A light-controlled single-atom nanozyme hydrogels for glutathione depletion mediated low-dose radiotherapy.

Due to the unique ability to mimic natural enzymes, single-atom nanoenzymes (SAE) have garnered significant attention and research in tumor therapy. However, their efficacy often faces challenges in terms of drug delivery methods, and the research regarding their applications in radiotherapy is scarce. Herein, we introduce a light-controlled SAE hydrogel platform (SH) for glutathione-depletion-mediated low-dose radiotherapy. The SH incorporates a Cu single-atom enzyme (CuSA), and upon irradiation with 1064 nm near-infrared light, the CuSA can convert light energy into heat, which in turn degrades the hydrogel, enabling the release of CuSA into tumor cells or tissues. The diffused CuSA not only can facilitate the conversion of H2O2into hydroxyl radicals (•OH), but also can effectively depletes cellular glutathione. This leads to increased sensitivity of tumor cells to radiotherapy, resulting in enhanced cytotoxicity even at low doses. The animal study results further confirmed the good tumor-killing efficacy of this SH system. To the best of our knowledge, this stands as the pioneering report on leveraging a single-atom enzyme for GSH depletion-mediated low-dose radiotherapy.

Features of combined gut bacteria and fungi from a Chinese cohort of colorectal cancer, colorectal adenoma, and post-operative patients.

Colorectal cancer (CRC) accounts for the third highest morbidity burden among malignant tumors worldwide. Previous studies investigated gut microbiome changes that occur during colorectal adenomas (CRA) progression to overt CRC, thus highlighting the importance of the gut microbiome in carcinogenesis. However, few studies have examined gut microbiome characteristics across the entire spectrum, from CRC development to treatment. The study used 16S ribosomal ribonucleic acid and internal transcribed spacer amplicon sequencing to compare the composition of gut bacteria and fungi in a Chinese cohort of healthy controls (HC), CRC patients, CRA patients, and CRC postoperative patients (PP). Our analysis showed that beta diversity was significantly different among the four groups based on the gut bacterial and fungal data. A total of 51 species of bacteria and 8 species of fungi were identified in the HC, CRA, CRC, and PP groups. Correlation networks for both the gut bacteria and fungi in HC vs. CRA, HC vs. CRC, and HC vs. PP indicated some hub bacterial and fungal genera in each model, and the correlation between bacterial and fungal data indicated that a highly significant negative correlation exists among groups. Quantitative polymerase chain reaction (qPCR) analysis in a large cohort of HC, CRC, CRA, and PP patients demonstrated a significantly increasing trend of Fusobacterium nucleatum, Bifidobacterium bifidum, Candida albicans, and Saccharomyces cerevisiae in the feces of CRC patients than that of HC patients (p < 0.01). However, the abundance levels of CRA and PP were significantly lower in HC patients than those in CRC patients. Further studies are required to identify the functional consequences of the altered bacterial/fungal composition on metabolism and CRC tumorigenesis in the host.

Synthesis and Functions of Resistant Starch.

Resistant starch (RS) has become a popular topic of research in recent years. Most scholars believe that there are 5 types of RS. However, accumulating evidence indicates that in addition to starch-lipid complexes, which are the fifth type of RS, complexes containing starch and other substances can also be generated. The physicochemical properties and physiologic functions of these complexes are worth exploring. New physiologic functions of several original RSs are constantly being discovered. Research shows that RS can provide health improvements in many patients with chronic diseases, including diabetes and obesity, and even has potential benefits for kidney disease and colorectal cancer. Moreover, RS can alter the short-chain fatty acids and microorganisms in the gut, positively regulating the body's internal environment. Despite the increase in its market demand, RS production remains limited. Upscaling RS production is thus an urgent requirement. This paper provides detailed insights into the classification, synthesis, and efficacy of RS, serving as a starting point for the future development and applications of RS based on the current status quo.

ALKBH5 promotes hypopharyngeal squamous cell carcinoma apoptosis by targeting TLR2 in a YTHDF1/IGF2BP2-mediated manner.

Hypopharyngeal squamous cell carcinoma (HPSCC) is one of the most aggressive cancers and is notorious for its extremely poor prognosis. However, very few molecular biological studies have been performed. As a novel method of epigenetic gene modulation, N6-methyladenosine (m6A) RNA modification occurs in HPSCC. The expression of the m6A demethylase AlkB homolog 5 (ALKBH5) is frequently downregulated in human HPSCC. Furthermore, we found that ALKBH5 impaired cell proliferation by regulating human Toll-like receptor 2 (TLR2) in an m6A-dependent manner in HPSCC cells. ALKBH5 decreased TLR2 m6A modification, which could be recognized by the m6A readers IGF2BP2 and YTHDF1. IGF2BP2 facilitates TLR2 mRNA stability, whereas YTHDF1 promotes TLR2 mRNA translation. The current work uncovered a critical function of ALKBH5 in TLR2 regulation and provides a novel role for m6A demethylation of mRNA in HPSCC. The inhibition of m6A modification of ALKBH5 in HPSCC deserves further clinical investigation.

Nec-1 enhances shikonin-induced apoptosis in leukemia cells by inhibition of RIP-1 and ERK1/2.

Necrostatin-1 (Nec-1) inhibits necroptosis by allosterically inhibiting the kinase activity of receptor-interacting protein 1 (RIP1), which plays a critical role in necroptosis. RIP1 is a crucial adaptor kinase involved in the activation of NF-κB, production of reactive oxygen species (ROS) and the phosphorylation of mitogen activated protein kinases (MAPKs). NF-κB, ROS and MAPKs all play important roles in apoptotic signaling. Nec-1 was regarded as having no effect on apoptosis. Here, we report that Nec-1 increased the rate of nuclear condensation and caspases activation induced by a low concentration of shikonin (SHK) in HL60, K562 and primary leukemia cells. siRNA-mediated knockdown of RIP1 significantly enhanced shikonin-induced apoptosis in K562 and HL60 cells. Shikonin treatment alone could slightly inhibit the phosphorylation of ERK1/2 in leukemia cells, and the inhibitory effect on ERK1/2 was significantly augmented by Nec-1. We also found that Nec-1 could inhibit NF-κB p65 translocation to the nucleus at a later stage of SHK treatment. In conclusion, we found that Nec-1 can promote shikonin-induced apoptosis in leukemia cells. The mechanism by which Nec-1 sensitizes shikonin-induced apoptosis appears to be the inhibition of RIP1 kinase-dependent phosphorylation of ERK1/2. To our knowledge, this is the first study to document Nec-1 sensitizes cancer cells to apoptosis.

The Relationship between Ultrasonographic Features of Hepatocellular Carcinoma and the Severity of Hepatocellular Carcinoma and the Expression of PTEN and Tg737.

To investigate the relationship between the ultrasonographic features of hepatocellular carcinoma (HCC) and the severity of HCC and the expression of tumor suppressor genes PTEN and Tg737, 90 patients with primary liver cancer are selected as the study subjects. The enhancement of liver tumor in arterial phase, portal venous phase, and delayed phase is observed by contrast-enhanced ultrasound (CEUS) before operation, and the echo intensity is compared with that of surrounding liver parenchyma. Immunohistochemistry is used to detect the expression of PTEN and Tg737 in hepatocellular carcinoma and paracancerous tissues. (1) In HCC, CEUS enhancement is characterized by rapid enhancement in arterial phase, enhancement in portal venous phase and delayed phase, and decreased hypoechoic changes. About 78.0% of the stage I-II liver cancer and 85.0% of the stage III-IV liver cancer show rapid enhancement and high echo in the arterial phase; only 8.0% of the stage I-II liver cancer shows moderate echo changes in the portal venous phase, while 32.5% (13/40) stage III-IV liver cancer shows moderate echo changes in the portal venous phase. (2) The positive rates of PTEN in liver cancer tissues and paracancerous tissues are 21.1% (19/90) and 70.0% (63/90), respectively, and the difference is statistically significant. The positive rates of Tg737 in liver cancer tissues and paracancerous tissues are 17.8% (16/90) and 75.6% (68/90), respectively, and the difference is statistically significant. Compared with PTEN and Tg737 negative groups, the ascending slope (RS) and initial elimination time (WT) of PTEN and Tg737 positive groups are significantly higher, indicating that the inflow velocity of contrast medium in the positive group is higher, the outflow time is shorter, and the lesions shows low enhancement rapidly. However, the expression of PTEN and Tg737 had no significant difference in maximal intensity (IMAX), peak time (TTP), and mean transit time (mTT). (3) Correlation analysis shows that the immunohistochemical scores of PTEN and Tg737 are not significantly correlated with IMAX, mTT, and TTP but positively correlated with RS (r = 0.359,P < 0.05), suggesting that the positive expressions of PTEN and Tg737 are negatively correlated with the inflow velocity of contrast medium. The immunohistochemical scores of PTEN and Tg737 are negatively correlated with WT, which indicated that the higher the expression intensity of PTEN is, the longer the outflow time of contrast medium is and the slower the outflow of contrast medium is. There is a significant correlation between the expression of PTEN and Tg737 proteins and CEUS parameters in hepatocellular carcinoma.

Author Correction: Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

YTHDF1-enhanced iron metabolism depends on TFRC m6A methylation.

Background: Among head and neck squamous cell carcinomas (HNSCCs), hypopharyngeal squamous cell carcinoma (HPSCC) has the worst prognosis. Iron metabolism, which plays a crucial role in tumor progression, is mainly regulated by alterations to genes and post-transcriptional processes. The recent discovery of the N6-methyladenosine (m6A) modification has expanded the realm of previously undiscovered post-transcriptional gene regulation mechanisms in eukaryotes. Many studies have demonstrated that m6A methylation represents a distinct layer of epigenetic deregulation in carcinogenesis and tumor proliferation. However, the status of m6A modification and iron metabolism in HPSCC remains unknown. Methods: Bioinformatics analysis, sample analysis, and transcriptome sequencing were performed to evaluate the correlation between m6A modification and iron metabolism. Iron metabolic and cell biological analyses were conducted to evaluate the effect of the m6A reader YTHDF1 on HPSCC proliferation and iron metabolism. Transcriptome-wide m6A-seq and RIP-seq data were mapped to explore the molecular mechanism of YTHDF1 function in HPSCC. Results: YTHDF1 was found to be closely associated with ferritin levels and intratumoral iron concentrations in HPSCC patients at Sir Run Run Shaw Hospital. YTHDF1 induced-HPSCC tumorigenesis depends on iron metabolism in vivo in vitro. Mechanistically, YTHDF1 methyltransferase domain interacts with the 3'UTR and 5'UTR of TRFC mRNA, then further positively regulates translation of m6A-modified TFRC mRNA. Gain-of-function and loss-of-function analyses validated the finding showing that TFRC is a crucial target gene for YTHDF1-mediated increases in iron metabolism. Conclusion: YTHDF1 enhanced TFRC expression in HPSCC through an m6A-dependent mechanism. From a therapeutic perspective, targeting YTHDF1 and TFRC-mediated iron metabolism may be a promising strategy for HPSCC.

[Increased serum IL-6 and soluble IL-6 receptor in breast cancer patients after radiotherapy are correlated with proportions of immune cells].

Objective To investigate the value of serum interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) levels of breast cancer patients in evaluating immune function after radiotherapy. Methods We randomly selected 55 cases of breast cancer patients who had received radiotherapy as an observation group, and 55 cases of normal healthy adults as a control group. ELISA was used to detect serum IL-6 and sIL-6R levels. Flow cytometry was used to detect CD45+CD19+ B lymphocytes, CD45+CD3+CD4+ T lymphocytes, CD45+CD3+CD8+ T lymphocytes and CD45+CD16+CD56+ NK cells in peripheral blood. The correlation of lymphocyte subsets with IL-6 or sIL-6R levels was analyzed. Results Serum IL-6 and sIL-6R levels of the observation group patients after radiotherapy were significantly higher than those before radiotherapy and in the control group, and the IL-6 and sIL-6R levels of patients of III or IV stage breast cancer increased significantly. Flow cytometry showed that the ratios of total T lymphocytes and NK cells in the observation group after radiotherapy were significantly reduced, while the ratio of B lymphocytes was significantly elevated. In addition, the levels of IL-6 and sIL-6R were positively correlated with the ratio of NK cells and negatively correlated with the ratio of B lymphocytes. Conclusion Serum IL-6 and sIL-6R levels in patients with breast cancer can be used as references for assessing the course of breast cancer and immune function after radiotherapy.

Cyclosporine A sensitizes lung cancer cells to crizotinib through inhibition of the Ca2+/calcineurin/Erk pathway.

BACKGROUND: Crizotinib has potent anti-tumor activity in patients with advanced MET-amplified non-small cell lung cancer (NSCLC). However, the therapeutic effect is still not satisfying. Thus, developing approaches that improve the efficacy of crizotinib remains a significant challenge. METHODS: MET-amplified NSCLC cell lines were treated with crizotinib and cyclosporine A (CsA). Cell viability was determined by MTS assay. The changes of apoptosis, cell cycle and calcineurin-Erk pathways were assessed by western blot. Xenograft mouse model, primary human NSCLC cells and hollow fiber assays were utilized to confirm the effects of CsA. FINDINGS: We demonstrated that CsA significantly increased the anti-tumor effect of crizotinib on multiple MET-amplified NSCLC cells in vitro and in vivo. Mechanistically, crizotinib treatment led to the activation of Ca2+-calcineurin (CaN)-Kinase suppressor of Ras 2 (KSR2) signaling, resulting in Erk1/2 activation and enhanced survival of cancer cells. CsA effectively blocked CaN-KSR2-Erk1/2 signaling, promoting crizotinib-induced apoptosis and G2/M arrest. Similarly, pharmacologic or genetic inhibition of Erk1/2 also enhanced crizotinib-induced growth inhibition in vitro. Xenograft studies further confirmed that CsA or Erk1/2 inhibitor PD98059 enhanced the anti-cancer activity of crizotinib through inhibition of CaN-Erk1/2 axis. The results were also validated by primary human NSCLC cells in vitro and hollow fiber assays in vivo. INTERPRETATION: This study provides preclinical evidences that combination therapy of CsA and crizotinib is a promising approach for targeted treatment of MET-amplified lung cancer patients. FUND: This work was supported by the National Natural Science Foundation of China, the Key Projects of Natural Foundation of Zhejiang Province, the Ten thousand plan youth talent support program of Zhejiang Province, the Zhejiang Natural Sciences Foundation Grant, and the Zhejiang medical innovative discipline construction project-2016.

Identification of key tumorigenesis­related genes and their microRNAs in colon cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors and its development involves multi­gene driven processes that affect the digestive system. The objective of this study was to identify tumorigenesis­associated gene signatures using microarray expression profiling data. The gene expression profiling of GSE39582, a dataset containing 566 colon cancer samples and 19 non­tumoral colorectal mucosae was downloaded from Gene Expression Omnibus (GEO) database. A total of 439 differentially expressed genes (DEGs) were extracted by GEO2R. Many of these DEGs were cancer­related, involved in the regulation of cell proliferation, extracellular matrix (ECM)­receptor interaction and phosphatidylinositol 3­kinase (PI3K)­Akt signaling pathway according to the results of pathway enrichment analysis in Database for Annotation, Visualization and Integrated Discovery (DAVID). Then, 10 genes were predicted to play an important role in the development of CRC. Transient receptor potential cation channel, subfamily M, and member 6 (TRPM6), a member of 10 hub genes, was confirmed to be downregulated in 16 (80%) of 20 colon cancer tissues using quantitative polymerase chain reaction (qPCR) technology. Furthermore, high expression of TRPM6 was indicative of a prolonged overall survival (OS) in CRC patients through the analysis of GSE39582. Hsa­let­7g and hsa­let­7f­1 were believed to be the regulatory miRNAs of TRPM6 by TCGA and miRanda database. In conclusion, this study may play a critical role in promoting the discovery of potential targets for diagnosis, treatment and prognosis of CRC.

Multiple Primary Malignant Tumors - A Clinical Analysis of 15,321 Patients with Malignancies at a Single Center in China.

Background: Multiple primary malignant tumors (MPMTs) are defined as two or more histologically distinct malignancies in one individual, standard treatments for MPMTs are not well established, we aimed to clinical analyze the factors influence the treatment efficacy of MPMTs. Methods: This study retrospectively analyzed 15,321 malignant tumor patients at the Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China, between March 2006 and June 2016. The survival analysis was performed with SPSS version 22.0 (SPSS Inc., Chicago, IL, USA) with Kaplan-Meier methodology. Results: The prevalence of MPMTs in our study was 1.09% (167/15321), with a male to female ratio of 2.34:1. Specifically, 98 patients harbored synchronous MPMTs, and 69 patients harbored metachronous MPMTs. The most common cancer pairs were digestive-digestive tumor (43 patients, 25.75%), digestive-lung cancer (32 patients, 19.16%), and head & neck-digestive tumor (11 patients, 6.59%). Among patients with synchronous and metachronous first primary cancers, 65.86% received surgery. 33.33% (27/81) of the patients with synchronous MPMTs received simultaneous resection. Of the 69 patients with metachronous MPMTs, 31.88% (22/69) were treated with surgery alone, 62.32% (43/69) received chemotherapy and/or radiotherapy for the first primary tumor, and 44.93% (31/69) received surgery for the other primary tumor. 98.20% (164/167) of patients with MPMTs were effectively followed up, the overall 2- and 5-year survival rates were 54.3% and 31.4%, respectively, with a median survival time of 28.0 months. Conclusions: The early diagnosis of rare MPMTs should not be neglected in patients not only when treated for a primary malignancy but also during long-term follow-up. Effective treatment for MPMTs may yield promising curative effect and warrants further investigation.

Autophagy inhibition contributes to Endostar sensitization in esophageal squamous cell carcinoma.

Endostar is a novel artificially-synthesized anti-angiogenesis drug, and has been approved for clinical use. Previous studies have indicated that patients with esophageal cancer could benefit from Endostar combined with chemotherapy or chemoradiotherapy. However, the most advantageous use of this drug remains to be elucidated. The role of autophagy in cancer treatment remains controversial. The results of the present study demonstrated that Endostar promotes autophagy activation, which is regulated via phosphorylation inhibition of the downstream signaling molecules of the vascular endothelial growth factor, AKT serine/threonine kinase and mechanistic target of rapamycin signaling pathways. Furthermore, inhibiting autophagy using the pharmacological inhibitor chloroquine facilitated the antiproliferative effect of Endostar and increased the number of apoptotic cells, compared with Endostar monotherapy. Taken together, the results of the present study suggest that autophagy activation induced by Endostar serves a protective role in human esophageal cancer treatment, and that autophagy inhibition promotes the antiproliferative role of Endostar. Therefore, the combination of Endostar with an autophagy inhibitor may be a novel prospective approach to improving the efficacy of Endostar for the treatment of patients with esophageal cancer.

Quantitation of cell-free DNA in blood is a potential screening and diagnostic maker of breast cancer: a meta-analysis.

INTRODUCTION: Increased cell-free DNA (cfDNA) levels in circulating blood have been associated with higher possibility of breast cancer, however, researchers have not reached an agreement on its analysis. MATERIALS AND METHODS: We conducted a meta-analysis of 12 retrospective studies to clarify the value of cfDNA quantification in screening and diagnosis of breast cancer. PubMed, EMBASE, Web of Science and Cochrane library were searched from January, 2000 to October, 2016. Pooled analyses were estimated using a random effects model. RESULTS: In total, 1003 primary breast cancer patients, 283 cases with benign breast disease and 575 healthy individuals were included. Pooled diagnostic odds ratio (DOR) was 27.63 (95% confidence interval [CI]: 10.96~69.61, I2 = 86.2%, P < 0.001) in discriminating between breast cancer and healthy controls; the area under the summary receiver operating characteristic (SROC) curve measured 0.91 (95% CI: 0.17~1.00). Analysis of available data in distinguishing breast cancer and benign breast disease showed a pooled DOR of 35.30 (95% CI: 7.58~164.39, I2 = 79.9%, P = 0.002) with an area under SROC of 0.91 (95% CI: 0.89~0.93). Ethnic group distribution based geographical factors suggested by meta-regression and subgroup analyses explained most of the heterogeneity. CONCLUSIONS: Quantification of cfDNA is a promising test in screening and diagnostic of breast cancer, but population-based standardization of test methods require completion prior to clinical use.

ENSO Modulations due to Interannual Variability of Freshwater Forcing and Ocean Biology-induced Heating in the Tropical Pacific.

Recent studies have identified clear climate feedbacks associated with interannual variations in freshwater forcing (FWF) and ocean biology-induced heating (OBH) in the tropical Pacific. The interrelationships among the related anomaly fields are analyzed using hybrid coupled model (HCM) simulations to illustrate their combined roles in modulating the El Niño-Southern Oscillation (ENSO). The HCM-based supporting experiments are performed to isolate the related feedbacks, with interannually varying FWF and OBH being represented individually or collectively, which allows their effects to be examined in a clear way. It is demonstrated that the interannual freshwater forcing enhances ENSO variability and slightly prolongs the simulated ENSO period, while the interannual OBH reduces ENSO variability and slightly shortens the ENSO period, with their feedback effects tending to counteract each other.

Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.

Autophagy is an evolutionarily conserved survival pathway in eukaryote and is frequently upregulated in cancer cells after chemotherapy or targeted therapy. Thus induction of autophagy has emerged as a drug resistance mechanism. In this study, we found that crizotinib induced a high level of autophagy in lung cancer cells through inhibition of STAT3. Ectopic expression of wild-type or constitutive activated STAT3 significantly suppressed the effect of crizotinib on autophagy. Interestingly, crizotinib-mediated inhibition of STAT3 is in a step-wise manner. Firstly it inhibited cytoplasmic STAT3, which leads to the phosphorylation of EIF2A, then inhibited nuclear STAT3, which leads to the downregulation of BCL-2. Cell death induced by crizotinib was greatly enhanced after the inhibition of autophagy by the pharmacological inhibitors or shRNAs against Beclin-1. Moreover, the autophagy inhibitor HCQ significantly augmented the anti-tumor effect of crizotinib in a mouse xenograft model. In conclusion, crizotinib can induce cytoprotective autophagy by suppression of STAT3 in lung cancer cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of crizotinib in the treatment of targeted lung cancer patients.

The role of STAT3 in autophagy.

Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the classic autophagy model and also into cancer therapy, especially for the emerging targeted therapy, because a series of targeted agents execute antitumor activities via blocking STAT3 signaling, which inevitably affects the autophagy pathway. Here, we review several of the representative studies and the current understanding in this particular field.

Autophagy: A novel therapeutic target for hepatocarcinoma (Review).

Autophagy is a highly conserved intracellular degradation process and plays an important role in hepatocarcinogenesis. Available data show that autophagy is involved in anti-hepatocarcinoma (HCC) therapies. Autophagy regulation involves a novel target for overcoming therapeutic resistance and sensitizing HCC to currently therapeutic methods. This is a systematic review on the interface of autophagy and the development of HCC and outlining the role of autophagy in current anti-HCC approaches. Understanding the significance of autophagy in anti-HCC therapy may offer a novel therapeutic target for improving anti-cancer efficacy and prolong survival for HCC patients.

Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib.

Autophagy is a critical survival pathway for cancer cells under conditions of stress. Thus, induction of autophagy has emerged as a drug resistance mechanism. This study is to determine whether autophagy is activated by a novel multikinase inhibitor linifanib, thereby impairing the sensitivity of hepatocellular carcinoma (HCC) cells to this targeted therapy. Here, we found that linifanib induced a high level of autophagy in HCC cells, which was accompanied by suppression of phosphorylation of PDGFR-ß and its downstream Akt/mTOR and Mek/Erk signaling pathways. Cell death induced by linifanib was greatly enhanced after autophagy inhibition by the pharmacological inhibitors or siRNAs against autophagy related genes, ATG5 and ATG7, in vitro. Moreover, HCQ, an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-HCC effect of linifanib in a mouse xenograft model. In conclusion, linifanib can induce cytoprotective autophagy by suppression of PDGFR-ß activities in HCC cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of linifanib in the treatment of HCC patients.

Epigenetic regulation of the human telomerase reverse transciptase gene: A potential therapeutic target for the treatment of leukemia (Review).

Telomerase activation is a critical step in human carcinogenesis through the maintenance of telomeres. Telomerase activity is primarily regulated by the human telomerase reverse transcriptase gene (hTERT), thus, an improved understanding of the transcriptional control of hTERT may provide potential therapeutic targets for the treatment of leukemia and other forms of cancer. Epigenetic modulation, a significant regulatory process in cell biology, has recently been shown to be involved in the regulation of the hTERT gene. Moreover, several epigenetic modifiers, including DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, are now in pre- and early clinical trials of leukemia as monotherapies or in combination with other drugs, and have achieved significant clinical success. In the present review, the epigenetic mechanisms associated with telomerase activity in leukemia, and the therapeutic potential of an antitelomerase strategy that combines epigenetic modifiers with telomerase hTR subunit small molecule inhibitors are discussed.