Cancer

FOXO3a knockdown promotes radioresistance in nasopharyngeal carcinoma by inducing epithelial-mesenchymal transition and the Wnt/β-catenin signaling pathway Publication date: 28 July 2019 Source: Cancer Letters, Volume 455 Author(s): Min Luo, Cheng Wu, Ergang Guo, Shan Peng, Linli Zhang, Wei Sun, Dongbo Liu, Guangyuan Hu, Guoqing Hu Abstract Mutations in the forkhead box O 3a (FOXO3a) gene are closely related to the progression of several types of cancers. However, few studies explore the relationship between FOXO3a and nasopharyngeal carcinoma (NPC). Our findings demonstrate that silencing FOXO3a promotes tumor radioresistance of NPC in vitro and in vivo through inducing EMT and activating Wnt/β-catenin signal pathway. These data establish that FOXO3a can be a novel and reliable NPC marker and a potential therapeutic target against NPC.

CD100-plexin-B1 induces epithelial-mesenchymal transition of head and neck squamous cell carcinoma and promotes metastasis Publication date: 28 July 2019 Source: Cancer Letters, Volume 455 Author(s): Chen Zhang, Hongjiang Qiao, Weinan Guo, Yuan Liu, Luting Yang, Yufeng Liu, Boquan Jin, Meng Fu, Gang Wang, Wei Li Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the most lethal cancers mainly due to the high rate of metastasis. Here, we find that the expression level of CD100 in HNSCC is positively correlated with the T category, pathological grade and lymph node metastasis of the tumor. The level of soluble CD100 (sCD100) is highly increased in serum of HNSCC patients, and sCD100 markedly induces the epithelial-mesenchymal transition (EMT) of HNSCC through its receptor, Plexin-B1 (PlxnB1), and promotes the metastasis in a xenograft mouse model. Furthermore, sCD100 promotes the stabilization of Snail through the regulation of the Vav1-Rac1/RhoA-p21-activated kinase pathway for the induction of EMT. Anti-CD100 antibody abolishes the CD100-induced EMT and prevents the metastasis of HNSCC, and anti-CD100 antibody also increases the drug sensitivity of HNSCC. Taken together, our study shows for the first time that CD100 induces the EMT of HNSCC and promotes the metastasis, and CD100 would be a candidate as a novel prognostic biomarker and a potential therapeutic target for HNSCC.

FA-NBs-IR780: Novel multifunctional nanobubbles as molecule-targeted ultrasound contrast agents for accurate diagnosis and photothermal therapy of cancer Publication date: 28 July 2019 Source: Cancer Letters, Volume 455 Author(s): Yamei Shen, Wei Lv, Hengli Yang, Wenbin Cai, Ping Zhao, Li Zhang, Jian Zhang, Lijun Yuan, Yunyou Duan Abstract Early accurate diagnosis and targeted therapy for cancer are essential to improve the prognosis of patients. With the emergence of molecular imaging, molecule-targeted ultrasound imaging for the non-invasive and precise detection of cancer has attracted increased attention. The investigation of molecule-targeted ultrasound contrast agents (UCAs) with excellent performance is urgently needed. In this study, we synthetized folic acid and IR-780 on self-made nanobubbles and prepared novel UCAs, named FA-NBs-IR780. The results showed that the conjugates had a uniform size distribution (591 ± 52 nm). In vitro and in vivo experiments demonstrated that FA-NBs-IR780 can target tumour cells via dual molecular targeting, perform enhanced-contrast ultrasound imaging and near-infrared fluorescence (NIRF) imaging for the precise detection of tumours, and induce targeted photothermal therapy in lesions irradiated at 808 nm. Ex vivo experiments further confirmed that FA-NBs-IR780 efficiently induced tumour cell apoptosis and inhibited tumour growth. The newly fabricated FA-NBs-IR780 were observed to be molecule-targeted dual-mode UCAs and may have potential applications in early accurate diagnosis and targeted therapy of cancer in the future.

miR-374a-5p promotes tumor progression by targeting ARRB1 in triple negative breast cancer Publication date: 10 July 2019 Source: Cancer Letters, Volume 454 Author(s): Dasom Son, Yesol Kim, Sera Lim, Hyeok-Gu Kang, Da-Hyun Kim, Jee Won Park, Woosung Cheong, Hyun Kyung Kong, Wonshik Han, Woong-Yang Park, Kyung-Hee Chun, Jong Hoon Park Abstract Triple negative breast cancer (TNBC) has higher aggressiveness and poorer outcomes compared with other subtypes of breast cancer. However, the genomic and molecular aberrations of TNBC are largely unknown. In this study, miR-374a-5p was discovered as a novel TNBC-specific miRNA and its functions and the molecular mechanisms involved were investigated. Combined gene expression profiling of miRNA-microarray and human transcriptome dataset analysis revealed that miR-374a-5p is specifically upregulated in TNBC patients. Functional studies using in vitro and in vivo models indicated that upregulated miR-374a-5p promotes tumor progression in TNBC. miR-374a-5p was also found to directly target arrestin beta 1 (ARRB1) that is specifically downregulated in TNBC patients in several human genomic datasets. Overexpressed ARRB1 reduced TNBC cell growth and migration, and the ARRB1 expression level is inversely correlated with the histological grade of the breast cancer and positively associated with TNBC patient survival, suggestive of a tumor-suppressive function of ARRB1 in breast cancer. Interestingly, increased ARRB1 activates AMPK in TNBC cells, associated with the expression of miR-374a-5p. Taken together, the findings suggest that miR-374a-5p is a potential prognostic marker of TNBC.

Glycochenodeoxycholate promotes hepatocellular carcinoma invasion and migration by AMPK/mTOR dependent autophagy activation Publication date: 10 July 2019 Source: Cancer Letters, Volume 454 Author(s): Lu Gao, Gang Lv, Rong Li, Wen-ting Liu, Chen Zong, Fei Ye, Xiao-yong Li, Xue Yang, Jing-hua Jiang, Xiao-juan Hou, Ying-ying Jing, Zhi-peng Han, Li-xin Wei Abstract Metastasis and recurrence severely impact the treatment effect of hepatocellular carcinoma (HCC). HCC complicated with cholestasis is more prone to recurrence and metastasis. Previous studies have implicated pathogenesis of HCC by bile acid; however, the underlying mechanism is unknown yet. Glycochenodeoxycholate (GCDC) is one of most important component of bile acid (BA). In the present study, the role of GCDC in HCC cells invasion was detected by in vitro and in vivo assays. GCDC was found to significantly enhance the invasive potential of HCC cells; Further studies showed that GCDC could induce autophagy activation and higher invasive capability in HCC cells. Interestingly, inhibition of autophagy by chloroquine (CQ) reversed this phenomenon. Subsequently, the correlation between TBA expression level and clinicopathological characteristics was analyzed in HCC patients. Clinically, high TBA level in HCC tissue was found to be associated with more invasive and poor survival in HCC patients. Mechanistic study showed that bile acid induced autophagy by targeting the AMPK/mTOR pathway in HCC cells. Therefore, our results suggest that bile acid may promote HCC invasion via activation of autophagy and the level of bile acid may serve as a potential useful indicator for prognosis of HCC patients.

Disruption of oncogenic liver-intestine cadherin (CDH17) drives apoptotic pancreatic cancer death Publication date: 10 July 2019 Source: Cancer Letters, Volume 454 Author(s): Xinjian Liu, Yue Huang, Hao Yuan, Xiaoqiang Qi, Yariswamy Manjunath, Diego Avella, Jussuf T. Kaifi, Yi Miao, Min Li, Kuirong Jiang, Guangfu Li Abstract Liver–intestine cadherin (CDH17) has been known to function as a tumor stimulator and diagnostic marker for almost two decades. However, its function in highly malignant pancreatic cancer (PC) has yet to be elucidated. Using different strategies including siRNA, shRNA, and CRISPR technology, we successfully induced knockdown and knockout of CDH17 in Panc02-H7 cells and established the corresponding stable cell lines. With these cells, we demonstrated that loss of CDH17 function not only suppressed Panc02-H7 cell growth in vitro but also significantly slowed orthotopic tumor growth in vivo, resulting in the significant life extension. In vitro studies demonstrated that impairing CDH17 inhibited cell proliferation, colony formation, and motility by mechanistically modulating pro- and anti-apoptosis events in PC cells, as CDH17 suppression obviously increased expression of Bad, cytochrome C, cleaved caspase 3, and cleaved PARP, and reduced expression of Bcl-2, Survivin, and pAkt. In vivo studies showed CDH17 knockout resulted in apoptotic PC tumor death through activating caspase-3 activity. Taken together, CDH17 functions as an oncogenic molecule critical to PC growth by regulating tumor apoptosis signaling pathways and CDH17 could be targeted to develop an anti-PC therapeutic approach.

ZY0511, a novel, potent and selective LSD1 inhibitor, exhibits anticancer activity against solid tumors via the DDIT4/mTOR pathway Publication date: 10 July 2019 Source: Cancer Letters, Volume 454 Author(s): Yan Li, Lei Tao, Zeping Zuo, Yang Zhou, Xinying Qian, Yiyun Lin, Hui Jie, Chunqi Liu, Zhuoling Li, Huaqin Zhang, Hu Zhang, Xiaobo Cen, Shengyong Yang, Yinglan Zhao Abstract Lysine-specific demethylase1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the mechanism underlying the role of LSD1 in oncogenesis is poorly understood, and more effective LSD1 inhibitors are needed. Here we report the biological activity of a novel LSD1 inhibitor named ZY0511. ZY0511 specifically inhibited LSD1 activity and the proliferation of various human cancer cells especially the HeLa and HCT116 cells. ZY0511 significantly increased the expression of DDIT4, a known mTORC1 suppressor, which was a direct downstream target of LSD1 confirmed by ChIP-PCR. ZY0511-induced LSD1 inhibition upregulated the expression of DDIT4 by altering histone H3K4 methylation levels at its promoter, thus suppressing mTORC1 activity. Knockdown of DDIT4 attenuated the anticancer effect of ZY0511. Intraperitoneal administration of ZY0511 significantly prevented the growth of HCT116 and HeLa xenografts in mice and showed no detectable toxicity. Moreover, DDIT4 expression was correlated with the sensitivity of human cancer cells to chemotherapy. Taken together, ZY0511 showed therapeutic potential for solid tumors, the induction of DDIT4 may be used as a predictive biomarker of LSD1 inhibitors.

Long non-coding RNA HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related hepatocellular carcinoma Publication date: 10 July 2019 Source: Cancer Letters, Volume 454 Author(s): Yunxia Liu, Jinyan Feng, Mingming Sun, Guang Yang, Hongfeng Yuan, Yinqi Wang, Yanan Bu, Man Zhao, Shuqin Zhang, Xiaodong Zhang Abstract Long noncoding RNA HULC is identified and highly expressed in hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) is a key driver of liver cancer. In the present study, we found that HULC remarkably elevated the levels of HBeAg, HBsAg, HBcAg, pgRNA, HBx, HBV DNA and covalently closed circular DNA (cccDNA), which activated the HBV replication in HBV-expressing hepatoma cells or de novo HBV-infected cell lines (PHH, HepG2-NTCP and dHepaRG). Mechanistically, HULC enhanced HBV cccDNA stability by down-regulating the APOBEC3B in hepatoma cells. HULC significantly up-regulated microRNA-539, which targeted the 3′UTR of APOBEC3B mRNA. Luciferase reporter gene assays revealed a putative STAT3-binding site located in the upstream of miR-539 promoter. Moreover, we identified that HULC was able to elevate HBx, which co-activated the STAT3 to stimulate the miR-539 promoter. Then, miR-539 down-regulated APOBEC3B and promoted HBV replication. Functionally, HULC enhanced the growth of hepatoma cells by activating HBV in vitro and in vivo, which could be blocked by overexpressing APOBEC3B. In conclusion, HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related HCC.

IL1RN mediates the suppressive effect of methionine deprivation on glioma proliferation Publication date: 10 July 2019 Source: Cancer Letters, Volume 454 Author(s): Kaikai Wang, Huailei Liu, Jiaqi Liu, Xiaoxiong Wang, Lei Teng, Jun Zhang, Yi Liu, Yizheng Yao, Jun Wang, Yuan Qu, Xin Chen, Fei Peng, Hongbo Liu, Ning Wang, Yingqiang Zhong, Xu Hou, Haiping Jiang, Ozal Beylerli, Xiang Liao, Xinjian Zhang Abstract Metabolic abnormality is one of the hallmarks of cancer cells, and limiting material supply is a potential breakthrough approach for cancer treatment. Increasing researchers have been involved in the study of glioma cell metabolism reprogramming since the significance of IDH1 was confirmed in glioma. However, the molecular mechanisms underlying metabolic reprogramming induced by methionine deprivation regulates glioma cell proliferation remain unclear. Here we demonstrated that methionine deprivation inhibited glioma cell proliferation via downregulating interleukin 1 receptor antagonist (IL1RN) both in vitro and in vivo, methionine deprivation or knocking down IL1RN induced glioma cell cycle arrest. Moreover, we confirmed that IL1RN is a tumor associated gene and its expression is negatively correlated with the survival time of glioma patients. Altogether these results demonstrate a strong rationale insight that targeting amino acid metabolism such as methionine deprivation/IL1RN related gene therapy may offer novel direction for glioma treatment.

Combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the initiation and recurrence of oral squamous cell carcinomas by repressing SOX2 Publication date: 10 July 2019 Source: Cancer Letters, Volume 454 Author(s): Xueyi Liang, Miao Deng, Chi Zhang, Fan Ping, Hongfei Wang, Yun Wang, Zhaona Fan, Xianyue Ren, Xiaoan Tao, Tong Wu, Jian Xu, Bin Cheng, Juan Xia Abstract Treatment of oral squamous cell carcinoma (OSCC) remains a challenge because of the lack of effective early treatment strategies and high incidence of relapse. Here, we showed that combined 4SC-202 (a novel selective class I HDAC inhibitor) and INK128 (a selective mTORC1/C2 inhibitor) treatment exhibited synergistic effects on inhibiting cell growth, sphere-forming ability, subcutaneous tumor formation and ALDH1+ cancer stem cells (CSCs) in OSCC. The initiation of OSCC was significantly inhibited by combined treatment in 4NQO-induced rat model. In addition, upregulated SOX2 was associated with advanced and metastatic tumors in OSCC patients and was responsible for the drug-resistance property of OSCC cells. The inhibitory effect of combined treatment on cell viability and ALDH1+ CSCs were attenuated by SOX2 verexpression. Furthermore, combined treatment can effectively overcome chemoresistance and inhibit the growth of recurrent OSCC in vitro and in vivo. Mechanistically, 4SC-202 and INK128 repressed SOX2 expression through miR-429/miR-1181-mediated mRNA degradation and preventing cap-dependent mRNA translation, respectively. These results suggest that combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the carcinogenesis and recurrence of OSCC by repressing SOX2. Graphical abstract