Medicarpin suppresses lung cancer cell growth in vitro and in vivo by inducing cell apoptosis.

Lung cancer (LC) is the leading cause of cancer deaths worldwide. Surgery, chemoradiotherapy, targeted therapy, and immunotherapy are considered dominant treatment strategies for LC in the clinic. However, drug resistance and meta-stasis are two major challenges in cancer therapies. Medicarpin (MED) is an isoflavone compound isolated from alfalfa, which is usually used in traditional medicine. This study was de sig ned to evaluate the anti-LC effect and reveal the underlying mechanisms of MED in vivo and in vitro. We found that MED could significantly inhibit proliferation, induce apoptosis, and cell cycle arrest of A549 and H157 cell lines. Basically, MED induced cell apoptosis of LC cells by upregu lating the expression of pro-apoptotic proteins BAX and Bak1, leading to the cleavage of caspase-3 (Casp3). Moreover, MED inhibited the proliferation of LC cells via downregulating the expression of proliferative protein Bid. Overall, MED inhibited LC cell growth in vitro and in vivo via suppressing cell proliferation and inducing cell apoptosis, suggesting the therapeutic potential of MED in treating LC.

A negative feedback loop between KLF9 and the EMT program dictates metastasis of hepatocellular carcinoma.

Metastasis is the primary cause of death of hepatocellular carcinoma (HCC), while the mechanism underlying this severe disease remains largely unclear. The Kruppel-like factor (KLF) family is one of the largest transcription factor families that control multiple physiologic and pathologic processes by governing the cellular transcriptome. To identify metastatic regulators of HCC, we conducted gene expression profiling on the MHCC97 cell series, a set of subclones of the original MHCC97 that was established by in vivo metastasis selection therefore harbouring differential metastatic capacities. We found that the expression of KLF9, a member of the KLF family, was dramatically repressed in the metastatic progeny clone of the MHCC97 cells. Functional studies revealed overexpression of KLF9 suppressed HCC migration in vitro and metastasis in vivo, while knockdown of KLF9 was sufficient to promote cell migration and metastasis accordingly. Mechanistically, we found the expression of KLF9 can reverse the pro-metastatic epithelial-mesenchymal transition (EMT) program via direct binding to the promoter regions of essential mesenchymal genes, thus repressing their expression. Interestingly, we further revealed that KLF9 was, in turn, directly suppressed by a mesenchymal transcription factor Slug, suggesting an intriguing negative feedback loop between KLF9 and the EMT program. Using clinical samples, we found that KLF9 was not only downregulated in HCC tissue compared to its normal counterparts but also further reduced in the HCC samples of whom had developed metastatic lesions. Together, we established a critical transcription factor that represses HCC metastasis, which is clinically and mechanically significant in HCC therapies.

Identification of key immune genes related to lymphatic metastasis of papillary thyroid cancer via bioinformatics analysis and experimental validation.

Objective: The current research aimed to development and validation in signature immune genes for lymphatic metastasis in papillary thyroid cancer (PTC). Method: Weighted correlation network analysis (WGCNA) was performed to identify genes closely correlated with lymphatic metastasis in PTC from TCGA database. Information on immune-related genes (IRGs) was obtained from the ImmPort database. Crossover genes were used with the R package clusterProfiler for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment. Key genes in the protein-protein interaction network of cross-targets were obtained using Cytoscape. Lasso and Random Forest (RF) models were utilized to identify pivotal genes. We constructed a nomogram based on the hub genes. The correlation between hub genes and immune cell infiltration was explored. We collected and assessed clinical samples via immunohistochemistry to detect the expression of hub genes. Result: In total, 122 IRGs were correlated with lymphatic metastases from PTC. There are 10 key IRGs in the protein-protein interaction network. Then, three hub genes including PTGS2, MET, and ICAM1 were established using the LASSO and RF models. The expression of these hub genes was upregulated in samples collected from patients with lymphatic metastases. The average area under the curve of the model reached 0.83 after a 10-fold and 200-time cross-validation, which had a good prediction ability. Immuno-infiltration analysis showed that the three hub genes were significantly positively correlated with resting dendritic cells and were negatively correlated with activated natural cells, monocytes, and eosinophils. Immunohistochemistry results revealed that lymph node metastasis samples had a higher expression of the three hub genes than non-metastasis samples. Conclusion: Via bioinformatics analysis and experimental validation, MET and ICAM1 were found to be upregulated in lymph node metastasis from papillary thyroid carcinoma. Further, the two hub genes were closely correlated with activated natural killer cells, monocytes, resting dendritic cells, and eosinophils. Therefore, these two genes may be novel molecular biomarkers and therapeutic targets in lymph node metastasis from papillary thyroid carcinoma.

c-Jun-mediated JMJD6 restoration enhances resistance of liver cancer to radiotherapy through the IL-4-activated ERK pathway.

Radiotherapy is widely used in the treatment of liver cancer, but the efficacy can be limited by radioresistance. In this study, we attempt to delineate the possible molecular mechanism of c-Jun-regulated Jumonji domain-containing protein 6/interleukin 4/extracellular signal-regulated kinase (JMJD6/IL-4/ERK) axis in radioresistance of liver cancer. The expression of c-Jun was quantified in liver cancer tissues and cell lines, and the results indicated that c-Jun was upregulated in liver cancer tissues and cells. We further illustrated the role of c-Jun following gain- and loss-of-function strategies in malignant phenotypes of liver cancer cells. It was established that c-Jun elevated JMJD6 expression and augmented the malignancy and aggressiveness of liver cancer cells. The in vivo effects of c-Jun on radioresistance in liver cancer were validated in nude mice, in response to IL-4 knockdown or the ERK pathway inhibitor, PD98059. In the presence of JMJD6 upregulation, the expression of IL-4 was elevated in mice with liver cancer, which enhanced the radiation resistance. Moreover, knockdown of IL-4 inactivated the ERK pathway, thereby reversing the radiation resistance caused by overexpressed JMJD6 in tumor-bearing mice. Taken together, c-Jun augments the radiation resistance in liver cancer by activating the ERK pathway through JMJD6-upregulated IL-4 transcription.

Functionalization of curcumin nanomedicines: a recent promising adaptation to maximize pharmacokinetic profile, specific cell internalization and anticancer efficacy against breast cancer.

Owing to its diverse heterogeneity, aggressive nature, enormous metastatic potential, and high remission rate, the breast cancer (BC) is among the most prevalent types of cancer associated with high mortality. Curcumin (Cur) is a potent phytoconstituent that has gained remarkable recognition due to exceptional biomedical viability against a wide range of ailments including the BC. Despite exhibiting a strong anticancer potential, the clinical translation of Cur is restricted due to intrinsic physicochemical properties such as low aqueous solubility, chemical instability, low bioavailability, and short plasma half-life. To overcome these shortcomings, nanotechnology-aided developments have been extensively deployed. The implication of nanotechnology has pointedly improved the physicochemical properties, pharmacokinetic profile, cell internalization, and anticancer efficacy of Cur; however, majority of Cur-nanomedicines are still facing grandeur challenges. The advent of various functionalization strategies such as PEGylation, surface decoration with different moieties, stimuli-responsiveness (i.e., pH, light, temperature, heat, etc.), tethering of specific targeting ligand(s) based on the biochemical targets (e.g., folic acid receptors, transferrin receptors, CD44, etc.), and multifunctionalization (multiple functionalities) has revolutionized the fate of Cur-nanomedicines. This study ponders the biomedical significance of various Cur-nanomedicines and adaptable functionalizations for amplifying the physicochemical properties, cytotoxicity via induction of apoptosis, cell internalization, bioavailability, passive and active targeting to the tumor microenvironment (TME), and anticancer efficacy of the Cur while reversing the multidrug resistance (MDR) and reoccurrence in BC. Nevertheless, the therapeutic outcomes of Cur-nanomedicines against the BC have been remarkably improved after adaptation of various functionalizations; however, this evolving strategy still demands extensive research for scalable clinical translation.

Recent Development and Future Prospects of Molecular Targeted Therapy in Prostate Cancer.

Prostate cancer (PC) is a rapidly increasing ailment worldwide. The previous decade has observed a rapid advancement in PC therapies that was evident from the number of FDA approvals during this phase. Androgen deprivation therapies (ADT) have traditionally remained a mainstay for the management of PCs, but the past decade has experienced the emergence of newer classes of drugs that can be used with or without the administration of ADT. FDA approved poly (ADP-ribose) polymerase inhibitors (PARPi) such as olaparib and rucaparib after successful clinical trials against gene-mutated metastatic castration-resistant prostate cancer. Furthermore, drugs like apalutamide, darolutamide and enzalutamide with androgen-targeted mechanism of action have manifested superior results in non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration- sensitive prostate cancer (mCSPC), and metastatic castration-resistant prostate cancer (m- CRPC) respectively with or without previously administered docetaxel. Relugolix, an oral gonadotropin- releasing hormone antagonist and a combination of abiraterone acetate plus prednisone were also approved by FDA after a successful trial in advanced PC and mCRPC respectively. This review aims to analyze the FDA-approved agents in PC during last decade and provide a summary of their clinical trials. It also presents an overview of the ongoing progress of prospective molecules still under trial.

Betulin ameliorates 7,12-dimethylbenz(a)anthracene-induced rat mammary cancer by modulating MAPK and AhR/Nrf-2 signaling pathway.

The aim of the present study is to explore the preventive efficacy of betulin (BE) in 7,12-dimethylbenz(a)anthracene (DMBA)-administered mammary cancer by modulating Ahr/Nrf2 signaling in experimental models. The mammary cancer was stimulated by the addition of DMBA (25 mg/kg/b.Wt) mixed in 1 ml of vehicle solution (sunflower oil and saline 1:1) through subcutaneous injection. The DMBA-exposed mammary tumor models showed low bodyweight, elevated quantities of lipid peroxidation molecules (TBARS and LOOH), and low enzymatic (GPx, SOD, and CAT), and nonenzymatic (GSH, vitamin C, and vitamin E) antioxidant activities in plasma and mammary tissues. Moreover, histopathological studies confirmed that invasive ductal carcinoma was observed in DMBA-induced mammary tissue of the experimental model. Dietary oral supplementation of BE prevents the loss of bodyweight, overproduces lipid peroxidation, and restores the antioxidant activities in DMBA-exposed experimental animals. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial antioxidant protein that involves preventing numerous cancers. Therefore, Nrf2-associated signaling concern is a significant target for preventing mammary cancer. This study observed an increased expression of MAPKs, Keap1, ARNT, AhR, and CYP1A1, whereas decreased expression of HO-1 and Nrf2 in DMBA-induced cancer-bearing experimental animals. The oral supplementation of BE effectively modulates the expression of MAPKs, AhR/Nrf2-associated protein expressions in DMBA-exposed experimental animals. This current study concluded that BE is a strong antioxidant, which triggers the MAPKs-mediated oxidative stress and inhibits proliferative markers by restoring the activity of Nrf2 signaling.

MiR-942 regulates the function of breast cancer cell by targeting FOXA2.

MicroRNA (MiR)-942 regulates the development of a variety of tumors, however, its function in breast cancer (BCa) has been less reported. Therefore, the present study investigated the regulatory effects of miR-942 on BCa cells. The expression of miR-942 in whole blood samples and BCa cell lines was detected by quantitative real-time (qRT)-PCR. Direct target gene for miR-942 was confirmed by dual-luciferase reporter assay. FOXA2 expression in adjacent tissues was detected by qRT-PCR. The effects of miR-942, or miR-942 with FOXA2, on the cell viability, proliferation, apoptosis, migration and invasion of BCa cells were determined by cell counting kit-8 (CCK-8), colony formation assay, flow cytometry, wound scratch and Transwell, respectively. The levels of N-Cadherin, E-Cadherin and Snail were determined by Western blot. Kaplan-Meier was used to explore the relationship among the expressions of miR-942 and FOXA2 and the prognosis of BCa patients. MiR-942 had high expressed in BCa, while its low expression significantly suppressed the cell viability, proliferation, migration and invasion of BCa, but increased cell apoptosis. Down-regulation of N-Cadherin and Snail and up-regulation of E-Cadherin were also induced by low-expression of miR-942. FOXA2, which was proved as the direct target gene for miR-942 and was low-expressed in BCa, partially reversed the effect of overexpressed miR-942 on promoting cell viability, proliferation, migration and invasion, and suppressed cell apoptosis. A lower survival rate was observed in BCa patients with a high expression of miR-942 and a low expression of FOXA2. MiR-942 promoted the progression of BCa by down-regulating the expression of FOXA2.

Locally Trapping the C-C Chemokine Receptor Type 7 by Gene Delivery Nanoparticle Inhibits Lymphatic Metastasis Prior to Tumor Resection.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Currently, no targeted treatment is available for TNBC, and the most common clinical therapy is tumor resection, which often promotes metastasis risks. Strong evidence suggests that the lymphatic metastasis is mediated by the C-C chemokine receptor type 7 (CCR7)/C-C motif chemokine ligand 21 crosstalk between tumor cells and the lymphatic system. It is hypothesized that CCR7 is a key immune modulator in the tumor microenvironment and the local blockade of CCR7 could effectively inhibit TNBC lymphatic metastasis. Accordingly, a plasmid encoding an antagonistic CCR7 affinity protein-CCR7 trap is delivered by tumor targeting nanoparticles in a highly metastatic 4T1 TNBC mouse model. Results show that CCR7 traps are transiently expressed, locally disrupt the signaling pathways in the tumor site, and efficiently inhibit TNBC lymphatic metastasis, without inducing immunosuppression as observed in systemic therapies using CCR7 monoclonal antibody. Significantly, upon applying CCR7 trap therapy prior to tumor resection, a 4T1 TNBC mouse model shows good prognosis without any further metastasis and relapse. In addition, CCR7 trap therapy efficiently inhibits the lymphatic metastasis in a B16F10 melanoma mouse model, indicating its great potential for various metastatic diseases treatment.

MicroRNA-4728 serves as a suppressor and antagonist of oncogenic MAPK in Burkitt lymphoma.

OBJECTIVE: This study identified the biological role of miR-4728 in Burkitt lymphoma (BL) process. METHODS: Ramos cells were used to analyze MicroRNA-4728 (miR-4728) biological functions. MiR-4728 expression was investigated in 14 randomly chosen tumor tissues and 12 noncancerous tissues by qRT-PCR. Cyquant assay was used to monitor cell proliferation. Colony formation assay was performed to study the effectiveness of miR-4728 on the proliferation of cells. The effects of miR-4728 on MAPK signaling pathway were detected by luciferase reporter assay. The significance of differences between groups were evaluated by SPSS. RESULTS: In this study, MiRNA-4728 was observed to down-regulated in BL tissues compared to the noncancerous tissues. Additionally, miR-4728 inhibited Ramos cell proliferation. Moreover, miR-4728 overexpression also decreased the MAPK signaling activity. CONCLUSION: Our results suggested that miR-4728 serves as a suppressor and antagonist of oncogenic MAPK in Burkitt lymphoma. The appropriate regulation of miR-4728 might be vital to improve BL treatment.

Clinical analysis of Primary Gastrointestinal Non-Hodgkin's Lymphoma.

OBJECTIVE: To study the clinical characteristics and prognostic factors of survival for patients with primary gastrointestinal non-Hodgkin's lymphoma (PGI-NHL). METHODS: A retrospective analysis was performed for 104 PGI-NHL patients who were admitted in Baoding First Central Hospital from July 2003 to January 2014. RESULTS: There were 58 males and 46 females. The median age of onset was 53 (15-83) years old. In terms of pathogenic sites, there were 51 gastric cases (49.00%) and 53 intestinal cases (51.00%), with the median survival of 35 (1-130) months. The 1-, 3- and 5-year overall survival (OS) rates were 88.40%, 80.70% and 78.80%, respectively. The factors influencing the progression-free survival (PFS) and OS rates were studied by univariate and multivariate analyses. The PFS and OS rates of patients with B-cell PGI-NHL were significantly higher than those of patients with T-cell PGI-NHL (P<0.05). The PFS and OS rates of patients with primary gastric lymphoma were significantly higher than those of patients with primary intestinal lymphoma (P<0.05), but the data were not associated with Ann Arbor stage or LDH level (P>0.05). Compared with non-surgical patients, only patients with intestinal lymphoma benefited from surgery (P<0.05). CONCLUSION: The pathogenic site and pathological type are risk factors that affect the survival of PGI-NHL patients, and chemotherapy should be given the first priority for patients with primary gastric lymphoma.