Association of germline rare pathogenic mutations in guideline-recommended genes with prostate cancer progression: A meta-analysis.

BACKGROUND: Germline mutations in several genes, mainly DNA repair genes, have been associated with prostate cancer (PCa) progression. However, primarily due to the rarity of mutations, statistical evidence for these associations is not consistently established. The objective of this study is to synthesize evidence from multiple studies using a meta-analysis. METHODS: Genes analyzed were chosen based on National Comprehensive Cancer Network guidelines recommendations (10 genes) and a commonly reported gene (NBN). PCa progression in this analysis was defined as either having metastases or PCa-specific mortality. We searched PubMed for papers published before April 26, 2021, using selected keywords. Pooled odds ratio (OR) was estimated in all races and Caucasians-only using both fixed- and random-effect models. RESULTS: The search identified 1028 papers and an additional five from a manual review of references. After a manual process that excluded noneligible studies, 11 papers remained, including a total of 3944 progressors and 20,054 nonprogressors. Combining results from these eligible studies, mutation carrier rates were significantly higher in progressors than nonprogressors for NBN, BRCA2, ATM (under both fixed- and random-effect models), for CHEK2 (under fixed-effect model only), and for PALB2 (under random-effect model only), p < 0.05. Pooled OR (95% confidence interval) was 6.38 (2.25-18.05), 3.41 (2.31; 5.03), 1.93 (1.17-3.20), and 1.53 (1.00-2.33) for NBN, BRCA2, ATM, and CHEK2, respectively, under fixed-effect model and 2.63 (1.12-6.13) for PALB2 under random-effect model. No significant association was found for the six remaining genes. Certainty of evidence was low for many genes due primarily to the limited number of eligible studies and mutation carriers. CONCLUSIONS: Statistical evidence for five genes was obtained in this first meta-analysis of germline mutations and PCa progression. While these results may help urologists and genetic counselors interpret germline testing results for PCa progression, more original studies are needed.

Determination of therapeutic agents efficiencies of microsatellite instability high colon cancer cells in post-metastatic liver biochip modeling.

Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Biological properties of CMS1 (MSI-H type) can affect therapeutic efficiencies of agents used in the treatment of CRC, and therefore become a new predictive factor of the treatment. But, the predictive impact of MSI-H status for adjuvant chemotherapy remains controversial. This study will assess whether there is any unnecessary or inappropriate use of treatment agents recommended for adjuvant therapy of stage 2 and 3 of disease and for palliative or curative treatment of liver metastatic disease in microsatellite instability high group, a molecular subtype of colon cancer. Within this scope, the efficiencies of fluorouracil- and oxaliplatin-based chemotherapeutic agents will be shown on stage 3 microsatellite instability high colon tumor cell lines first, and then a microfluidic model will be created, imitating the metastasis of colon cancer to the liver. In the microfluidic chip model, we will create in liver tissue, where the metastasis of microsatellite instability high colon cancer will be simulated; the effectiveness of chemotherapeutic agents, immunotherapy agents, and targeted agents on tumor cells as well as drug response will be assessed according to cell viability through released biomarkers from the cells. The proposed hypothesis study includes the modeling and treatment of patient-derived post-metastatic liver cancer in microfluidics which has priority at the global and our region and consequently develop personal medication.

Rh2-enriched Korean ginseng (Ginseng Rh2+) inhibits tumor growth and development of metastasis of non-small cell lung cancer.

BACKGROUND AND OBJECTIVE: While there are multiple studies on the anti-tumoral effects of Panax ginseng as active ingredients (one or more ginsenosides derived from the extract) or as a whole plant extract, there is a lack of studies to assess the effects Panax ginseng's of active ingredients combined with the whole plant extract. Our aim was to study the effect of whole ginseng, enriched in the anti-tumoral Rh2 component and other ginsenosides (Ginseng Rh2+), on the metastatic capacity of non-small cell lung cancer (NSCLC). METHODS: We evaluated the effects of Ginseng Rh2+ on survival, migration and motility, induction of apoptosis, and expression of its apoptosis-related proteins in non-small cell lung cancer (NSCLC) cells in vitro and on primary tumor growth and metastatic capacity in a syngeneic mouse lung cancer model in vivo. The effects of Ginseng Rh2+ on NSCLC cells were studied in vitro using: a colorimetric tetrazolium salt (XTT) assay, annexin V-FITC/PI, western blotting, wound healing motility assay, Transwell migration and cell adhesion assays. In vivo, mice were inoculated with Lewis mouse lung carcinoma cells subcutaneously to evaluate local tumor growth, or intravenously to evaluate the effects of Ginseng Rh2+ on development of experimental metastases. Mice were treated by intraperitoneal administration of Ginseng Rh2+ (0.005-0.5 g kg-1) on days 6, 10, and 14 after tumor injection. RESULTS: We found that Ginseng Rh2+ increased the apoptosis of NSCLC cells in vitro, demonstrating dose dependent down-regulation of the Bcl-2 anti-apoptotic gene and concurrent up-regulation of the Bax pro-apoptotic gene. Ginseng Rh2+ inhibited the tumor cells' capacity to attach to the ECM-related matrix and reduced cell migration. In vivo, Ginseng Rh2+ inhibited local tumor growth and reduced the development of experimental lung metastases. CONCLUSION: Our study suggests that Ginseng Rh2+ may potentially be used as a therapeutic agent for treatment of NSCLC.

Oral administration of EGCG solution equivalent to daily achievable dosages of regular tea drinkers effectively suppresses miR483-3p induced metastasis of hepatocellular carcinoma cells in mice.

The effect of non-cytotoxic doses of epigallocatechin-3-gallate (EGCG) on the metastatic capability of human hepatocellular carcinoma (HCC) cells was investigated in vitro and in vivo. miR483-3p, a microRNA whose expression correlates inversely with survival and positively with disease progression in HCC patients, was found to promote HCC cell migration and invasion in vitro as well as lung metastasis in nude mice established by the tail-vein injection of HCC cells. The induction of reactive oxygen species (ROS) and downregulation of antioxidant defense factors Nrf2 and SOD2 appeared to be an important underlying mechanism and treatment with a non-cytotoxic dose of EGCG effectively reversed the miR483-3p-induced enhancement of HCC cell migration and invasion in vitro. Moreover, administration through drinking water at doses (0.1% and 0.5% EGCG solution, respectively) equivalent to the intake of regular to heavy tea drinkers could also significantly inhibit lung metastasis of HCC cells based on the estimation from the USDA Database for the Flavonoid Content of Selected Foods and FDA guidelines for the conversion of animal dose to human equivalent dose. EGCG also significantly counteracted the miR483-3p-induced alteration in the expression of epithelial-mesenchymal transition (EMT) markers, E-cadherin and vimentin, and downregulated the endogenous expression of miR483-3p in HCC cells through an epigenetic mechanism that led to the hypermethylation of the miR483-3p promoter region. The data from our study illustrate that miR483-3p promotes HCC metastasis likely through the induction of oxidative stress and uncover a novel role of EGCG for protection against miR483-3p-mediated HCC metastasis via the epigenetic modulation of miR483-3p expression. These findings therefore provide further evidence supporting that regular tea consumption may contribute to protection against miR-483-3p-induced ROS and the associated HCC progression.

Ginsenoside Rg3 Suppresses Epithelial-Mesenchymal Transition via Downregulating Notch-Hes1 Signaling in Colon Cancer Cells.

Invasion and metastasis are the major causes leading to the high mortality of colon cancer. Ginsenoside Rg3 (Rg3), as a bioactive ginseng compound, is suggested to possess antimetastasis effects in colon cancer. However, the underlying molecular mechanisms remain unclear. In this study, we reported that Rg3 could effectively inhibit colon cancer cell invasion and metastasis through in vivo and in vitro studies. In addition, Rg3 suppressed the epithelial-mesenchymal transition (EMT) of HCT15 cells and SW48 cells evidenced by detecting EMT related markers E-cadherin, vimentin, and snail expression. Furthermore, inhibition of Notch signaling by LY411,575 or specific Hes1 siRNA obviously repressed colon cancer cell migration and metastasis, and induced increase in E-cadherin and decrease in vimentin and snail. Meanwhile, the expression of NICD and Hes1 was obviously decreased in the presence of Rg3. However, Rg3 failed to suppress EMT in Hes1 overexpressed colon cancer cells. In particular, Rg3 significantly reversed IL-6-induced EMT promotion and blocked IL-6- induced NICD and Hes1 upregulations. Overall, these findings suggested that Rg3 could inhibit colon cancer migration and metastasis via suppressing Notch-Hes1-EMT signaling.

Carotenoids in Cancer Metastasis-Status Quo and Outlook.

Metastasis represents a major obstacle in cancer treatment and the leading cause of cancer-related deaths. Therefore, the identification of compounds targeting the multi-step and complex process of metastasis could improve outcomes in the management of cancer patients. Carotenoids are naturally occurring pigments with a plethora of biological activities. Carotenoids exert a potent anti-cancer capacity in various cancer models in vitro and in vivo, mediated by the modulation of signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of the epithelial-mesenchymal transition and regulatory molecules, such as matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), urokinase plasminogen activator (uPA) and its receptor (uPAR), hypoxia-inducible factor-1α (HIF-1α), and others. Moreover, carotenoids modulate the expression of genes associated with cancer progression and inflammatory processes as key mediators of the complex process involved in metastasis. Nevertheless, due to the predominantly preclinical nature of the known anti-tumor effects of carotenoids, and unclear results from certain carotenoids in specific cancer types and/or specific parts of the population, a precise analysis of the anti-cancer effects of carotenoids is essential. The identification of carotenoids as effective compounds targeting the complex process of cancer progression could improve the outcomes of advanced cancer patients.

Chebulinic acid inhibits MDA-MB-231 breast cancer metastasis and promotes cell death through down regulation of SOD1 and induction of autophagy.

Triple-negative breast cancers (TNBC) are highly aggressive and drug resistant accounting for majority of cases with poor outcome. Purified natural compounds display substantial anticancer activity with reduced cytotoxicity providing a new avenue to combat TNBC. Chebulinic acid (CA), a polyphenol derived from the fruits of various medicinal plants has potent anticancer activity. Here, we demonstrate that CA shows significant cytotoxicity against triple negative MDA-MB-231 cells. CA exhibited cytotoxicity to MDA-MB-231 cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Further, CA mitigated MDA-MB-231 cells viability and proliferation as shown by reduced live cell count, crystal violet staining, colony formation assay, soft agar assay and cell cycle analysis. Wound healing assay and trans-well migration assay demonstrated that CA significantly inhibited migration of MDA-MB-231 cells. Also reduced MMP9 expression was observed in CA-treated cells by gelatin zymography. CA negatively regulated mesenchymal characteristics of MDA-MB-231 cells demonstrated by F-actin staining and reduced expression of N-cadherin by confocal microscopy and western blot analysis. Annexin V/propidium iodide (PI) and active caspase-3 staining showed that CA was able to induce apoptosis in MDA-MB-231 cells but did not activate caspase-3. Two-dimensional gel electrophoresis based proteomic analysis demonstrated that CA regulated proteins belonging to the oxidative stress pathway, apoptotic pathway and proteins with antiproliferative activity. Western blot analysis analysis revealed that CA negatively regulated superoxide dismutase 1 (SOD1) and enhanced oxidative stress in MDA-MB-231 cells. SOD1 in-gel activity assay also showed reduced SOD1 activity upon CA treatment. Overexpression studies with GFP-LC3 and tandem tagged RFP-GFP-LC-3 also demonstrated enhanced autophagy upon CA treatment.

Accurate quantification of copy-number aberrations and whole-genome duplications in multi-sample tumor sequencing data.

Copy-number aberrations (CNAs) and whole-genome duplications (WGDs) are frequent somatic mutations in cancer but their quantification from DNA sequencing of bulk tumor samples is challenging. Standard methods for CNA inference analyze tumor samples individually; however, DNA sequencing of multiple samples from a cancer patient has recently become more common. We introduce HATCHet (Holistic Allele-specific Tumor Copy-number Heterogeneity), an algorithm that infers allele- and clone-specific CNAs and WGDs jointly across multiple tumor samples from the same patient. We show that HATCHet outperforms current state-of-the-art methods on multi-sample DNA sequencing data that we simulate using MASCoTE (Multiple Allele-specific Simulation of Copy-number Tumor Evolution). Applying HATCHet to 84 tumor samples from 14 prostate and pancreas cancer patients, we identify subclonal CNAs and WGDs that are more plausible than previously published analyses and more consistent with somatic single-nucleotide variants (SNVs) and small indels in the same samples.

miR-34a-5p suppresses the invasion and metastasis of liver cancer by targeting the transcription factor YY1 to mediate MYCT1 upregulation.

BACKGROUND: In recent years, microRNAs (miRNAs) are reported to act as molecular biomarkers for cancer diagnosis, treatment, and prognosis (including liver cancer) and to be involved in the development and progression of cancer and other physiological and pathological changes. However, the role of miR-34a-5p in liver cancer is still largely unknown. METHODS: In our study, the expression of miR-34a-5p in liver cancer tissues and HCC cell lines was detected by qRT-PCR. The CCK-8, scratch wound-healing motility and Transwell assays were used to evaluate the effect on cell proliferation, migration and invasion. The expression of YY1, E-cadherin, N-cadherin and vimentin was analysed by western blotting. The dual luciferase assay was performed to confirm whether YY1 is a target of miR-34a-5p. The combination of YY1 and MYCT1 was detected by chromatin immunoprecipitation (ChIP) assay. RESULTS: The results showed that miR-34a-5p was downregulated in liver cancer tissues and HCC cell lines. Overexpression of miR-34a-5p inhibited the proliferation, migration and invasion of liver cancer cells. YY1 was a direct target of miR-34a-5p, and the expression of YY1 could reverse the influence of miR-34a-5p on the proliferation, migration and invasion of liver cancer cells. YY1 inhibited MYCT1 expression by directly binding to its promoter region, and knockdown of MYCT1 reversed the influence of miR-34a-5p on the proliferation, migration and invasion of liver cancer cells. CONCLUSION: Our results suggest that miR-34a-5p could inhibit the invasion and metastasis of hepatoma cells by targeting YY1-mediated MYCT1 transcriptional repression.

Cinobufacini Inhibits Colon Cancer Invasion and Metastasis via Suppressing Wnt/ß-Catenin Signaling Pathway and EMT.

Cinobufacini is a well-known Chinese medicine extracted from Venenum Bufonis, also called Chan Su. It has been used clinically for various cancers, including colon cancer. However, the function of Cinobufacini on colon cancer invasion and metastasis, and its underlying molecular mechanism, is still not clear. In this study, we investigated the function and mechanism of Cinobufacini on colon cancer invasion and metastasis both in vitro and in vivo studies. Human colon cancer cells were cultured. CCK assay was used to detect the effect of Cinobufacini on colon cancer cells proliferation. The invasion and migration abilities were observed by transwell assays, and the expression of invasion and migration related genes MMP2, MMP9, and epithelial-to-mesenchymal transition (EMT) relate genes were observed by Western blot assays. An orthotopic xenograft model in nude mice was established using colon cancer HCT116 cells, and the function of Cinobufacini on colon cancer invasion and metastasis were observed in vivo. We found Cinobufacini significantly inhibited colon cancer cell proliferation in a dose/time-dependent manner; the invasion and migration abilities of colon cancer were decreased after treated with Cinobufacini. The metastasis and EMT related genes MMP9, MMP2, N-cadherin and Snail were obviously down-regulated, while the expression of E-cadherin was up-regulated after treatment with Cinobufacini. The Wnt/ß-catenin signaling pathway related genes were observed using WB,and results show that the expression of ß-catenin, wnt3a, c-myc, cyclin D1, and MMP7 were all down-regulated after being treated with cinobufacini, while the expression of APC was up-regulated. In vivo studies of the volume and weight of orthotopic xenograft tumors showed significantly shrinkage in the Cinobufacini group compared to the control group. The enterocoelia and liver metastasis tumors were significantly decreased, and the expression of MMP9, MMP2, and ß-catenin were also down-regulated, while E-cadherin was up-regulated in vivo after the treatment with Cinobufacini. Our data proves that Cinobufacini can inhibit colon cancer invasion and metastasis both in vitro and in vivo; the mechanism is related by suppressing the Wnt/ß-catenin signaling pathway and then inhibiting the EMT of CRC.

Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer.

The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2- breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2- breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies.

Suppression of migration, invasion, and metastasis of cisplatin-resistant head and neck squamous cell carcinoma through IKKß inhibition.

We explored the role of the transcription factor, NF-κB, and its upstream kinase IKKß in regulation of migration, invasion, and metastasis of cisplatin-resistant head and neck squamous cell carcinoma (HNSCC). We showed that cisplatin-resistant HNSCC cells have a stronger ability to migrate and invade, as well as display higher IKKß/NF-κB activity compared to their parental partners. Importantly, we found that knockdown of IKKß, but not NF-κB, dramatically impaired cell migration and invasion in these cells. Consistent with this, the IKKß inhibitor, CmpdA, also inhibited cell migration and invasion. Previous studies have already shown that N-Cadherin, an epithelial-mesenchymal transition (EMT) marker, and IL-6, a pro-inflammatory cytokine, play important roles in regulation of HNSCC migration, invasion, and metastasis. We found that cisplatin-resistant HNSCC expressed higher levels of N-Cadherin and IL-6, which were significantly inhibited by CmpdA. More importantly, we showed that CmpdA treatment dramatically abated cisplatin-resistant HNSCC cell metastasis to lungs in a mouse model. Our data demonstrated the crucial role of IKKß in control of migration, invasion, and metastasis, and implicated that targeting IKKß may be a potential therapy for cisplatin-resistant metastatic HNSCC.

MiR-3653 inhibits the metastasis and epithelial-mesenchymal transition of colon cancer by targeting Zeb2.

Aberrant expression of microRNAs (miRNAs) has been widely recognized to play critical roles in the pathogenic processes of colon cancer. However, the expression and functions of miR-3653 in colon cancer remain uncovered. This study revealed for the first time that miR-3653 expression was significantly decreased in colon cancer tissues and cell lines. MiR-3653 overexpression led to decreased migration and invasion of HCT116 cells while miR-3653 knockdown resulted in opposite influence of the metastatic behaviors of HT29 cells. qRT-PCR and western blot demonstrated that miR-3653 suppressed the epithelial-mesenchymal transition (EMT) of colon cancer cells using both gain- and loss- of function assay. Mechanically, miR-3653 was found to interact with the 3'-UTR of Zeb2 through the complementary sequences and inhibited the expression of Zeb2 in colon cancer cells. Rescue experiments demonstrated that the inhibitory effect of miR-3653 overexpression on cell metastasis and EMT was abrogated by forced expression of Zeb2. This study demonstrates that miR-3653 suppresses the metastasis and EMT of colon cells by targeting Zeb2, and serves as a promising biomarker and therapeutic target in colon cancer.

CDC20 associated with cancer metastasis and novel mushroom­derived CDC20 inhibitors with antimetastatic activity.

Aberrant expression of cell division cycle 20 (CDC20) is associated with malignant progression and poor prognosis in various types of cancer. The development of specific CDC20 inhibitors may be a novel strategy for the treatment of cancer with elevated expression of CDC20. The aim of the current study was to elucidate the role of CDC20 in cancer cell invasiveness and to identify novel natural inhibitors of CDC20. The authors found that CDC20 knockdown inhibited the migration of chemoresistant PANC­1 pancreatic cancer cells and the metastatic MDA­MB­231 breast cancer cell line. By contrast, the overexpression of CDC20 by plasmid transfection promoted the metastasizing capacities of the PANC­1 cells and MCF­7 breast cancer cells. It was also identified that a triterpene mixture extracted from the mushroom Poria cocos (PTE), purified triterpenes dehydropachymic acid, and polyporenic acid C (PPAC) downregulated the expression of CDC20 in PANC­1 cells dose­dependently. Migration was also suppressed by PTE and PPAC in a dose­dependent manner, which was consistent with expectations. Taken together, the present study is the first, to the best of our knowledge, to demonstrate that CDC20 serves an important role in cancer metastasis and that triterpenes from P. cocos inhibit the migration of pancreatic cancer cells associated with CDC20. Further investigations are in progress to investigate the specific mechanism associated with CDC20 and these triterpenes, which may have future potential use as natural agents in the treatment of metastatic cancer.

Metastatic Prostate Cancer: Effects of Genetic Testing on Care.

The National Comprehensive Cancer Network now recommends BRCA1/2 genetic testing in men with metastatic prostate cancer. The purpose of this article is to provide a review of principles of genetic testing in prostate cancer and highlight the significance of clinical genetic testing of BRCA1/2 and other genes (CHEK2, HOXB13, PALB2), including Lynch syndrome genes (MLH1, MSH2, MSH6, and PMS2) in men with metastatic prostate cancer. The potential impact of genetic testing on systemic treatments and the significance of the pathogenic results for at-risk family members is discussed.

Blueberry Malvidin-3-galactoside Suppresses Hepatocellular Carcinoma by Regulating Apoptosis, Proliferation, and Metastasis Pathways In Vivo and In Vitro.

Anthocyanin, a natural antioxidant, is reported to have cytotoxicity against cancer cells; however, the mechanism remains unclear. The aim of the present study was to investigate the mechanism by which malvidin-3-galactoside (M3G), the prominent anthocyanin in blueberry, suppresses the development of hepatocellular carcinoma. In vitro, M3G suppressed the proliferation, polarization, migration, and invasion activities of HepG2 cells by regulating the protein expression of cyclin D1, cyclin B, cyclin E, caspase-3, cleaved caspase-3, Bax, p-JNK, and p-p38, activating phosphatase and tensin homologue deleted on chromosome 10 (PTEN), accompanied by a decrease in the p-AKT level, and lowering the protein expression levels of MMP-2 and MMP-9. In vivo, M3G promoted the apoptosis of liver tumor cells, as determined by immunohistochemistry (cleaved caspase-3, Ki-67, PTEN, and p-AKT), a terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and hematoxylin-eosin staining. Overall, these results suggest that M3G, as an adjuvant ingredient or nutritional supplement, may be beneficial for liver cancer prevention and the modulatory mechanism seems to be associated with inhibition of proliferation, apoptosis, migration, and invasion-related pathways.

Urtica dioica extract suppresses miR-21 and metastasis-related genes in breast cancer.

BACKGROUND: Breast cancer has a high prevalence among women worldwide. Tumor invasion and metastasis still remains an open issue that causes most of the therapeutic failures and remains the prime cause of patient mortality. Hence, there is an unmet need to develop the most effective therapeutic approach with the lowest side effects and highest cytotoxicity that will effectively arrest or eradicate metastasis. METHODS: An MTT assay and scratch test were used to assess the cytotoxicity and migration effects of Urtica dioica on the breast cancer cells. The QRT-PCR was used to study the expression levels of miR-21, MMP1, MMP9, MMP13, CXCR4, vimentin, and E-cadherin. RESULTS: The results of gene expression in tumoral groups confirmed the overexpression of miR-21, MMP1, MMP9, MMP13, vimentin, and CXCR4, and the lower expression of E-cadherin compared to control groups (P<0.05). Moreover, the results of the MTT assay show that Urtica dioica significantly inhibited breast cancer cell proliferation. Moreover, findings from the scratch assay exhibited the inhibitory effects of Urtica dioica on the migration of breast cancer cell lines. CONCLUSION: Urtica dioica extract could inhibit cancer cell migration by regulating miR-21, MMP1, MMP9, MMP13, vimentin, CXCR4, and E-Cadherin. Moreover, our findings demonstrated that the extract could decrease miR-21 expression, which substantially lessens the overexpressed MMP1, MMP9, MMP13, vimentin, and CXCR4 and increases E-cadherin in the tumoral group.

Effects of Yishengukang decoction on expression of bone-specific alkaline phosphatase, carboxyterminal propeptide of type â procollagen, and carboxyterminal cross-linked telepeptide of type â collagen in malignant tumor patients with bone metastasis.

OBJECTIVE: To investigate the effect of Yishengukang decoction on the expression of the metabolic bone markers, bone-specific alkaline phosphatase (BAP), carboxyterminal propeptide of type Ⅰ procollagen (PICP), and arboxyterminal cross-linked telepeptide of type Ⅰ collagen (ICTP), in cancer patients with bone metastasis. METHODS: Patients (n = 180) were divided into three groups: (a) bone metastasis patients treated with Yishengukang and pamidronate disodium injection (treatment group, n = 60); (b) bone metastasis patients treated with pamidronate disodium injection alone (control group, n = 60); (c) cancer patients without metastatic bone lesion (non-bone metastasis group, n = 60). Serum levels of the metabolic markers BAP, PICP, and ICTP were detected by enzyme-linked immunosorbent assay pre- and post-therapy. RESULTS: A significant decrease in serum BAP level was observed in the treatment group compared with the control group. However there were no significant differences in serum levels of PICP and ICTP before or after treatment compared with the control group. CONCLUSION: Yishengukang decoction combined with pamidronate disodium injection reduced serum BAP level to a greater extent that pamidronate disodium injection alone. Furthermore, the combined therapy was more beneficial in regulating imbalanced bone metabolism after bone metastasis, and may represent the molecular mechanism underpinning the effects of Yishengukang decoction.

Expression of metastasis suppressor gene AES driven by a Yin Yang (YY) element in a CpG island promoter and transcription factor YY2.

We recently found that the product of the AES gene functions as a metastasis suppressor of colorectal cancer (CRC) in both humans and mice. Expression of amino-terminal enhancer of split (AES) protein is significantly decreased in liver metastatic lesions compared with primary colon tumors. To investigate its downregulation mechanism in metastases, we searched for transcriptional regulators of AES in human CRC and found that its expression is reduced mainly by transcriptional dysregulation and, in some cases, by additional haploidization of its coding gene. The AES promoter-enhancer is in a typical CpG island, and contains a Yin-Yang transcription factor recognition sequence (YY element). In human epithelial cells of normal colon and primary tumors, transcription factor YY2, a member of the YY family, binds directly to the YY element, and stimulates expression of AES. In a transplantation mouse model of liver metastases, however, expression of Yy2 (and therefore of Aes) is downregulated. In human CRC metastases to the liver, the levels of AES protein are correlated with those of YY2. In addition, we noticed copy-number reduction for the AES coding gene in chromosome 19p13.3 in 12% (5/42) of human CRC cell lines. We excluded other mechanisms such as point or indel mutations in the coding or regulatory regions of the AES gene, CpG methylation in the AES promoter enhancer, expression of microRNAs, and chromatin histone modifications. These results indicate that Aes may belong to a novel family of metastasis suppressors with a CpG-island promoter enhancer, and it is regulated transcriptionally.

The expression and function of Frizzled-7 in human renal cell Carcinoma

Purpose: Wnt/b-catenin has emerged as an important signal pathway in renal cell carcinoma (RCC) pathogenesis. Frizzled 7 (Fzd7) is a member of Frizzled (Fzd) receptor family which binds with Wnt ligands and transduces canonical and non-canonical pathways. However, the expression of Fzd7 in human RCC is poorly investigated. Methods: 53 RCC tissues and peri-tumor tissues were collected from the patients treated with radical nephrectomy. The expression of Fzd7 was investigated by immunohistochemical staining. Three RCC cells were transfected with Fzd7shRNA and GFPshRNA to investigate the function of Fzd7 in RCC cells. Results: The immunohistochemical analysis showed that Fzd7 protein expression level was significantly increased in RCC tissues when compared with peri-tumor tissues, which suggested that Fzd7 might be involved in the formation of tumors. However, the Fzd7 expression was not correlated with clinicopathological parameters. Three RCC cell lines: 786-O, Caki-1, and OS-RC-2 also expressed Fzd7. With Fzd7 expression being interfered by shRNA, the RCC cell proliferation was mildly decreased. Wnt3a could stimulate the RCC cells proliferation, but the stimulation was decreased when Fzd7 expression was interfered. Restoring the Fzd7 expression led to the proliferation stimulation effect of Wnt3a being restored. Conclusions: This paper suggests that Fzd7 may act as one of the molecules that take part in the course of RCC formation. Fzd7 can be activated by Wnt3a to stimulate cell proliferation (AU)

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