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Risk prediction tools for colorectal cancer (CRC) have potential to improve the efficiency of population-based screening by facilitating risk-adapted strategies. However, such an applicable tool has yet to be established in the Chinese population. In this study, a risk score was created using data from the China Kadoorie Biobank (CKB), a nationwide cohort study of 409,854 eligible participants. Diagnostic performance of the risk score was evaluated in an independent CRC screening programme, which included 91,575 participants who accepted colonoscopy at designed hospitals in Zhejiang Province, China. Over a median follow-up of 11.1 years, 3136 CRC cases were documented in the CKB. A risk score was created based on nine questionnaire-derived variables, showing moderate discrimination for 10-year CRC risk (C-statistic = 0.68, 95 % CI: 0.67-0.69). In the CRC screening programme, the detection rates of CRC were 0.25 %, 0.82 %, and 1.93 % in low-risk (score <6), intermediate-risk (score: 6-19), and high-risk (score >19) groups, respectively. The newly developed score exhibited a C-statistic of 0.65 (95 % CI: 0.63-0.66), surpassing the widely adopted tools such as the Asia-Pacific Colorectal Screening (APCS), modified APCS, and Korean Colorectal Screening scores (all C-statistics = 0.60). In conclusion, we developed a novel risk prediction tool that is useful to identify individuals at high risk of CRC. A user-friendly online calculator was also constructed to encourage broader adoption of the tool., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glioma-associated oncogene homolog 1 (GLI1) is a core component of the Hedgehog (HH) signalling pathway and is a transcription activator of numerous oncogenes, such as SOX9, VEGFA, BCL2, and CDK2. The complex regulation of GLI1 involves numerous pathways and molecules, including HH-dependent and independent, epigenetic and post-transcriptional mechanisms. Here, we report the discovery, characterization and function of a novel sense promoter-associated ncRNA, paGLI1 that is overexpressed in infiltrating glioma. We show that paGLI1 promotes GLI1 gene transcription through binding to and recruitment of the transcription factor complex FUS/P65 by interacting with paGLI1 DNA sequence. This interaction facilitates FUS/P65 binding to the GLI1 promoter to activate GLI1 transcription and hence its downstream oncogenes, which results in enhancement of glioma cell proliferation and invasiveness. Importantly, over-expression of paGLI1 is a significant unfavorable prognosticator for both disease-specific and progression-free survival in glioma patients, with relative risks being 2.932 (95% confidence interval: 1.280 to 6.713) (P < 0.05) and 2.284 (95% confidence interval: 1.051 to 4.966) (P < 0.05), respectively. The novel paGLI1/FUS/P65 regulatory mechanisms play important roles in infiltrating glioma progression and may serve as potential targets for future therapeutics., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Substantial progress has been made in cancer screening in China due to the substantial efforts of all levels of the government. Four large-scale population-based screening programs have been launched since 2005. In these programs, individuals at high risk for the most common types of cancer are screened with no cost. However, there are still wide gaps remaining between the cancer screening objectives and reality. In this review, we summarize the current status of cancer screening, identify the major achievements and challenges of cancer screening, and propose some suggested improvements based on the existing evidence. The main challenges include low participation rates, the uneven distribution of medical sources, inadequate funding, and insufficient screening quality. Some suggestions that should be considered to improve the quality of cancer screening include advertising to increase awareness, providing universal training of staff involved in screening programs, optimizing the definition of high-risk populations, integrating new technologies into cancer screening programs, and implementing appropriate management measures among individuals with positive screening results., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Patients with Her2-positive breast cancer exhibit de novo resistance or develop acquired resistance in less than one year after Her2 targeting treatment, but the mechanism is not fully elucidated. Compensatory pathways such as the IGF-1R/IRS-1 pathway, are activated, leading to aberrant enhanced PI3K/Akt/mTOR pathway activity to attenuate the efficacy of trastuzumab. Cullin7 could participate in the degradation of IRS-1 in a mTOR/S6K dependent manner. Whether Cullin7 participates in trastuzumab resistance needs to be further investigated. Here, we reveals that Cullin7 is overexpressed in trastuzumab-resistant Her2 positive breast cancer cells. Knockdown of Cullin7 reduces degradation of Ser phosphorylation of IRS-1, attenuates activation of the PI3K/AKT pathway, and partly restores trastuzumab sensitivity in trastuzumab-resistant Her2 positive breast cancer cells. IGFBP-3 expression is decreased in trastuzumab-resistant Her2 positive breast cancer cells, which leads to release of the Wnt signaling pathway inhibition and an increase in Cullin7 expression, as mediated by TCF7L2. Overexpression of Cullin7 in Her2-amplified breast cancer tissues has clinical implications because it positively correlates with shorter disease-free survival (DFS) and inadequate response to trastuzumab. Thus, our results suggest a critical role for Cullin7 in response to trastuzumab, which has significant implications for selection of the optimal therapeutic strategy for Her2 positive breast cancers., (Copyright © 2019 Elsevier B.V. All rights reserved.)

NAD(P)H: quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme which is associated with poor prognosis in human breast, colon, lung and liver cancers. However, the molecular mechanisms underlying the pro-tumorigenic function of NQO1 remains unclear. This study investigated the function of NQO1 in the context of hepatocellular carcinoma (HCC) development. We found that NQO1 was frequently up-regulated in human liver cancer, and its high expression level was correlated with the tumor stage and low survival rate of HCC patients. Loss-of-function of NQO1 inhibited growth in HCC cells with increased apoptosis in vitro, and suppressed orthotopic tumorigenicity in vivo. Mechanistically, high level of NQO1 in HCC cells enhanced protein stability of X-linked inhibitor of apoptosis protein (XIAP) by increasing its phosphorylation at Ser 87. Reintroduction of wile type XIAP and the phospho-mimic mutants XIAP S87D significantly reversed NQO1 knock-down/out induced growth inhibition and apoptosis. In mouse model with orthotopically implanted hepatocarcinoma, NQO1 suppression and NQO1 inhibitor suppressed tumor growth and induced apoptosis. NQO1 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Single-cell RNA sequencing and transcriptome analysis enable novel discovery and precise characterization of new cell types and states, which improves the understanding of the cellular context of tumorigenesis. Herein, we applied this powerful approach to analyze 368 single cells from three esophageal squamous cell carcinoma (ESCC) and two esophageal adenocarcinoma (EAC) tumors. Using inferred copy number variation analysis, we successfully distinguished carcinoma cells from heterogeneous cellular populations, identifying gene signatures and crucial cancer-related signaling pathways related to ESCC and EAC. In particular, we found that NOTCH signaling was exclusively activated in ESCC, but not in EAC. ESCC tumors with higher NOTCH activity were associated with significantly worse survival rates than those with lower NOTCH activity. Collectively, this study revealed that ESCC and EAC are distinct in terms of cellular transcriptome profiles, which leads to a wide range of intratumoral cellular heterogeneity. The findings suggest that different therapeutic strategies that target the differences between two types of esophageal cancers are required, guiding cancer-specific future drug development., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The overexpression of ABCB1 in cancer cells is a major factor contributing to the development of multidrug resistance (MDR) and treatment failure in cancer patients. Therefore, re-sensitization of MDR cancer cells to anticancer drugs remains an important aspect in chemotherapy. The progress in developing clinically applicable synthetic inhibitors of ABCB1 has been slow, mostly due to complications associated with intrinsic toxicities and unforeseen drug-drug interactions. Here, we explored the drug-repositioning approach for cancer therapy by targeting ABCB1-mediated MDR in human cancer cells. We found that DPI-201106, a positive inotropic agent, selectively inhibits the drug efflux function of ABCB1, and in doing so, re-sensitizes ABCB1-overexpressing MDR cancer cells to conventional anticancer drugs. Furthermore, the ATPase activity of ABCB1 and docking analysis of DPI-201106 in the drug-binding pocket of ABCB1 were determined to confirm the interaction between DPI-201106 and ABCB1 protein. In summary, we revealed an additional action and a potential clinical application of DPI-201106 to reverse ABCB1-mediated MDR in human cancer cells, which may be beneficial for cancer patients who have developed multidrug resistance and no longer respond to conventional chemotherapy, and should be further investigated., (Copyright © 2018 Elsevier B.V. All rights reserved.)

One of the major challenges in cancer chemotherapy is the development of multidrug resistance phenomenon attributed to the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells. Therefore, re-sensitizing MDR cancer cells to chemotherapy by directly inhibiting the activity of ABC transporters has clinical relevance. Unfortunately, previous attempts of developing clinically applicable synthetic inhibitors have failed, mostly due to problems associated with toxicity and unforeseen drug-drug interactions. An alternative approach is by repositioning drugs with known pharmacological properties as modulators of ABCB1 and ABCG2. In this study, we discovered that the transport function of ABCB1 and ABCG2 is strongly inhibited by SIS3, a specific inhibitor of Smad3. More importantly, SIS3 enhances drug-induced apoptosis and resensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic drugs at non-toxic concentrations. These findings are further supported by ATPase assays and by a docking analysis of SIS3 in the drug-binding pockets of ABCB1 and ABCG2. In summary, we revealed an additional action of SIS3 that re-sensitizes MDR cancer cells and a combination therapy with this drug and other chemotherapeutic agents may be beneficial for patients with MDR tumors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

lncRNAs regulate the initiation and progression of osteosarcoma, although the mechanism by which this occurs remains unknown. The present study shows that over-expression of the lncRNA DANCR increased osteosarcoma cell proliferation, migration, and invasion in vitro, as well as promoted xenograft tumor growth and lung metastasis in vivo. Mechanistically, DANCR promoted osteosarcoma progression by mediating cancer stem cells (CSCs) features. Moreover, pull-down assays and luciferase reporter assays indicated that DANCR upregulated expression of the receptor tyrosine kinase AXL by competitively binding to miR-33a-5p. Furthermore, DANCR enhanced the expression of proteins downstream of the AXL-Akt pathway. DANCR was consistently significantly increased in osteosarcoma tissues, and its expression was positively correlated with tumor size and metastasis as an independent poor prognostic factor. Furthermore, both in patient tumors and xenograft tumors, DANCR expression was positively related to AXL and negatively related to miR-33a-5p. Taken together, our results suggest that DANCR is a crucial upregulator of osteosarcoma and an independent predictor of prognosis. DANCR increases CSCs function by upregulating AXL via competitively binding to miR-33a-5p, and this function is sequentially performed through the PI3K-Akt signaling pathway., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In a previous study, we demonstrated that Tanshinone IIA effectively inhibits CRC angiogenesis in vivo, but the underlying mechanisms were not elucidated. In this report, we describe experiments in which HIF-1α levels were manipulated to probe the effect of hypoxia on CRC cell angiogenesis. We studied the effects of Tan IIA on CRC pro-angiogenic factor and on human umbilical vein endothelial cell angiogenesis in normoxia and hypoxia. Our results show that Tan IIA not only lowers HIF-1α levels and inhibits secretion of VEGF and bFGF, but also efficiently suppresses the proliferation, tube formation and metastasis of HUVECs. Interruption of the HIF-1α/β-catenin/TCF3/LEF1 signaling pathway occurs in the hypoxic microenvironment. The mechanism involves HIF-1α inhibition of TGF-β1 secretion, which drives angiogenesis by promoting β-catenin nuclear localization and TCF/LEF activation. To test an improved delivery system for Tan IIA, we loaded the drug into mesoporous silica nanoparticles (MSN-NH 2 ) and found that it effectively targets HIF-1α overexpression in a mouse colon tumor model. Finally, Tan IIA sodium sulfonate exhibits anti-angiogenesis activity in CRC patients by reducing levels of angiogenin, VEGF and bFGF expression. Our research provides a new anti-angiogenesis strategy and strengthens support for the use of Tan IIA as an angiogenesis inhibitor., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Thoracic neoplasms, which include lung cancers, esophageal carcinoma, and thymic epithelial tumors, are the leading causes of tumor-related death and a major health concern worldwide. The development of neoplasms is a multistep process involving both genetic and epigenetic alterations. A growing body of research provides evidence that aberrant DNA methylation, including DNA hypermethylation in promoter regions, global DNA hypomethylation and the overexpression of DNA methyltransferases, plays an important role in tumorigenesis. In this review, we summarize published observations of methylation pattern disruptions in thoracic tumors, and discuss how these abnormalities contribute to the development of cancers. We review recent findings showing that suppressing the activity of the DNA methylating enzymes DNMTs can have potent anti-cancer effects, and discuss the possibility of developing novel therapies for thoracic tumors based on DNMT inhibition., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Recent studies have shown that oncolytic adenovirus specifically targeted tumor cells while sparing normal cells. Here, we report a novel E1A-mutant adenovirus (M6) with antisense HPV16 E6 E7 DNA inserted into the deleted 6.7K/gp19K region of E3. The target effects of M6 on HPV16-positive cervical cancer cells were evaluated in vivo and in vitro. By using cytopathic effect (CPE) and viral replication assays, we verified M6 was competent to selectively replicate in cervical cancer cells in vitro. Moreover, we found infection of M6 was able to inhibit the expression of HPV16 E6 and E7 oncogenes and induce apoptosis of HPV16-positive cervical cancer cells. Further analysis in vitro revealed that the invasive ability of SiHa cells was significantly inhibited by M6. To determine if M6 synergized with radiotherapy-induced anti-tumor activity against HPV16-related cancer cells, we transfected SiHa cells with M6 followed by a single exposure to radiation. A significantly suppression of cell growth and induced apoptosis was observed in SiHa cells received M6 transfection combined with radiotherapy. Animal experiments showed that M6 transfection notably improved the survival of tumor-bearing mice in combination with radiotherapy, much superior to that of those treated by Adv5/dE1A plus radiation or M6 alone. These findings indicated the anti-tumoral efficacy of M6 on HPV16-positive cervical cancer cells and its synergic therapeutic application in radiation for cervical cancer., (2009 Elsevier Ireland Ltd. All rights reserved.)

c-FLIP inhibits caspase-8 activation and cell apoptosis mediated by death receptors. The present study aims at determining the effects of c-FLIP targeted vector-based short hairpin RNA (shRNA) on cell growth and evaluating its modulation of responsiveness to drugs and radiotherapy in cervical adenocarcinoma Hela cells. cFLIP expression of the cells transfected with shRNA against c-FLIP was significantly down-regulated after 72 h. c-FLIP silencing markedly suppressed cell proliferation and increased cell apoptosis. The activation of caspase-8 and caspase-3 was induced with shRNA targeting cFLIP with the passage of time after transfection. Furthermore, Vector-based shRNA against c-FLIP subsequently increased the sensitivity to cisplatin, iritican and Co60 radiotherapy by about 4- to 6-folds in Hela cells. Our data suggest that vector-based shRNA effectively inhibited c-FLIP expression, enhanced the expression level of caspase-8 and caspase-3 to induce cell apoptosis, probably with the higher efficacy in combination therapies with conventional chemotherapy and radiotherapy in cervical adenocarcinoma.