COL11A1 promotes esophageal squamous cell carcinoma proliferation and metastasis and is inversely regulated by miR-335-5p.

BACKGROUND: Esophagus squamous cell carcinoma (ESCC) is a sort of cancer that occurs in the esophageal epithelial tissue. This study performed integrated bioinformatics analysis of Gene Expression Omnibus (GEO) datasets GSE32424, GSE29968, and GSE130078. Collagen type XI alpha 1 (COL11A1) was identified as the hub gene in ESCC progression. The involvement of COL11A1 in ESCC development was next determined using in vitro functional tests. METHODS: Hub genes were identified through integrated bioinformatics analysis. The real-time reverse transcription-polymerase chain reaction was implemented for detecting the expression of COL11A1 mRNA in esophageal cancer cells. KYSE-30 cells were transfected using a vector encoding COL11A1. The proliferation of cells was determined using the Cell Counting Kit-8 (CCK-8) assay. Detection of the cell migration and invasion was made through making use of the transwell test. The development of ESCC cells in vivo was evaluated in naked mice. The interplay among COL11A1 and microRNA-335-5p (miR-335-5p) was discovered using a luciferase reporter experiment. RESULTS: In vitro studies showed the upregulation of COL11A1 in ESCC cell lines obtained from ESCC patients and upregulation of COL11A1 was correlated with poor disease-free survival of ESCC patients, thereby implying an oncogenic involvement of COL11A1 in ESCC. Overexpression of COL11A1 enhanced the proliferation of ESCC cells, invasion, and migration; whereas COL11A1 knockdown impeded the proliferation of ESCC cells, invasion, and migration. Additionally, miRNA pathway analysis in combination with TargetScan's online prediction and the luciferase reporter assay suggested miR-335-5p targeting and negatively regulating the COL11A1 3' untranslated region (3'UTR) within ESCC cells. MiR-335-5p overexpression diminished the development of ESCC cells. Additionally, co-expression of COL11A1 ameliorated the repressive influence of miR-335-5p overexpression on the growth and metastasis of ESCC cells. CONCLUSIONS: Using comprehensive bioinformatics analysis, the current study identified COL11A1 as an oncogene in ESCC. The mechanistic studies indicated that COL11A1 promoted ESCC cell progression and that miR-335-5p negatively regulated the expression of COL11A1 in ESCC.

Linc00941 regulates esophageal squamous cell carcinoma via functioning as a competing endogenous RNA for miR-877-3p to modulate PMEPA1 expression.

Esophageal squamous cell carcinoma (ESCC) represents one of the most common malignancies and is the fifth leading cause of cancer-related deaths. Long intergenic non-coding RNAs (lincRNAs) have been suggested to be dysregulated in various types of cancers, and a growing number of lincRNAs have been implicated to be functional in the ESCC progression. In this study, we examined the role of linc00941 in the ESCC progression and explored the underlying molecular mechanisms. The bioinformatics analysis identified the up-regulation of linc00941 in the ESCC tissues. Further in vitro studies showed that linc00941 was up-regulated in ESCC cell lines. The loss-of-function studies demonstrated that linc00941 knockdown suppressed ESCC cell proliferation, invasion and migration, and also suppressed the in vivo tumor growth. Furthermore, bioinformatics prediction along with luciferase reporter assay and RNA immunoprecipitation assay implied that linc00941 acted as a competing endogenous RNA for miR-877-3p, and linc00941 regulated ESCC cell progression via at least targeting miR-877-3p. Subsequently, miR-877-3p targeted prostate transmembrane protein, androgen induced 1 (PMEPA1) 3' untranslated region and repressed PMEPA1 expression in ESCC cells; overexpression of PMEPA1 attenuated the inhibitory effects of linc00941 knockdown on the ESCC cell progression. Linc00941 knockdown suppressed epithelial-mesenchymal transition (EMT) via targeting miR-877-3p/PMEPA1 axis in ESCC cells. In conclusion, our results indicated the oncogenic role of linc00941 in ESCC, and knockdown of linc00941 suppressed ESCC cell proliferation, invasion, migration and EMT via interacting with miR-877-3p/PMEPA1 axis.

QTMP, a Novel Thiourea Polymer, Causes DNA Damage to Exert Anticancer Activity and Overcome Multidrug Resistance in Colorectal Cancer Cells.

Colorectal cancer (CRC) is one of the most common malignancies, and multidrug resistance (MDR) severely restricts the effectiveness of various anticancer drugs. Therefore, the development of novel anticancer drugs for the treatment of CRC patients with MDR is necessary. Quaternized thiourea main-chain polymer (QTMP) is a self-assembled nanoparticle with good water solubility. Notably, QTMP is not a P-glycoprotein (P-gp) substrate, and it exhibits potent cytotoxic activity against CRC cells, including HCT116/DDP and P-gp-mediated multidrug-resistant Caco2 cells. QTMP also exhibits a strong anticancer activity against SW480 cells in vivo. Interestingly, reactive oxygen species (ROS) and reactive nitrogen species (RNS) production were increased in a concentration-dependent manner in QTMP-treated HCT116, SW480 and Caco2 cells. Importantly, QTMP causes DNA damage in these CRC cells via direct insertion into the DNA or regulation of ROS and/or RNS production. QTMP also induces caspase-dependent apoptosis via overproduction of ROS and RNS. Therefore, QTMP is a promising anticancer therapeutic agent for patients with CRC, including those cancer cells with P-gp-mediated MDR. The present study also indicates that the design and synthesis of anticancer drugs based on thiourea polymers is promising and valuable, thereby offering a new strategy to address MDR, and provides reference resources for further investigations of thiourea polymers.

Clinical application of the AUC-guided dosage adjustment of docetaxel-based chemotherapy for patients with solid tumours: a single centre, prospective and randomised control study.

BACKGROUND: Docetaxel (DTX) is a widely used anti-tumour drug, and its dosage is solely determined by body surface area (BSA). Adverse events, such as neutropenia or unsatisfied efficacy, likely occur because of differences in the pharmacokinetics (PK) and pharmacodynamics of patients. Thus, a feasible dosage adjustment method is needed. METHODS: A total of 209 eligible patients who provided consent were enrolled and randomised into two groups to receive the BSA- and PK-guided dosage adjustments of DTX-based chemotherapy (3 weeks per cycle). The AUC of DTX was detected, and the therapeutic window for Chinese patients was determined. The proportion of patients within the therapeutic window was evaluated. Neutropenia was examined in accordance with the toxicity grading standard suggested by the World Health Organisation. Tumour response was assessed in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint was the incidence of neutropenia, and the secondary endpoints were disease control rate (DCR) and 3-year survival rate. RESULTS: The therapeutic window for Chinese patients was 1.7-2.5 mg·h/L. The proportion of patients within the therapeutic window was 63.89% versus 28.33% (P < 0.0001), and the incidence of neutropenia was 68.33% versus 38.89% (P = 0.001) in the experimental group versus the control group in the sixth cycle, respectively. DCR was 72% versus 85% (P = 0.018) in the control group versus the experimental group. The 3-year survival rate of the PK group was significantly higher than that of the BSA group (P = 0.034). CONCLUSIONS: The PK-guided dosage adjustment of DTX could significantly increase the proportion of patients within the therapeutic window, decrease the incidence of neutropenia and increase the DCR and the 3-year survival rate. The PK-guided dosage adjustment based on the dynamic monitoring of AUC could be a useful method for oncologists to improve individualised treatment options, optimise drug efficacy and reduce drug toxicity.

Combined Therapeutic Effects of 131I-Labeled and 5Fu-Loaded Multifunctional Nanoparticles in Colorectal Cancer.

BACKGROUND: Owing to its combined effects, the co-delivery of different therapeutics is a promising option for the treatment of cancer. In the present study, tumor-targeting poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) nanoparticles were developed for the transportation of two molecules, namely chemotherapeutic drug 5-fluorouracil (5Fu) and radionuclide iodine-131 (131I), in a single platform. METHODS: The obtained nanoparticles (Cetuximab [Cet]-PEG-PLA-5Fu-131I) were spherical (diameter approximately 110 nm) and pH-sensitive. The targeting effect of nanoparticles via Cet was confirmed in colorectal cancer cells using a fluorescent assay. The combined effects of Cet-PEG-PLA-5Fu-131I on cell viability and apoptosis were evaluated in colorectal cancer cells by Cell Counting Kit-8 and flow cytometry assays. RESULTS: Blank nanoparticles (Cet-PEG-PLA) showed good biocompatibility, and Cet-PEG-PLA-5Fu-131I nanoparticles were the most effective in terms of inhibition of cell viability and induction of apoptosis compared with monotherapy using Cet-PEG-PLA-5Fu or Cet-PEG-PLA-131I. In the xenograft mouse model, compared with using Cet-PEG-PLA-5Fu or Cet-PEG-PLA-131I alone, Cet-PEG-PLA-5Fu-131I nanoparticles exhibited prolonged circulation in the blood and accumulation in the tumor, thus resulting in enhanced antitumor efficacy. Additionally, combined radio-chemotherapy with Cet-PEG-PLA-5Fu-131I nanoparticles was associated with smaller tumor sizes than monotherapy, revealing the superior antitumor effects of Cet-PEG-PLA-5Fu-131I nanoparticles. These effects were further evidenced by histological and immunohistochemical analyses. CONCLUSION: The multifunctional Cet-PEG-PLA-5Fu-131I nanoparticles are promising candidates for the co-delivery of 5Fu-mediated chemotherapy and 131I-mediated radiotherapy.

Enhanced antitumor efficacy in colon cancer using EGF functionalized PLGA nanoparticles loaded with 5-Fluorouracil and perfluorocarbon.

BACKGROUND: Tumor recurrence and metastasis occur at a high rate in patients with colon cancer. Identification of effective strategies for the treatment of colon cancer is critical. Recently, poly (lactic-co-glycolic acid) (PLGA) has been shown to have potential as a broad therapeutic drug delivery system. We designed a dual-loaded nanoparticle drug delivery system to overcome the limitations of chemotherapeutic drugs used to treat colon cancer. METHODS: We developed epidermal growth factor (EGF) functionalized PLGA nanoparticles (NPs) co-loaded with 5-fluorouracil (5Fu) and perfluorocarbon (PFC) (EGF-PLGA@5Fu/PFC) for targeted treatment of colon cancer. CCK-8 assay, Hoechst33342 staining and flow cytometry were performed to investigate the functions of EGF-PLGA@5Fu/PFC NPs in SW620 cells. Beside, animal experiment, histological analysis and immunofluorescence staining were adopted to further confirm the role of EGF-PLGA@5Fu/PFC NPs in vivo. RESULTS: The findings showed that EGF-PLGA@5Fu /PFC NPs had an average size 200 nm and a 5Fu-loading efficiency of 7.29%. Furthermore, in vitro release was pH-sensitive. Targeted EGF-PLGA@5Fu/PFC NPs exhibited higher cellular uptake than non-targeted NPs into colon cancer cells. In addition, EGF-PLGA@5Fu/PFC NPs suppressed cell viability and induced apoptosis in SW620 cells to a greater extent than non-targeted NPs. In tumor xenografted mice, EGF-PLGA@5Fu/PFC NPs suppressed tumor growth more effectively than 5Fu, PLGA@5Fu or PLGA@5Fu/PFC NPs. Histopathological analysis further demonstrated that EGF-targeted NPs inhibited tumor growth to a greater extent than non-targeted or non-NP treatments. The improved therapeutic outcomes observed in this study were due to relief of tumor hypoxia by transport of oxygen by PFC to the tumors. CONCLUSION: We constructed a biocompatible nanodrug delivery system based on functionalized nanoparticles that provided a novel strategy for selective delivery of chemotherapy drugs to tumors.

Euphorbia factor L2 inhibits TGF-ß-induced cell growth and migration of hepatocellular carcinoma through AKT/STAT3.

BACKGROUND: Euphorbia factor L2 has potent effects on ascites, hydropsy and cancers. PURPOSE: We investigated the pharmacological effects of Euphorbia factor L2 (EFL2) on hepatocellular carcinoma (HCC). METHODS: MTT assay was conducted to determine the proliferative activity of EFL2 on Hep G2 and SMMC-7721 cells. Wound-healing assay, colony formation assay, western blotting and quantitative PCR were carried out to examine the cell migration, p-AKT and p-STAT3 signaling. Moreover, we used human tumor xenograft BALB/c nude mice to detect the effect of EFL2 on HCC in vivo. RESULTS: EFL2 inhibited the proliferation of SMMC-7721 and Hep G2 cells in concentration- and time-dependent manners. EFL2 also suppressed the cell migration and colony formation of hepatocellular carcinoma cells. Using a transforming growth factor-ß (TGF-ß)-induced epithelial-mesenchymal transition (EMT) model, we provided evidences that EFL2 could also inhibit TGF-ß induced cell growth, vimentin, N-cadherin expressions, activation of p-AKT and p-STAT3, whereas up-regulate E-cadherin expression. Furthermore, EFL2 inhibited tumor growth and STAT3 phosphorylation in vivo. CONCLUSION: In conclusion, EFL2 has the potential to be explored as a candidate treatment agent for HCC by inhibiting cell growth and migration both in vitro and in vivo.

Isoliquiritigenin suppresses the proliferation and induced apoptosis via miR-32/LATS2/Wnt in nasopharyngeal carcinoma.

Nasopharyngeal Carcinoma is limited by the various severe side-effects and surgery is rarely performed. Iosliquiritigenin has a series of biological activities, such as antiviral, anti-free radical and antitumor. However, the role and underlying mechanism of isoliquiritigenin in nasopharyngeal carcinoma have not been understood yet. Herein, the results revealed that isoliquiritigenin could inhibit cell proliferation in nasopharyngeal carcinoma cell lines, including C666-1 and CNE2, in both Cell Counting Kit-8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU) assay. In addition, isoliquiritigenin promoted nasopharyngeal carcinoma cell apoptosis, with the up-regulations of Bax, Caspase-3 and Caspase-9 and the down-regulation of Bcl-2. Meanwhile, isoliquiritigenin suppressed nasopharyngeal carcinoma cells migration and invasion with the down-regulation of matrix metalloproteinases (MMP)-2 and MMP-9. Furthermore, the expression of miR-32 was up-regulated in the nasopharyngeal carcinoma tissues, while isoliquiritigenin could significantly down-regulate the expression of miR-32. And over-expression of miR-32 promoted the nasopharyngeal carcinoma cells growth, migration and invasion, and suppressed apoptosis. However, isoliquiritigenin treatment dramatically inhibited the effect of miR-32. Besides, luciferase reporter assay confirmed that large tumor suppressor 2 (LATS2) was a direct target of miR-32. And isoliquiritigenin increased the expression of LATS2, while silencing of LATS2 promoted the nasopharyngeal carcinoma cells growth. Moreover, western blotting discovered that isoliquiritigenin inhibited nasopharyngeal carcinoma cells growth via Wnt signaling pathway. Finally, CNE2 cells transplanted xenografts tumor model in nude mice were performed and it suggested that isoliquiritigenin could inhibit the development of xenografts nude mice, along with the decrease of tumor volume and the expression of miR-32 and LATS2. Overall, isoliquiritigenin was confirmed to be a potent anti-nasopharyngeal carcinoma compound both in vitro and in vivo, and accomplished by regulation of miR-32/LATS2/Wnt.

Overexpression of miR-301a-3p promotes colorectal cancer cell proliferation and metastasis by targeting deleted in liver cancer-1 and runt-related transcription factor 3.

Colorectal cancer (CRC) is the third most common type of cancer. MicroRNAs have been reported to participate in the progression of various cancers. In previous studies, miR-301a-3p expression was shown to be upregulated in CRC tissues. However, the underlying mechanism of miR-301a-3p in CRC has not yet been elucidated. Herein, the level of miR-301a-3p was found to be significantly upregulated in CRC clinical tissues and cell lines (HT29 and SW620). In addition, overexpression of miR-301a-3p obviously promoted cell proliferation, migration and invasion, and inhibited cell apoptosis in CRC cells. Meanwhile, upregulated miR-301a-3p expression also enhanced the expressions of Bax, caspase-3, caspase-9, matrix metalloproteinase (MMP)-2, and MMP-9, while the expression of Bax-2 was decreased. Furthermore, deleted in liver cancer-1 (DLC-1) and runt-related transcription factor 3 (RUNX3) were verified to be direct target genes of miR-301a-3p. Furthermore, overexpression of DLC-1 and RUNX3 revealed antitumor effects in CRC cell lines with the inhibition of cell proliferation, migration and invasion, and the induction of cell apoptosis. In addition, the expressions of Bax, caspase-3, caspase-3, MMP-2, and MMP-9 could be decreased after upregulating the expressions of DLC-1 and RUNX3, along with the upregulation of Bax-2. Moreover, overexpression of miR-301a-3p could promote the growth of xenograft tumors and liver metastasis in vivo, along with reducing the expressions of DLC-1 and RUNX3. Overall, miR-301a-3p might act as a tumor inducer in CRC cells through negatively regulating DLC-1 and RUNX3.

Overall Survival Benefit from Trastuzumab-Based Treatment in HER2-Positive Metastatic Breast Cancer: A Retrospective Analysis.

AIM: The purposes of our study were to compare the clinical outcomes of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) patients with or without trastuzumab treatment and HER2-negative patients, and to explore factors that might predict the survival benefit associated with trastuzumab treatment in HER2-positive breast cancer. PATIENTS AND METHODS: A total of 421 patients with mBC were analyzed in this retrospective study. All patients had first-line chemotherapy with or without trastuzumab. They were classified into 3 groups according to their HER2 status and trastuzumab treatment: HER2-positive mBC patients with or without trastuzumab treatment and HER2-negative patents. RESULTS: Trastuzumab administration in HER2-positive mBC patients significantly prolonged overall survival (33 vs. 26 months; P = 0.003) and led to a 49.8% reduction in death risk. In the subgroup analysis, HER2-positive patients with hormone receptor (HR)-negative status (29 vs. 17 months; P = 0.000) or visceral metastasis (30 vs. 21 months; P = 0.000) had more survival benefit when treated with trastuzumab. CONCLUSIONS: Trastuzumab administration significantly improved the overall survival in HER2-positive mBC patients, who gained a prognosis comparable to that of patients with HER2-negative disease. HR status and metastasis site might be important surrogate makers that predict survival benefit from trastuzumab-based treatment.

lncRNA-PVT1 Facilitates Invasion Through Upregulation of MMP9 in Nonsmall Cell Lung Cancer Cell.

Lung cancer is the most common solid tumor around the world. It has been reported that upregulation of long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (lncRNA-PVT1) is closely associated with tumor metastasis. However, the function and underlying molecular mechanism of lncRNA-PVT1 in nonsmall cell lung cancer (NSCLC) invasion remain unknown. In this study, we found that overexpression of lncRNA-PVT1 promoted the invasive ability of NSCLC cells, whereas silence of lncRNA-PVT1 suppressed cell invasion. Furthermore, we found that lncRNA-PVT1 upregulated MMP9 expression in a post-transcriptional manner. Specifically, lncRNA-PVT1 directly interacted with miR-200a and miR-200b, which suppressed MMP9 expression. Taken together, lncRNA-PVT1 functions as a competitive endogenous RNA to regulate MMP9 expression through competitively binding the common microRNAs, miR-200a and miR-200b. These findings suggest that lncRNA-PVT1 could predispose NSCLC patients to metastases and may serve as a promising target for antimetastatic therapies.

Hormone receptor status predicts the clinical outcome of human epidermal growth factor 2-positive metastatic breast cancer patients receiving trastuzumab therapy: a multicenter retrospective study.

OBJECTIVES: Trastuzumab, a humanized monoclonal antibody that binds human epidermal growth factor receptor 2 (HER2), dramatically improves the clinical outcomes of HER2-positive breast cancer. Emerging evidence implied that the clinical behavior and sensitivity to targeted agents in HER2-positive breast cancer differed by hormone receptor (HR) status. The objective of this study was to determine the effect of the HR status on survival benefit of HER2-positive metastatic breast cancer when treated with anti-HER2-targeted therapy in People's Republic of China. METHODS: Metastatic breast cancer patients with HER2-positive diseases across six cancer centers in People's Republic of China were retrospectively analyzed in our study. Patients were classified into four groups according to HR/HER2 status and trastuzumab treatment: HER2+/HR+ patients with first-line trastuzumab treatment, HER2+/HR+ patients with no trastuzumab treatment, HER2+/HR- patients with first-line trastuzumab treatment, and HER2+/HR- patients with no trastuzumab treatment. Kaplan-Meier analysis, log-rank test, and multivariate analysis were performed during analysis. RESULTS: A total of 295 patients were included in the final analysis. The median overall survival was 30 months (95% confidence interval: 27.521-32.479). Among patients with HER2+/HR- disease, significant survival benefit was observed when treated with trastuzumab (30 vs 21 months, P=0.000). However, in patients with HER2+/HR+ disease, trastuzumab administration had a survival improvement trend but no significant statistical differences (36 vs 30 months, P=0.258). In the multivariate analysis, HR status was an independent predictor of overall survival and trastuzumab treatment had significantly decreased risk of death in HER2+/HR- patients (hazard ratio =0.330). CONCLUSION: HR status is an independent predictor of overall survival in HER2-positive metastatic breast cancer patients and patients with HER2+/HR- subtype might be associated with more survival benefits when treated with trastuzumab-based regimens.