Haijuan Wang

Administration of PUMA adenovirus increases the sensitivity of esophageal cancer cells to anticancer drugs.

Esophageal cancer is one of the most lethal human tumors, characterized by relative chemoresistance and poor prognosis. Researchers have been seeking for multimodality to improve its outcome of therapy. PUMA (p53 upregulated modulator of apoptosis) is a potent proapoptotic molecule that is rapidly induced in cells following DNA damage and is required for p53-induced apoptosis. We evaluated the therapeutic potential of PUMA adenovirus against esophageal cancer cell lines (KYSE-150, KYSE-410, KYSE-510 and YES-2). Infection with Ad-PUMA (PUMA Adenovirus) resulted in the more powerful cytotoxicity in these cell lines compared with Ad-p53. Furthermore, we assessed the efficacy of a combined treatment with Ad-PUMA and anticancer drug (cisplatin, paclitaxel, 5-fluorouracil, respectively) for these cells and found PUMA significantly increased the chemosensitivity of esophageal cancer cells, which may result from more abundant apoptosis induction. Interestingly, Ad-PUMA was found to be more efficient than Ad-p53 in inhibiting cell growth and enhancing the chemosensitivity of esophageal cancer cell lines irrespective of the p53 status. These results suggest that Ad-PUMA is a potent cytotoxic agent and could be a promising alternative in the cancer gene therapy in combination with chemotherapeutic agents.

RNA interference of metastasis-associated gene 1 inhibits metastasis of B16F10 melanoma cells in a C57BL/6 mouse model.

Background information. MTA1 (metastasis‐associated gene 1) has been reported to be overexpressed in cancers with high potential to metastasize. Studies of the molecular mechanisms revealed that MTA1 plays an important role in the process of metastasis of many types of cancer. However, the role of MTA1 in melanoma development is unclear.

Enriched CD44+/CD24− population drives the aggressive phenotypes presented in triple-negative breast cancer (TNBC)

The mechanism underlying the aggressive behaviors of triple negative breast cancer (TNBC) is not well characterized yet. The association between cancer stem cell (CSC) population and the aggressive behaviors of TNBC has not been established. We found the CD44(+)/CD24(-) cell population was enriched in TNBC tissues and cell lines, with a higher capacity of proliferation, migration, invasion and tumorigenicity as well as lower adhesion ability. The CD44(+)/CD24(-) cell population with cancer stem cell-like properties may play an important role in the aggressive behaviors of TNBC. This discovery may lead to new therapeutic strategies targeting CD44(+)/CD24(-) cell population in TNBC.

Adenoviral‐mediated gene transfer of Gadd45a results in suppression by inducing apoptosis and cell cycle arrest in pancreatic cancer cell

The extremely poor prognosis of patients with pancreatic ductal adenocarcinoma indicates the need for novel therapeutic approaches. The growth arrest and DNA damage‐inducible (Gadd) gene Gadd45a is a member of a group of genes that are induced by DNA damaging agents and growth arrest signals.

MTA1 regulates higher-order chromatin structure and histone H1-chromatin interaction in-vivo

In the current study, for the first time, we found that metastasis‐associated gene 1 (MTA1) was a higher‐order chromatin structure organizer that decondenses the interphase chromatin and mitotic chromosomes. MTA1 interacts dynamically with nucleosomes during the cell cycle progression, prominently contributing to the mitotic chromatin/chromosome structure transitions at both prophase and telophase. We showed that the decondensation of interphase chromatin by MTA1 was independent of Mi‐2 chromatin remodeling activity. H1 was reported to stabilize the compact higher‐order chromatin structure through its interaction with DNA. Our data showed that MTA1 caused a reduced H1‐chromatin interaction in‐vivo. Moreover, the dynamic MTA1‐chromatin interaction in the cell cycle contributed to the periodical H1‐chromatin interaction, which in turn modulated chromatin/chromosome transitions. Although MTA1 drove a global decondensation of chromatin structure, it changed the expression of only a small proportion of genes. After MTA1 overexpression, the up‐regulated genes were distributed in clusters along with down‐regulated genes on chromosomes at parallel frequencies.

Metastasis-associated gene 1 promotes invasion and migration potential of laryngeal squamous cell carcinoma cells.

Overexpression of the metastasis-associated gene 1 (MTA1) has previously been found to be associated with progression of various cancer types to the metastasis stage. The function of MTA1 in laryngeal squamous cell carcinoma (LSCC) remains unclear. To explore the significance of MTA1 in the invasion and migration processes in LSCC, gene transfection and RNA interference (RNAi) were performed to study the biological function of MTA1 in the LSCC cell line, HEP-2. Results showed that MTA1 promoted the invasion, adhesion and migration behavior of LSCC cells. RNAi against MTA1 significantly decreased the malignant phenotypes of cancer cells. MTA1 may be important in the process of LSCC invasion and metastasis.

The Efficacy and Safety of Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors for Advanced Melanoma: A Meta-Analysis of Clinical Trials Following the PRISMA Guidelines

AbstractThe purpose of this study was to investigate the efficacy and safety of programmed cell death 1 (PD-1) and programmed cell death 1 ligand (PD-L1) inhibitors using a meta-analysis of present trials for advanced melanoma.A fully recursive literature search of the primary electronic databases for available trials was performed. The objective response rate (ORR) and the median progression-free survival (PFS) of clinical responses were considered the main endpoints to evaluate the efficacy, whereas Grade 3–4 adverse effects (AEs) were analyzed to evaluate safety.The ORR of PD-1 and PD-L1 inhibitors was 30% (95% CI: 25–35%). No significant difference in the ORR was observed after the comparisons of low-dose, median-dose, and high-dose cohorts. In addition, the rate of Grade 3–4 AEs was 9% (95% CI: 6–12%). According to the 3 randomized controlled trials that compared PD-1 inhibitors with chemotherapy, the difference between these 2 groups was found to be statistically significant with respect to the ORR, PFS and the incidence of Grade 3–4 AEs; that is, the relative risk (RR) of the ORR was 3.42 (95% CI: 2.49–4.69, P < 0.001), the hazard ratio (HR) of the PFS was 0.50 (95% CI: 0.44–0.58, P < 0.001), and the RR of Grade 3–4 AEs was 0.45 (95% CI: 0.31–0.65, P < 0.001).According to a meta-analysis of limited concurrent studies, PD-1 and PD-L1 inhibitors appear to be associated with improved response rates, superior response durability and tolerable toxicity in patients with advanced melanoma.

A feasibility study on gene therapy of pancreatic carcinoma with Ad-PUMA

Pancreatic cancer is one of the most malignant tumors with high mortality and poor prognosis even with the aggressive conventional therapies. Biotherapy based on the understanding of tumorigenesis mechanism is ongoing to improve the outcomes of cancer patients. We sought here to evaluate the therapeutic potential of a proapoptotic gene, PUMA, in pancreatic cancer. We found that PUMA was differently expressed in a series of pancreatic ductal adenocarcinoma cancer cell lines, and adenovirus-mediated expression of PUMA (Ad-PUMA) in these cells resulted in massive apoptosis. PUMA was more potent than p53 in suppressing growth of cancer cells. RT-PCR and Western Blot revealed that exogenous PUMA was expressed 6 h after Ad-PUMA infection. Furthermore, we assessed the efficacy of Ad-PUMA combining anticancer drugs (5-fluorouracil, cisplatin, gemcitabine hydrochloride, respectively) in these pancreatic cancer cell lines. Data revealed that PUMA significantly sensitized pancreatic carcinoma cell lines to chemotherapeutics, which may be resulted from abundant apoptosis induction. In nude mice with PANC-1 xenografts, Ad-PUMA treatment significantly inhibited the tumor growth. These results suggest that PUMA is a potent molecular tool in suppressing tumor growth sensitizing pancreatic carcinoma cells to chemical drugs. PUMA plays roles in negatively regulating cancer cell growth and may be a promising tool for cancer biotherapy, with or without combination with chemotherapeutic agents.

Bioinformatic exploration of MTA1-regulated gene networks in colon cancer

Metastasis-associated gene 1 (MTA1) controls a series of biological processes in tumor progression. Tumor progression is a complex process regulated by a gene network. The global cancer gene regulatory network must be analyzed to determine the position of MTA1 in the molecular network and its cooperative genes by further exploring the biological functions of this gene. We used TCGA data sets and GeneCards database to screen MTA1-related genes. GO and KEGG pathway analyses were conducted with DAVID and gene network analysis via STRING and Cytoscape. Results showed that in the development of colon cancer, MTA1 is linked to certain signal pathways, such as Wnt/Notch/nucleotide excision repair pathways. The findings also suggested that MTA1 demonstrates the closest relationship in a coregulation process with the key molecules AKT1, EP300, CREBBP, SMARCA4, RHOA, and CAD. These results lead MTA1 exploration to an in-depth investigation in different directions, such as Wnt, Notch, and DNA repair.

Overexpression of Forkhead box L1 (FOXL1) inhibits the proliferation and invasion of breast cancer cells.

Forkhead box L1 (FOXL1) is a member of the Forkhead box (FOX) superfamily and was reported to be dysregulated in various types of cancers. However, its expression pattern and underlying cellular function in breast cancer remain largely unexplored. Thus, the aim of this study was to detect FOXL1 expression in breast cancer and to analyze its role in the progression of breast cancer. Our results demonstrated that FOXL1 expression at both the mRNA and protein levels was downregulated in breast cancer tissues and cell lines. Ectopic FOXL1 suppressed breast cancer cell proliferation, migration, and invasion in vitro. Furthermore, overexpression of FOXL1 significantly attenuated tumor growth in breast xenograft models in vivo. Finally, overexpression of FOXL1 significantly downregulated the protein expression levels of β-catenin, c-Myc, and cyclin D1 in MDA-MB-231 cells. Taken together, the present study demonstrated that FOXL1 inhibited the proliferation, invasion, and migration of breast cancer in vitro and breast tumor growth in vivo through deactivating the Wnt/β-catenin signaling pathway. Thus, these findings suggest that FOXL1 may be a potential novel target for breast cancer therapy.