatocellular carcinoma.

MicroRNAs (miRNAs) were involved in cancer progression, and the targeting of miRNAs by natural agents has opened avenues for cancer treatment and drug development. miR-16 functions as a tumor suppressor and is frequently deleted or downregulated in various human cancers, including hepatocellular carcinoma (HCC). In the present study, we employed a miR-16-responsive luciferase reporter to screen candidate compounds that modulate miR-16 expression from a natural product library. One compound, sanguinarine (SG), was capable of activating miR-16 in HCC cells with wildtype or mutated p53 expression but not in p53-deleted HCC cells. Mechanistic investigations revealed that SG increased p53 occupancy on the miR-16-2 promoter and decreased the expression of miR-16 target genes, including Bcl-2 and cyclin D1. Moreover, SG significantly inhibited HCC cell proliferation in a p53-dependent manner by inducing cell cycle arrest and reactive oxygen species (ROS)-associated apoptosis. Silencing miR-16 by treatment with anti-miR16 miRNA inhibitors rescued the cell viability repression effect caused by SG. Importantly, SG dramatically suppressed tumor growth in an HCC xenograft model, with little cytotoxicity. Taken together, our results provide a preclinical proof-of-concept for SG as a potential strategy for HCC treatment based on the restoration of miR-16 tumor suppressor function.

PAI-1/PIAS3/Stat3/miR-34a forms a positive feedback loop to promote EMT-mediated metastasis through Stat3 signaling in Non-small cell lung cancer.

AIM: This study intented to clarify the intracellular effect of PAI-1 on Non-small cell lung cancer (NSCLC) metastasis and the precise mechanism involved. METHODS: The metastatic properties of NSCLC cells were determined by transwell assays and wound-healing assay in vitro. The mRNA and protein expressions of genes were analyzed by Real-time qPCR and western blot, respectively. Pulmonary metastasis model of NSCLC cells was established to evaluate the pro-metastasis effect of PAI-1 and anti-metastatic effect of miR-34a in vivo. The gene targets of miR-34a were confirmed by luciferase reporter assays. Chromatin immunoprecipitation assay was employed to detect the transcriptional regulation of miR-34a. Co-immunoprecipitation assay was performed to observe the interaction of proteins. RESULTS: PAI-1, which was elevated in NSCLC patients with recurrence and metastasis, augmented NSCLC metastasis and was negatively related to the prognosis of NSCLC. miR-34a, which was decreased in NSCLC patients with metastasis, attenuated NSCLC metastasis and was positively correlated with the prognosis of NSCLC. Moreover, PAI-1 was identified as the target gene of miR-34a and activated the Stat3 signaling pathway to promote epithelial-mesenchymal transition (EMT) in NSCLC cells. PAI-1 interacted with PIAS3 to regulate Stat3-dependent gene expression and miR-34a was transcriptionally suppressed by Stat3 to form a positive regulatory loop through Stat3 signaling. CONCLUSION: Our findings suggest that PAI-1 and miR-34a, which can be clinically utilized as biomarkers for the clinical prognosis or diagnosis of NSCLC, are potential targets for the treatment of NSCLC.