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Radiotherapy is among the main methods for treating cervical cancer; however, its therapeutic effect is limited by radioresistance. Thus, identifying effective drugs to overcome radioresistance is necessary. Arenobufagin, a bufadienolide compound, has been shown to exhibit anticancer effects. The aim of this study was to clarify the effect of arenobufagin on the radiosensitivity of cervical cancer and to explore the potential molecular mechanisms. The roles of arenobufagin in the radiosensitivity of cervical cancer cells were examined using cytotoxicity assays, colony formation assays, scratch tests, apoptosis assays, comet assays, and mouse models. The cervical cancer cells were irradiated after treatment with arenobufagin, and the extracted proteins were concentrated using nanoabsorbent microspheres. Western blotting was used to detect the expression of NF-κB signal-related proteins in the proteins concentrated by nanoabsorbent microspheres. Arenobufagin inhibited cell proliferation, increased cell apoptosis, promoted DNA damage, and inhibited the growth of transplanted tumors; thus, the radiosensitivity of C33A cells was enhanced. Mechanistically, we found that arenobufagin enhanced radiosensitivity by inhibiting the NF-κB signaling pathway. In conclusion, this study demonstrated that arenobufagin enhanced the radiosensitivity of cervical cancer cells in vitro and in vivo. The underlying mechanism might involve the inhibition of cell viability, an increase in DNA damage, and the induction of cell apoptosis by inhibiting the NF-κB pathway.

Xueping Wang, Zhixing Guo, Xingping Wu, Da Chen, Fang Wang, Lewei Yang, Min Luo, Shaocong Wu, Chuan Yang, Lamei Huang, Liwu Fu State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of ChinaCorrespondence: Liwu Fu, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, 651 Dongfengdong Road, Guangzhou, 510060, People’s Republic of China, Email fulw@mail.sysu.edu.cnIntroduction: Various studies have reported that anti-PD-1/PD-L1 treatment may lead to the rapid development of tumors called hyperprogressive disease (HPD). A nomogram for HPD prediction in NSCLC patients is urgently needed.Methods: This retrospective cohort study included 176 cases for establishing a model of HPD prediction and 85 cases for validation in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. HPD was defined as tumor growth rate (TGR, ≥ 2), tumor growth kinetics (TGK, ≥ 2) or time to treatment failure (TTF, ≤ 2 months). Univariate and multivariate logistic regression were used to estimate the specified factors associated with HPD. Then, the nomogram was developed and validated.Results: Anti-PD-1/PD-L1 therapy resulted in a 9.66% (17/176) incidence of HPD in advanced NSCLC. The overall survival (OS) and progression-free survival (PFS) in patients with HPD were significantly shorter than those in patients without HPD (OS: 7.00 vs 12.00 months, P< 0.01; PFS: 2.00 vs 5.00 months, P< 0.001, respectively). The HPD prediction nomogram included APTT (P< 0.01), CD4+ CD25+ CD127-low cells (Treg cells) (P< 0.01), the presence of liver metastasis (P< 0.05), and more than two metastatic sites (P< 0.05). Then, patients were divided into two groups by the “HPD score” calculated by the nomogram. The C-index was 0.845, while the area under the curve (AUC) was 0.830 (sensitivity 75.00%, specificity 91.70%). The calibration plot of HPD probability showed an optimal agreement between the actual observation and prediction by the nomogram. In the validation cohort, the AUC was up to 0.960 (sensitivity 88.70%, specificity 89.80%).Conclusions: The nomogram was constructed with the presence of liver metastasis, more than two metastatic sites, lengthened APTT and a high level of Treg cells, which could be used to predict HPD risk.Keywords: PD-1/PD-L1 inhibitors, hyperprogressive disease, non-small cell lung cancer, nomogram

Hepatocellular carcinoma (HCC) is a common malignancy with a dismal prognosis. It is of great importance to identify biomarkers for the prediction of patients' survival.The mRNA expression level of deoxyribonuclease 1 like 3 (DNASE1L3) and its correlation with survival were accessed in 424 samples from The Cancer Genome Atlas database. Its expression level was confirmed by real-time quantitative polymerase chain reaction and western blotting in 20 pairs of postsurgical specimens. In addition, immunohistochemistry staining of DNASE1L3 was also performed in 113 postoperative samples, using a histochemistry score system. The relationship between patients' survival and DNASE1L3 expression level was evaluated by the Kaplan-Meier method.DNASE1L3 is downregulated in both mRNA and protein levels in HCC tissues, compared with adjacent normal tissues. 52 of 113 HCC specimens showed positive DNASE1L3 protein expression. Patients with positive DNASE1L3 expression had significantly longer overall survival, compared with patients with negative expression (p = 0.023). However, the DNASE1L3 fails to discriminate progression-free survival (p = 0.134). Multivariate COX analysis revealed that positive DNASE1L3 expression and higher differentiation were significantly associated with better overall survival.This study demonstrated that positive DNASE1L3 expression is an independent prognostic factor for better survival in HCC patients following radical resection. ispartof: AGING-US vol:12 issue:2 pages:1171-1185 ispartof: location:United States status: published

Hepatocellular carcinoma (HCC) is a common malignant tumor in China. Advanced treatment like transcatheter hepatic arterial chemoembolization (TACE) has prolonged the lives of many HCC patients. However, the prognosis of most HCC patients remains unsatisfactory. Recently, circular RNAs (circRNAs) have been gradually unveiled to exert considerable functions in cancer. Promising circRNAs in HCC remains to be further elucidated. Gene expression was assessed by qRT-PCR and western blot. The function of circ-DENND4C in HCC was estimated by both in vitro and in vivo experiments. The location of circ-DENND4C in HCC cells was determined by subcellular fractionation and FISH assays. The association among molecules were analyzed through RNA pull down, RIP and luciferase reporter assays. circ-DENND4C (DENN domain containing 4C), an oncogene identified in breast cancer, was overexpressed in HCC cells. Also, circ-DENND4C exerted pro-tumor functions in HCC through activating Wnt/β-catenin pathway. Importantly, circ-DENND4C could augment transcription factor 4 (TCF4) expression to activate Wnt/β-catenin signaling via sequestering miR-195-5p. Moreover, following rescue assays disclosed that circ-DENND4C mediated malignant phenotypes in HCC cells via up-regulating TCF4 through sponging miR-195-5p. circ-DENND4C boosted TCF4 expression to modulate malignant behaviors of HCC cells via activating Wnt/β-catenin pathway, which might offer a promising target for HCC treatment.

Multifarious biological functions of long noncoding RNAs (lncRNAs) have been reported in various cancers including bladder cancer (BCa). This study aims to determine the biological role of a certain lncRNA in BCa. Consistent with the data of The Cancer Genome Atlas database, it was validated that lncRNA HLA complex group 22 (HCG22) was weakly expressed in BCa samples and lowly expressed HCG22 was closely correlated with low overall survival of the BCa patient. To verify the role of HCG22 in BCa progression, functional experiments were carried out in two representative BCa cells (J82 and T24) and the negative effects of HCG22 expression on the cell proliferation, migration, and epithelial-mesenchymal transition were identified. Mechanistically, polypyrimidine tract-binding protein 1 (PTBP1), which was highly expressed in BCa tissues and cell lines, was negatively regulated by HCG22 and the PTBP1-mediated Warburg effect was also obstructed by HCG22. Furthermore, HCG22 modulated the expression of PTBP1 through destabilizing human antigen R (HuR). And functional rescue assays confirmed that HCG22 functioned in bladder cancer through downregulating PTBP1. In conclusion, the present study revealed that HCG22 inhibited BCa progression via the HuR/PTBP1 axis, opening new prospects for potent therapeutic regimens for BCa patients.

Increased Six1 expression is commonly observed in a variety of cancers and is positively correlated with cancer progression and metastasis. Nevertheless, the mechanism by which Six1 affects the development of hepatocellular carcinoma (HCC) is still unclear. A series of experiments involving cell counting kit‐8, colony formation and Transwell assay was used to determine cell proliferation, migration and invasion respectively. Histological examination and immunofluorescence assay were also performed. The messenger RNA and protein expression of interesting genes were determined by real‐time reverse transcription‐polymerase chain reaction and western blotting respectively. We found that Six1 was up‐regulated in HCC and was associated with worse histological grade and poor survival rate. Increased expression of Six1 was shown to be able to boost cell growth, invasion, migration and epithelial‐mesenchymal transition (EMT), whereas silencing of Six1 suppressed these malignant phenotypes. Mechanistic investigations revealed that, in macrophages, matrix metalloproteinase 9 (MMP‐9) was up‐regulated by Six1. Interestingly, Six1 expression in macrophages was also able to trigger MMP‐9 induction in HCC cells. Moreover, macrophage Six1 expression was able to induce interleukin‐6 (IL‐6) up‐regulation and increase the activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells, which accounted for the elevated levels of MMP‐9 and the higher invasive levels seen in HCC. Increased expression of Six1 in HCC aggravates the malignant behaviour of cancer cells, and we provide novel evidence that macrophage Six1 can stimulate cancer cell invasion by elevating MMP‐9 expression.

Background Hepatocellular carcinoma (HCC) is a common malignant tumor in China. Advanced treatment like transcatheter hepatic arterial chemoembolization (TACE) has prolonged the lives of many HCC patients. However, the prognosis of most HCC patients remains unsatisfactory. Recently, circular RNAs (circRNAs) have been gradually unveiled to exert considerable functions in cancer. Promising circRNAs in HCC remains to be further elucidated. Methods Gene expression was assessed by qRT-PCR and western blot. The function of circ-DENND4C in HCC was estimated by both in vitro and in vivo experiments. The location of circ-DENND4C in HCC cells was determined by subcellular fractionation and FISH assays. The association among molecules were analyzed through RNA pull down, RIP and luciferase reporter assays. Results circ-DENND4C (DENN domain containing 4C), an oncogene identified in breast cancer, was overexpressed in HCC cells. Also, circ-DENND4C exerted pro-tumor functions in HCC through activating Wnt/β-catenin pathway. Importantly, circ-DENND4C could augment transcription factor 4 (TCF4) expression to activate Wnt/β-catenin signaling via sequestering miR-195-5p. Moreover, following rescue assays disclosed that circ-DENND4C mediated malignant phenotypes in HCC cells via up-regulating TCF4 through sponging miR-195-5p. Conclusion circ-DENND4C boosted TCF4 expression to modulate malignant behaviors of HCC cells via activating Wnt/β-catenin pathway, which might offer a promising target for HCC treatment.

LS is a colorectal cancer (CRC) predisposing syndrome with an autosomal dominant mode of inheritance Lynch et al...

Background: Immune-checkpoint inhibitors treatment (ICIs) like anti-PD-1/PD-L1 checkpoint inhibitors has been considered as a standard treatment and produced significant effects in patients with non-small cell lung cancer (NSCLC). However, various studies have reported that anti-PD-1/PD-L1 treatment may lead to the rapid development of tumors called hyperprogressive disease (HPD). It is urgent to determine biomarkers and develop a nomogram for HPD prediction in patients with NSCLC before anti-PD-1/PD-L1 treatment. Methods: This retrospective cohort study included 176 cases (collected from January 1, 2016 to September 31, 2019) for establishing a model of HPD prediction, and 37 cases (collected from October 1, 2019 to April 31, 2020) for validation in the patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors in Sun Yat-sen University Cancer Center. HPD was defined as tumor growth rate (TGR, ≥ 2), or tumor growth kinetics (TGK, ≥ 2) or time to treatment failure (TTF, ≤ 2 months). Univariate and multivariate logistic regression were used to estimate the specified factors associated with HPD. Then the nomogram was developed and validated. Finding: The anti-PD-1/PD-L1 therapy resulted in 9.66% (17/176) incidences of the HPD phenomenon in advanced NSCLC. The overall survival (OS) and progression free survival (PFS) in patients with HPD were significantly shorter than those patients without HPD (OS: 8.82 months [95%CI, 4.91-12.74 months] vs. 15.74 months [95%CI, 13.95-17.53 months], P

MicroRNAs (miRNAs) are a family of noncoding RNAs of ∼22 nt in length that play important roles in the tumor initiation and progression processes. The aberrant expression status of miR-18a has been reported in hepatocellular carcinoma (HCC). However, the biological role and the underlying mechanism of miR-18a in HCC progression are still to be elucidated. In this study, we examined the expression level of miR-18a in HCC cell lines using the quantitative real-time PCR method. We showed that miR-18a expression in human HCC cell lines was elevated compared with the normal liver cell line. Meanwhile, increasing miR-18a expression by an miR-18a mimic in HCC cell lines promoted cell proliferation and migration, while inhibiting miR-18a expression by an miR-18a inhibitor caused the opposite effects. Using the bioinformatic analyses method, we found that the 3′-untranslated regions (3′-UTRs) of interferon regulatory factor 2 (IRF2) and chromobox protein homolog 7 (CBX7) contain putative binding sequences for miR-18a. Further, luciferase assay validated that both IRF2 and CBX7 were the direct targets of miR-18a in HCC. Moreover, we revealed that overexpression of IRF2 and CBX7 has similar effects as miR-18a downregulation on HCC cell lines. Our results illustrated that miR-18a plays a positive role in HCC progression process by stimulating cell proliferation and migration partly through regulating IRF2 and CBX7.

Objectives MicroRNAs (miRNAs) were identified to be involved in various biological functions by regulating the degradation or suppressing the translation of their downstream target genes. Recent studies have identified miR-29a acts as tumor suppressor in hepatocellular carcinoma (HCC) progression. However, the underlying functions for miR-29a in HCC still to be investigated. Methods The expression of miR-29a expression in HCC tissues and corresponding adjacent normal tissues was detected using qRT-PCR analyses. Cell proliferation ability was assessed using CCK8 assay, cell colony forming and flow cytometry analysis. Bioinformatics, the dual luciferase reporter assay, qRT-PCR and western blot analysis were used to demonstrate that SIRT1 was a target of miR-29a. Results Here, we demonstrated that miR-29a was significantly downregulated in HCC tissues compared with corresponding adjacent normal tissues. Lower miR-29a expression associated with tumor size and vascular invasion of HCC. Furthermore, Lower miR-29a predicted a poor disease free survival (DFS) and overall survival (OS) time for HCC patients. Function assays showed that overexpression of miR-29a effectively suppressed cell proliferation, cell colony forming ability, and cell cycle progression. MiR-29a overexpression also inhibited the cell cycle related protein expression of CyclinD1 and CDK4, but increasing the P21 expression. Furthermore, Bioinformatics and the dual luciferase reporter assay analysis results demonstrated that miR-29a specifically targeted the 3'-UTR of SIRT1 mRNA and regulated its protein expression. Increased SIRT1 expression rescued the inhibited effects induced by miR-29a overexpression in HCC cells. Conclusions Thus, these results indicated that miR-29a may serve as a potential target of HCC treatment.

Introduction: Ovarian cancer is the first leading cause of cancer-related deaths among gynecologic malignancies, and the 7th most common female cancer worldwide. However, previous studies on changes in the long-term survival of ovarian cancer were limited. Methods: Our data were extracted from Surveillance, Epidemiology, and End Results (SEER) registries to assess the incidence and relative survival changes of patients with ovarian cancer during 1983-2012. Patients with ovarian cancer were stratified by age, race, and socioeconomic status (SES). Cox regression analysis and Spearman rank correlation analysis were performed by STATA 12 software. Results: The overall incidence of ovarian cancer per 100,000 decreased from 13.7 to 12.4 to 10.8 over three decades with peak incidence occurring in the 70+ age group at 47.6, 45.7 and 40.2 in each respective decade. Median survival improved from 34 months to 46 months to 52 months over three decades, with the 5-year relative survival rate (RSR) increasing from 39.3% to 43.4% to 45.4% (p < 0.0001). However, Whites showed higher median survival (34 months) than Blacks (27 months) in the first decade, and the survival difference significantly increased to 16 months in the third decade. Additionally, the median survival difference between the low-poverty group and high poverty group increased from 4 months to 12 months in the three decades. Discussion: This study demonstrated the decreasing incidence of ovarian cancer with an observed improvement in relative survival over three decades in a large sample. However, the survival gaps among races and SESs significantly widened over the three decades.