Cancer Letters

Targeting the EphB4 receptor tyrosine kinase sensitizes HER2-positive breast cancer cells to Lapatinib Publication date: 10 April 2020 Source: Cancer Letters, Volume 475 Author(s): Jinlei Ding, Yating Yao, Gena Huang, Xiaonan Wang, Jingyan Yi, Nan Zhang, Chongya Liu, Kainan Wang, Yuan Zhang, Min Wang, Pixu Liu, Mingliang Ye, Man Li, Hailing Cheng Abstract Clinical data analysis reveals that the expression of the EphB4 receptor tyrosine kinase is significantly elevated in HER2-positive breast cancer and high levels of EphB4 strongly correlate with poor disease prognosis. However, the impact of EphB4 activation on HER2-positive breast cancer cells and the potential of EphB4 as a therapeutic target remain to be explored. Here, we show that EphB4 overexpression confers gain-of-function activities to HER2-positive breast cancer cells, rendering resistance to a HER2/EGFR inhibitor Lapatinib. Furthermore, using integrated transcriptomic and tyrosine phosphoproteomic analyses, followed by biochemical confirmation, we establish that EphB4 activation engages the SHP2/GAB1-MEK signaling cascade and downstream c-MYC activation, and thereby limits the overall drug responses to Lapatinib. Finally, we demonstrate that, in HER2-positive breast tumors, inhibition of EphB4 combined with Lapatinib is more effective than either alone. These findings provide new insights into the signaling networks dictating therapeutic response to Lapatinib as well as a rationale for co-targeting EphB4 in HER2-positive breast cancer.

Suppression of asparagine synthetase enhances the antitumor potency of ART and artemalogue SOMCL-14-221 in non-small cell lung cancer Publication date: 10 April 2020 Source: Cancer Letters, Volume 475 Author(s): Ruoxuan Xiao, Chunyong Ding, Hongwen Zhu, Xia Liu, Jing Gao, Qian Liu, Dayun Lu, Naixia Zhang, Ao Zhang, Hu Zhou Abstract Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality. Artemisinin (ART) and SOMCL-14-221 (221), a spirobicyclic analogue of ART, have been reported to inhibit the proliferation of A549 cells with unclear underlying mechanism. In the present study, we validated that both ART and 221 inhibited the proliferation and migration of NSCLC cells and the growth of A549 xenograft tumors without appreciable toxicity. The proteomic data revealed proteins upregulated in ART and 221 groups were involved in “response to endoplasmic reticulum stress” and “amino acid metabolism”. Asparagine synthetase (ASNS) was identified as a key node protein in these processes. Interestingly, knockdown of ASNS improved the antitumor potency of ART and 221 in vitro and in vivo, and treatments with ART and 221 disordered the amino acid metabolism of A549 cells. Moreover, ART and 221 activated ER stress, and inhibition of ER stress abolished the anti-proliferative effects of ART and 221. In conclusion, this study demonstrates that ART and 221 suppress tumor growth by triggering ER stress, and the inhibition of ASNS enhances the antitumor activity of ART and 221, which provides new strategy for drug combination therapy.

Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4 Publication date: 10 April 2020 Source: Cancer Letters, Volume 475 Author(s): Dong Ha Kim, Sojung Park, HyeongRyul Kim, Yun Jung Choi, Seon Ye Kim, Ki Jung Sung, Young Hoon Sung, Chang-Min Choi, Miyong Yun, Young-Su Yi, Chae Won Lee, Sang-Yeob Kim, Jae Cheol Lee, Jin Kyung Rho Abstract Tumor-derived exosomes (TEXs) contain enriched miRNAs that act as novel non-invasive biomarkers for cancer diagnosis and play a role in cancer progression. We investigated the exosomal miRNAs that affect cancer progression in non-small cell lung cancer (NSCLC) and identified the specific molecules involved. We identified that specific miRNAs in NSCLC cell-released exosomes can modulate angiogenesis, among which miR-619-5p was the most potent inducer. RCAN1.4 was identified as a target of miR-619-5p and its suppression promoted angiogenesis. Furthermore, the suppression of RCAN1.4 induced cell proliferation and metastasis in NSCLC cells. In patients with NSCLC, the level of RCAN1.4 expression was significantly lower, and that of miR-619-5p significantly higher, in tumor than normal lung tissues. miR-619-5p expression was higher than normal in exosomes isolated from the plasma of NSCLC patients. Finally, hypoxic conditions induced miR-619-5p upload into NSCLC cell-derived exosomes. Our findings indicate that exosomal miR-619-5p promotes the growth and metastasis of NSCLCs by regulating RCAN1.4 and can serve as a diagnostic indicator for these lung cancers. Graphical abstract Tumor-derived exosomes (TEXs) contain enriched miRNAs that act as novel non-invasive biomarkers for cancer diagnosis and play a role in cancer progression. We investigated the exosomal miRNAs that affect cancer progression in non-small cell lung cancer (NSCLC) and identified the specific molecules involved. NSCLC cell-derived exosomal miR-619-5p targets RCAN1.4, and it has a dual function in tumor progression as the promotion of angiogenesis in HUVECs, and proliferation and metastasis in NSCLC cells. In addition, hypoxic conditions induce the secretion of exosomes containing miR-619-5p in certain NSCLC cells.

Autophagy regulation as a promising approach for improving cancer immunotherapy Publication date: 10 April 2020 Source: Cancer Letters, Volume 475 Author(s): Nestor Ishimwe, Wenbin Zhang, Jieying Qian, Yunjiao Zhang, Longping Wen Abstract Autophagy plays a critical role in intracellular metabolism and maintaining cellular homeostasis. Certain tumor cells present a higher basal autophagy rate and autophagy inhibition can lead to impaired metabolic dysfunction in autophagy-dependent tumor cells. Autophagy status in immune cells dictates their fate and response to antigen; however, autophagy in immune cells may be beneficial or detrimental depending on the developmental stage of the cell and more specifically its degree of differentiation. Autophagy-deficient hosts present variations in many metabolites, proteins and enzymes that may have tumor-promoting or -inhibiting effects. The centrality of autophagy in the metabolism of some cancers and immune cells poses as a critical target whose mechanisms must be further unraveled to optimize patient response and prevent tumor recurrence.

Plasma membrane Ca2+-permeable channels and sodium/calcium exchangers in tumorigenesis and tumor development of the upper gastrointestinal tract Publication date: 10 April 2020 Source: Cancer Letters, Volume 475 Author(s): JianHong Ding, Zhe Jin, Xiaoxu Yang, Jun Lou, Weixi Shan, Yanxia Hu, Qian Du, Qiushi Liao, Jingyu Xu, Rui Xie Abstract The upper gastrointestinal (GI) tumors are multifactorial diseases associated with a combination of oncogenes and environmental factors. Currently, surgery, chemotherapy, radiotherapy and immunotherapy are relatively effective treatment options for the patients with these tumors. However, the asymptomatic phenotype of these tumors during the early stages poses as a significant limiting factor to diagnosis and often renders treatments ineffective. Therefore, new early diagnosis and effective therapy for upper GI tumors are urgently needed. Ca2+ is a pivotal intracellular second messenger and plays a crucial role in living cells by regulating several processes from cell division to death. The aberrant Ca2+ homeostasis is related to many human pathological conditions and diseases, including cancer, and thus the changes in the expression and function of plasma membrane Ca2+ permeable channels and sodium/calcium exchangers are frequently described in tumorigenesis and tumor development of the upper GI tract, including voltage-gated Ca2+ channels (VGCC), transient receptor potential (TRP) channels, store-operated channels (SOC) and Na+/Ca2+ exchanger (NCX). This review will summarize the current knowledge about plasma membrane Ca2+ permeable channels and sodium/calcium exchangers in the upper GI tumors and provide a synopsis of recent advancements on the role and involvement of these channels in upper GI tumors as well as a discussion of the possible strategies to target these channels and exchangers for diagnosis and therapy of the upper GI tumors.

Comment on “Circular RNAs and their emerging roles as diagnostic and prognostic biomarkers in ovarian cancer,” Cancer Lett. 2020 Jan 2; 473 (2020) 139-147 Publication date: 10 April 2020 Source: Cancer Letters, Volume 475 Author(s): Yezhao Wang

Loss of hnRNPA2B1 inhibits malignant capability and promotes apoptosis via down-regulating Lin28B expression in ovarian cancer Publication date: 10 April 2020 Source: Cancer Letters, Volume 475 Author(s): Yu Yang, Qinglv Wei, Yuling Tang, Yuanyuan Wang, Qingya Luo, Hongyan Zhao, Min He, Haocheng Wang, Qi Zeng, Weiliang Lu, Jing Xu, Tao Liu, Ping Yi Abstract Ovarian cancer has the highest mortality rate among all gynecological cancers with its pathogenic mechanisms largely unknown. Here, we uncovered that ovarian cancer tissues exhibit higher heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) expression than normal ovarian epithelium tissues. Increased hnRNPA2B1 level matches along with poor prognosis of ovarian cancer patients. Importantly, hnRNPA2B1 inhibition hampers growth, reduces mobility of ovarian cancer cells in vitro and hinders xenograft tumor formation in vivo. Transcriptome profiling analysis reveals that hnRNPA2B1 dictates the expression of various important genes involved in tumorigenesis and Lin-28 Homolog B (Lin28B) is down-regulated upon hnRNPA2B1 loss. hnRNPA2B1 regulates expression of Lin28B via binding to Lin28B mRNA and enhancing its stability. Furthermore, knockdown of Lin28B reduces proliferation and mobility of ovarian cancer cells and impairs tumorigenesis in vivo, whereas Lin28B overexpression promotes xenograft tumor formation. Finally, re-expression of Lin28B in hnRNPA2B1 knockdown cells results in rescued phenotypes. Collectively, our results demonstrate that hnRNPA2B1 facilitates the malignant phenotype of ovarian cancer through activating Lin28B expression.

Natural killer T cell cytotoxic activity in cervical cancer is facilitated by the LINC00240/microRNA-124-3p/STAT3/MICA axis Publication date: 1 April 2020 Source: Cancer Letters, Volume 474 Author(s): Yan Zhang, Xin Li, Jun Zhang, Hua Liang Abstract Long noncoding RNAs play significant roles in diverse cancers. In this study, we found that LINC00240 expression was markedly increased in cervical cancer. Functional in vitro assays in cervical cancer cells showed that LINC00240 enhanced the growth, migration, and invasion of cervical cancer cells. The target of LINC00240 was confirmed as microRNA(miR)-124-3p. Inhibition of miR-124-3p significantly enhanced cervical cancer progression via targeting of STAT3, which is greatly activated in tumor-infiltrating immune cells. LINC00240 expression was able to induce STAT3 expression via sponging of miR-124-3p, and showed a positive association with STAT3 expression in cervical cancer tissues. MHC class I-related chain (MIC)-A plays a key role in activating natural killer T (NKT) cells and serves as a downstream target of STAT3. Here, MICA was inhibited by up-regulation of LINC00240, and could be rescued by STAT3 knockdown. In addition, LINC00240 overexpression suppressed the cytotoxic activity of NKT cells by affecting the STAT3/MICA axis. Subsequently, we found that LINC00240 expression promoted cervical cancer progression via induction of miR-124-3p/STAT3/MICA-mediated NKT cell tolerance. Considering these findings, we conclude that LINC00240 might be a novel target for cervical cancer.

Mitochondrial oxidative stress by Lon-PYCR1 maintains an immunosuppressive tumor microenvironment that promotes cancer progression and metastasis Publication date: 1 April 2020 Source: Cancer Letters, Volume 474 Author(s): Cheng-Liang Kuo, Han-Yu Chou, Yi-Chieh Chiu, An Ning Cheng, Chi-Chen Fan, Yu-Ning Chang, Chung-Hsing Chen, Shih Sheng Jiang, Nien-Jung Chen, Alan Yueh-Luen Lee Abstract Mitochondrial Lon is a chaperone protein whose upregulation increases the production of mitochondrial reactive oxygen species (ROS). However, there is a lack of information in detail on how mitochondrial Lon regulates cancer metastasis through ROS production in the tumor microenvironment (TME). Our results show that elevated Lon promotes epithelial-mesenchymal transition (EMT) via ROS-dependent p38 and NF-κB-signaling. We further identified pyrroline-5-carboxylate reductase 1 (PYCR1) as a client of chaperone Lon, which induces mitochondrial ROS and EMT by Lon. Mitochondrial Lon induces ROS-dependent production of inflammatory cytokines, such as TGF-β, IL-6, IL-13, and VEGF-A, which consequently activates EMT, angiogenesis, and M2 macrophage polarization. In addition, Lon expression is induced upon the activation and M2 polarization of macrophages, which further promotes M2 macrophages to enhance the immunosuppressive microenvironment and metastatic behaviors in the TME. This raises the possibility that manipulation of the mitochondrial redox balance in the TME may serve as a therapeutic strategy to improve T cell function in cancer immunotherapy.

Loss of cytoskeleton protein ADD3 promotes tumor growth and angiogenesis in glioblastoma multiforme Publication date: 1 April 2020 Source: Cancer Letters, Volume 474 Author(s): Karrie Mei-Yee Kiang, Pingde Zhang, Ning Li, Zhiyuan Zhu, Lei Jin, Gilberto Ka-Kit Leung Abstract Adducin 3 (ADD3) is a crucial assembly factor in the actin cytoskeleton and has been found to be aberrantly expressed in various cancers, including glioblastoma multiforme (GBM). It has previously been studied in array-based studies with controversial findings as to its functional role in glioma. In microarray analyses of 452 glioma specimens, we found significant downregulation of ADD3 in GBM, but not in less malignant gliomas, compared to normal brain tissue, which suggests that its downregulation might underlie critical events during malignant progression. We also found that ADD3 was functionally dependent on cell-matrix interaction. In our in vivo study, the proliferative and angiogenic capacity of ADD3-depleted GBM cells was promoted, possibly through PCNA, while p53 and p21 expression was suppressed, and pro-angiogenic signals were induced through VEGF-VEGFR-2-mediated activation in endothelial cells. With correlative in vitro, in vivo, and clinical data, we provide compelling evidence on the putative tumor-suppressive role of ADD3 in modulating GBM growth and angiogenesis. As a preclinical study, our research offers a better understanding of the pathogenesis of glioma malignant progression for the benefit of future investigations.