Prostate cancer (CaP) is the second most common cancer in men worldwide in 2012, and radiation therapy is one of the most common definitive treatment options for localized CaP. However, ...radioresistance is a major challenge for the current radiotherapy, accumulating evidences suggest microRNAs (miRNAs), as an important regulator in cellular ionizing radiation (IR) responses, are closely correlated with radiosensitivity in many cancers. Here, we identified microRNA‐16‐5p(miR‐16‐5p) is significantly upregulated in CaP LNCaP cells following IR and can enhance radiosensitivity through modulating Cyclin D1/E1–pRb–E2F1 pathway. To identify the expression profile of miRNAs in CaP cells exposed to IR, we performed human miRNA probe hybridization chip analysis and miR‐16‐5p was found to be significantly overexpressed in all treatment groups that irradiated with different doses of X‐rays and heavy ions (12C6+). Furthermore, overexpression of miR‐16‐5p suppressed cell proliferation, reduced cell viability, and induced cell cycle arrest at G0/G1 phase, resulting in enhanced radiosensitivity in LNCaP cells. Additionally, miR‐16‐5p specifically targeted the Cyclin D1/E1–3′‐UTR in LNCaP cells and affected the expression of Cyclin D1/E1 in both mRNA and protein levels. Taken together, miR‐16‐5p enhanced radiosensitivity of CaP cells, the mechanism may be through modulating Cyclin D1/Cyclin E1/pRb/E2F1 pathway to cause cell cycle arrest at G0/G1 phase. These findings provided new insight into the correlation between miR‐16‐5p, cell cycle arrest, and radiosensitivity in CaP, revealed a previously unrecognized function of miR‐16‐5p–Cyclin D1/E1–pRb–E2F1 regulation in response to IR and may offer an alternative therapy to improve the efficiency of conventional radiotherapy.
microRNA‐16‐5p (miR‐16‐5p) is significantly upregulated in prostate cancer (LNCaP) cells following ionizing radiation (IR) and can enhance radiosensitivity through modulating Cyclin D1/E1‐pRb‐E2F1 pathway.
Transforming growth factor β (TGF‐β) is part of the transforming growth factor β superfamily which is involved in many physiological processes and closely related to the carcinogenesis. Here, we ...discuss the TGF‐β structure, function, and its canonical Smads signaling pathway. Importantly, TGF‐β has been proved that it plays both tumor suppressor as well as an activator role in tumor progression. In an early stage, TGF‐β inhibits cell proliferation and is involved in cell apoptosis. In an advanced tumor, TGF‐β signaling pathway induces tumor invasion and metastasis through promoting angiogenesis, epithelial–mesenchymal transition, and immune escape. Furthermore, we are centered on updated research results into the inhibitors as drugs which have been studied in preclinical or clinical trials in tumor carcinogenesis to prevent the TGF‐β synthesis and block its signaling pathways such as antibodies, antisense molecules, and small‐molecule tyrosine kinase inhibitors. Thus, it is highlighting the crucial role of TGF‐β in tumor therapy and may provide opportunities for the new antitumor strategies in patients with cancer.
We discuss the TGF‐β structure, function, and its canonical Smads signaling pathway. TGF‐β plays both tumor suppressor as well as an activator role in tumor progression. We are centered on updated research results into the inhibitors as drugs which have been studied in preclinical or clinical trials in tumor carcinogenesis to prevent the TGF‐β synthesis and block its signaling pathways such as antibodies, antisense molecules, and small‐molecule tyrosine kinase inhibitors.
As an important biomarker for the early stage of apoptosis, cytochrome c (Cyt c) has been recognized as a key component of the intrinsic apoptotic pathway. Fluorescence imaging tools enabling ...detection of Cyt c in apoptotic signaling have been rarely explored, though they are critical for cell biology and clinical theranostics. Here, we designed a novel label-free N-doped carbon dot (N-doped CD)-based nanosensor that enables fluorescence activation imaging of Cyt c release in cell apoptosis. The inner filter effect of Cyt c towards N-doped CDs enabled quantitative Cyt c measurement. The nanosensor exhibited high sensitivity and selectivity, rapid response, good cell-membrane permeability and low cytotoxicity. All these features are favorable for in situ visualization of Cyt c for apoptosis research. Notably, the developed nanosensor was successfully applied to monitor intracellular release of Cyt c, and to visualize Cyt c in living zebrafish for the first time. Moreover, it also provided a viable platform for cell-based screening of apoptosis-inducing compounds. In virtue of these advantages and potential, the developed assay not only holds great significance for the better understanding of certain diseases at the cellular level, but also provides an invaluable platform for apoptotic studies and screening of anti-cancer drugs toward drug development.
Quiescent cancer cells are major impediments to effective radiotherapy (RT) and exhibit limited sensitivity to traditional photon therapy. Herein, the functional role and underlying mechanism of ...carbon ions in overcoming the radioresistance of quiescent cervical cancer HeLa cells were determined. Briefly, serum withdrawal was used to induce synchronized quiescence in HeLa cells. Quiescent HeLa cells displayed strong radioresistance and DNA repair potential. After irradiation with carbon ions, the DNA damage repair pathway may markedly rely on error‐prone nonhomologous end‐joining in proliferating cells, whereas the high‐precision homologous recombination pathway is more relevant in quiescent cells. This phenomenon could be explained by the ionizing radiation (IR)‐induced cell cycle re‐entry of quiescent cancer cells. There are three strategies for eradicating quiescent cancer cells using high‐linear energy transfer (LET) carbon ions: direct cell death through complex DNA damage; apoptosis via an enhanced mitochondria‐mediated intrinsic pathway; forced re‐entry of quiescent cancer cells into the cell cycle, thereby improving their susceptibility to IR. Silencing β‐catenin signaling is essential for maintaining the dormant state in quiescent cells. Herein, carbon ions activated the β‐catenin pathway in quiescent cells, and inhibition of this pathway improved the resistance of quiescent HeLa cells to carbon ions by alleviating DNA damage, improving DNA damage repair, maintaining quiescent depth, and inhibiting apoptosis. Collectively, carbon ions conquer the radioresistance of quiescent HeLa cells by activating β‐catenin signaling, which provides a theoretical basis for improved therapeutic effects in patients with middle‐advanced‐stage cervical cancer with radioresistance.
Cyclin D1 (CCND1), a mediator of cell cycle control, has a G870A polymorphism which results in the formation of two splicing variants: full‐length CCND1 (CCND1a) and C‐terminally truncated CCND1 ...species (CCND1b). However, the role of CCND1a and CCND1b variants in cancer chemoresistance remains unknown. Therefore, this study aimed to explore the molecular mechanism of alternative splicing of CCND1 in breast cancer (BC) chemoresistance. To address the contribution of G870A polymorphism to the production of CCND1 variants in BC chemoresistance, we sequenced the G870A polymorphism and analysed the expressions of CCND1a and CCND1b in MCF‐7 and MCF‐7/ADM cells. In comparison with MCF‐7 cells, MCF‐7/ADM cells with the A allele could enhance alternative splicing with the increase of SC‐35, upregulate the ratio of CCND1b/a at both mRNA and protein levels, and activate the CDK4/CyclinD1‐pRB‐E2F1 pathway. Furthermore, CCND1b expression and the downstream signalling pathway were analysed through Western blotting and cell cycle in MCF‐7/ADM cells with knockdown of CCND1b. Knockdown of CCND1b downregulated the ratio of CCND1b/a, demoted cell proliferation, decelerated cell cycle progression, inhibited the CDK4/CyclinD1‐pRB‐E2F1 pathway and thereby decreased the chemoresistance of MCF‐7/ADM cells. Finally, CCND1 G870A polymorphism, the alternative splicing of CCDN1 was detected through Sequenom Mass ARRAY platform, Sanger sequencing, semi‐quantitative RT‐PCR, Western blotting and immunohistochemistry in clinical BC specimens. The increase of the ratio of CCND1b/a caused by G870A polymorphism was involved in BC chemoresistance. Thus, these findings revealed that CCND1b/a ratio caused by the polymorphism is involved in BC chemoresistance via CDK4/CyclinD1‐pRB‐E2F1 pathway.
TP53, a crucial tumor suppressor gene, is the most commonly mutated gene in human cancers. Aside from losing its tumor suppressor function, mutant p53 (mutp53) often acquires inherent, novel ...oncogenic functions, which is termed "gain-of-function". Emerging evidence suggests that mutp53 is highly associated with advanced malignancies and poor prognosis, which makes it a target for development of novel cancer therapies. Herein, we provide a summary of our knowledge of the mutp53 types and mutp53 spectrum in cancers. The mechanisms of mutp53 accumulation and gain-of-function are also summarized. Furthermore, we discuss the gain-of-function of mutp53 in cancers: genetic instability, ferroptosis, microenvironment, and stemness. Importantly, the role of mutp53 in the clinic is also discussed, particularly with regard to chemotherapy and radiotherapy. Last, emphasis is given to emerging strategies on how to target mutp53 for tumor therapy. Thus, this review will contribute to better understanding of the significance of mutp53 as a target for therapeutic strategies.
Pre-mRNA splicing is a fundamental process that plays a considerable role in generating protein diversity. Pre-mRNA splicing is also the key to the pathology of numerous diseases, especially cancers. ...In this review, we discuss how aberrant splicing isoforms precisely regulate three basic functional aspects in cancer: proliferation, metastasis and apoptosis. Importantly, clinical function of aberrant splicing isoforms is also discussed, in particular concerning drug resistance and radiosensitivity. Furthermore, this review discusses emerging strategies how to modulate pathologic aberrant splicing isoforms, which are attractive, novel therapeutic agents in cancer. Last we outline current and future directions of isoforms diagnostic methodologies reported so far in cancer. Thus, it is highlighting significance of aberrant splicing isoforms as markers for cancer and as targets for cancer therapy.
A substantial number of long noncoding RNAs (lncRNAs) have been identified as potent regulators of human disease. Human leukocyte antigen complex group 18 (HCG18) is a new type of lncRNA that has ...recently been proven to play an important role in the occurrence and development of various diseases. Studies have found that abnormal expression of HCG18 is closely related to the clinicopathological characteristics of many diseases. More importantly, HCG18 was also found to promote disease progression by affecting a series of cell biological processes. This article mainly discusses the expression characteristics, clinical characteristics, biological effects and related regulatory mechanisms of HCG18 in different human diseases, providing a scientific theoretical basis for its early clinical application.
Cyclin D1 (CCND1), a crucial mediator of cell cycle progression, possesses many mutation types with different mutation frequencies in human cancers. The G870A mutation is the most common mutation in ...CCND1, which produces two isoforms: full-length CCND1a and divergent C-terminal CCND1b. The dysregulation of the CCND1 isoforms is associated with multiple human cancers. Exploring the molecular mechanism of CCND1 isoforms has offer new insight for cancer treatment. On this basis, the alterations of CCND1 gene are described, including amplification, overexpression, and mutation, especially the G870A mutation. Subsequently, we review the characteristics of CCND1 isoforms caused by G870A mutation. Additionally, we summarize cis-regulatory elements, trans-acting factors, and the splice mutation involved in splicing regulation of CCND1. Furthermore, we highlight the function of CCND1 isoforms in cell cycle, invasion, and metastasis in cancers. Importantly, the clinical role of CCND1 isoforms is also discussed, particularly concerning prognosis, chemotherapy, and radiotherapy. Last, emphasis is given to the corrective strategies that modulate the cancerous CCND1 isoforms. Thus, it is highlighting significance of aberrant isoforms of CCND1 as targets for cancer therapy.
During the process of oxidative phosphorylation, protons are pumped into the mitochondrial intermembrane space to establish a mitochondrial membrane potential (MMP). The electrochemical gradient ...generated allows protons to return to the matrix through the ATP synthase complex and generates ATP in the process. MitoQ is a lipophilic cationic drug that is adsorbed to the inner mitochondrial membrane; however, the cationic moiety of MitoQ remains in the intermembrane space. We found that the positive charges in MitoQ inhibited the activity of respiratory chain complexes I, III, and IV, reduced proton production, and decreased oxygen consumption. Therefore, a pseudo-MMP (PMMP) was formed via maintenance of exogenous positive charges. Proton backflow was severely impaired, leading to a decrease in ATP production and an increase in AMP production. Excess AMP activates AMP kinase, which inhibits the MTOR (mechanistic target of rapamycin) pathway and induces macroautophagy/autophagy. Therefore, we conclude that MitoQ increases PMMP via proton displacement with exogenous positive charges. In addition, PMMP triggered autophagy in hepatocellular carcinoma HepG2 cells via modification of mitochondrial bioenergetics pathways.
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