Mcl-1 suppresses abasic site repair following bile acid-induced hepatic cellular DNA damage.

In cholestasis, increases in bile acid levels result in the generation of reactive oxygen species and the induction of DNA damage and mutation. It is believed that bile acid accumulation is associated with liver tumorigenesis. However, the mechanism that underpins this phenomenon remains to be elucidated. Mcl-1, which is overexpressed in hepatic cells, is a pro-survival member of the Bcl-2 family. In this study, we observed that Mcl-1 potently suppresses the repair of bile acid-induced abasic (apurinic/apyrimidinic) sites in DNA lesions. Upon exposure of hepatic cells to glycochenodeoxycholate, one of the major conjugated human bile acids, we observed an increase in AP site accumulation along with induction of poly(ADP-ribose) polymerase and XRCC1 ( X-Ray Repair Cross Complementing 1). In addition, accumulation of Mcl-1 was observed in the nuclei of QGY-7703 cells in response to glycochenodeoxycholate stimulation. Knockdown of endogenous Mcl-1 by RNA interference significantly accelerated the repair of DNA lesions in glycochenodeoxycholate-treated cells. However, unlike XRCC1, poly(ADP-ribose) polymerase was induced following Mcl-1 knockdown. Conversely, poly(ADP-ribose) polymerase suppression was observed following glycochenodeoxycholate treatment of cells overexpressing Mcl-1. Moreover, AP-site counting analyses revealed that DNA repair activity was enhanced in cells overexpressing poly(ADP-ribose) polymerase under glycochenodeoxycholate stress conditions. It is well known that poly(ADP-ribose) polymerase plays a crucial role in the base excision repair pathway. Thus, our findings suggest that Mcl-1 suppresses base excision repair by inhibiting poly(ADP-ribose) polymerase induction following glycochenodeoxycholate-induced DNA damage. These results potentially explain how bile acid accumulation results in genetic instability and carcinogenesis.

In Vivo Enrichment and Elimination of Circulating Tumor Cells by Using a Black Phosphorus and Antibody Functionalized Intravenous Catheter.

The circulating tumor cell (CTC) count is closely related to cancer recurrence and metastasis. The technology that can in vivo destroy CTCs may bring great benefits to patients, which is an urgent clinical demand. Here, a minimally invasive therapeutic intravenous catheter for in vivo enriching and photothermal killing of CTCs is developed. The surface of catheter is modified with anti-EpCAM antibody and the interior is filled with black phosphorus nanosheets (BPNSs). CTCs in the peripheral blood are captured by the catheter continually with the aid of circulation. The captured CTCs are used for downstream analyses or in vivo eliminated by the near-infrared (NIR) photothermal effect of BPNSs. A capture efficiency of 2.1% is obtained during the 5 min of treatment, and 100% of the captured CTCs are killed by following NIR light irradiation in both an in vitro closed-loop circulation system and an in vivo rabbit model. This cost-effective modality for lowering the CTCs burden can be a good supplement to traditional therapies, which holds great promise as an effective clinical intervention for cancer patients.

Prodrug-Loaded Zirconium Carbide Nanosheets as a Novel Biophotonic Nanoplatform for Effective Treatment of Cancer.

Conventional chemotherapy and photothermal therapy (PTT) face many major challenges, including systemic toxicity, low bioavailability, ineffective tissue penetration, chemotherapy/hyperthermia-induced inflammation, and tumor angiogenesis. A versatile nanomedicine offers an exciting opportunity to circumvent the abovementioned limitations for their successful translation into clinical practice. Here, a promising biophotonic nanoplatform is developed based on the zirconium carbide (ZrC) nanosheet as a deep PTT-photosensitizer and on-demand designed anticancer prodrug SN38-Nif, which is released and activated by photothermia and tumor-overexpressed esterase. In vitro and in vivo experimental evidence shows the potent anticancer effects of the integrated ZrC@prodrug biophotonic nanoplatform by specifically targeting malignant cells, chemotherapy/hyperthermia-induced tumor inflammation, and angiogenesis. In mouse models, the ZrC@prodrug system markedly inhibits tumor recurrence, metastasis, inflammation and angiogenesis. The findings unravel a promising biophotonic strategy for precision treatment of cancer.

Eradication of tumor growth by delivering novel photothermal selenium-coated tellurium nanoheterojunctions.

Two-dimensional nanomaterial-based photothermal therapy (PTT) is currently under intensive investigation as a promising approach toward curative cancer treatment. However, high toxicity, moderate efficacy, and low uniformity in shape remain critical unresolved issues that hamper their clinical application. Thus, there is an urgent need for developing versatile nanomaterials to meet clinical expectations. To achieve this goal, we developed a stable, highly uniform in size, and nontoxic nanomaterials made of tellurium-selenium (TeSe)-based lateral heterojunction. Systemic delivery of TeSe nanoparticles in mice showed highly specific accumulation in tumors relative to other healthy tissues. Upon exposure to light, TeSe nanoparticles nearly completely eradicated lung cancer and hepatocellular carcinoma in preclinical models. Consistent with tumor suppression, PTT altered the tumor microenvironment and induced immense cancer cell apoptosis. Together, our findings demonstrate an exciting and promising PTT-based approach for cancer eradication.

Immunogenic exosome-encapsulated black phosphorus nanoparticles as an effective anticancer photo-nanovaccine.

Tumor vaccines are a promising form of cancer immunotherapy, but difficulties such as neo-antigen identification, activation of immune cells, and tumor infiltration prevent their clinical breakthrough. Interestingly, nanotechnology-based photothermal therapy (PTT) has great potential to overcome these barriers. Previous studies have shown that serum exosomes (hEX) from hyperthermia-treated tumor-bearing mice displayed an array of patient-specific tumor-associated antigens (TAAs), and strong immunoregulatory abilities in promoting dendritic cell (DC) differentiation and maturation. Here, we developed a tumor vaccine (hEX@BP) by encapsulating black phosphorus quantum dots (BPQDs) with exosomes (hEX) against a murine subcutaneous lung cancer model. In comparison with BPQDs alone (BP), hEX@BP demonstrated better long-term PTT performance, greater elevation of tumor temperature and tumor targeting efficacy in vivo. Vaccination with hEX@BP in combination with PTT further demonstrated an outstanding therapeutic efficacy against established lung cancer, and promoted the infiltration of T lymphocytes into the tumor tissue. Our findings demonstrated that hEX@BP might be an innovative cancer photo-nanovaccine that offers effective immuno-PTT against cancers.

ß-catenin regulates IRF3-mediated innate immune signalling in colorectal cancer.

OBJECTIVE: ß-catenin is one of the most critical oncogenes associated with many kinds of human cancers, especially in the human CRC. Innate immunity recognizes tumour derived damage-associated molecular patterns (DAMPs) and primes the anti-tumour adaptive responses. While the function of ß-catenin in CRC tumourigenesis is well established, its impact on innate immune evasion is largely unknown. The aim of this study is to characterize the role of ß-catenin in inhibiting RIG-I-like receptor (RLR)-mediated IFN-ß signalling in colorectal cancer. MATERIALS AND METHODS: Immunohistochemical staining and western blotting were conducted to study the expression of ß-catenin, IRF3 and phospho-IRF3 (p-IRF3) in CRC samples and cell lines. Plaque assay determining virus replication was performed to assess the regulation of ß-catenin on IFN-ß signalling. The inhibition of ß-catenin on RLR-mediated IFN-ß signalling was further studied by real-time analyses and reporter assays in the context of lentiviral-mediated ß-catenin stably knocking down. Lastly, co-immunoprecipitation and nuclear fractionation assay were conducted to monitor the interaction between ß-catenin and IRF3. RESULTS: We found that high expression of ß-catenin positively correlated with the expression of IRF3 in CRC cells. Overexpression of ß-catenin increased the viral replication. Conversely knocking down of ß-catenin inhibited viral replication. Furthermore, our data demonstrated that ß-catenin could inhibit the expression of IFN-ß and interferon-stimulated gene 56 (ISG56). Mechanistically, we found that ß-catenin interacted with IRF3 and blocked its nuclear translocation. CONCLUSION: Our study reveals an unprecedented role of ß-catenin in enabling innate immune evasion in CRC.

Hyper activation of ß-catenin signalling induced by IKKε inhibition thwarts colorectal cancer cell proliferation.

OBJECTIVE: Aberrant activation of Wnt/ß-catenin signalling contributes significantly to the development of human colorectal cancers and ß-catenin is the key signalling molecule transducing canonical Wnt/ß-catenin signalling. Therefore, ß-catenin is a promising therapeutic target for cancer treatment. This study demonstrates that the oncogenic IKKε kinase phosphorylates ß-catenin to restrain its hyper activation, therefore promoting colorectal cancer (CRC) cell proliferation. MATERIALS AND METHODS: IKKε and ß-catenin expression levels in human colorectal cancer tissues and cell lines were analysed by immunohistochemical staining and Western blotting. The regulation of IKKε on Wnt/ß-catenin signalling pathway was studied by reporter assay and real-time PCR analysis in the context of IKKε stably knocking down. Co-immunoprecipitation was conducted to monitor the interaction between IKKε and ß-catenin. Kinase assay was performed to measure ß-catenin post-translational modifications induced by IKKε. RESULTS: Oncogenic IKKε kinase is required for the proliferation of colorectal cancer cells. Mechanistically, inhibition of IKKε results in ß-catenin hyper activation and thwarts CRC cell proliferation. Furthermore, IKKε phosphorylates ß-catenin and inhibits the activation of ß-catenin signalling. CONCLUSION: Our study suggests that IKKε is a potential target to combat CRC induced by aberrant Wnt/ß-catenin signalling.