bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2847: Tenascin C expression in neural microenvironment enhances perineural invasion and is associated with locoregional recurrence-related poor prognosis in pancreatic ductal adenocarcinoma
Authors: Furuhashi Satoru , Sakaguchi Takanori , Murakami Tomohiro , Fukushima Mayu , Morita Yoshifumi , Ikegami Koji , Kikuchi Hirotoshi , Baba Megumi , Setou Mitsutoshi , Takeuchi Hiyoya 
Published: August 2019

Abstract
Background: Perineural invasion (PNI) is commonly seen in pancreatic ductal adenocarcinoma (PDAC) and worsens the postoperative prognosis. However, the associated mechanisms in cancer progression remain unclear. Tenascin C (TNC), an extracellular matrix glycoprotein, is abundant in cancer stroma and modulates tumor progression. The aim of this study was to evaluate the functional roles of TNC in the neural microenvironment of PDAC.
Methods: We immunohistochemically examined TNC expression in 78 resected PDAC specimens. TNC staining in perineural sites at the invasive front was classified as low or high intensity, by comparison with adjacent non-cancerous tissues in the same section. The relationships between TNC expression and clinicopathological features were retrospectively analyzed. Furthermore, interactions between cancer cells and nerves after supplementation with TNC were investigated when co-culturing a PDAC cell line with a mouse dorsal root ganglion (DRG) in vitro.
Results: High perineural TNC expression at the invasive front, seen in 30 (38%) patients, was associated with PNI (p = 0.006), pathological T stage ≥ 3 (p = 0.01), and postoperative locoregional recurrence (p = 0.002). It was independently associated with postoperative, poor recurrence-free survival in multivariate analysis (p = 0.045). In the in vitro co-culture model, supplementation with TNC significantly enhanced both neurotropism of PDAC cells and tumor tropism of a DRG. On the other hand, when PDAC cells and a DRG were cultured separately, TNC did not affect cancer cell proliferation or neural outgrowth.
Conclusions: Strong perineural TNC expression was a prognostic indicator of locoregional recurrence-related poor prognosis. The neurotropism of PDAC induced by TNC suggests that TNC could serve as a therapeutic target for PDAC.
Citation Format: Satoru Furuhashi, Takanori Sakaguchi, Tomohiro Murakami, Mayu Fukushima, Yoshifumi Morita, Koji Ikegami, Hirotoshi Kikuchi, Megumi Baba, Mitsutoshi Setou, Hiyoya Takeuchi. Tenascin C expression in neural microenvironment enhances perineural invasion and is associated with locoregional recurrence-related poor prognosis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2847.
Abstract 2850: Characterization of cadherin 6 as a novel therapeutic target in metastatic ovarian carcinoma
Authors: Burdiel Miranda , Bartolomé Ruben , Jaén Marta , Casal Ignacio 
Published: August 2019

Abstract
Cadherin 6 (CDH6) is a type II cadherin containing a RGD motif in a similar way to LI-cadherin (CDH17) and VE-cadherin (CDH5), which are able to activate α2β1 integrin signalling to promote lung and liver metastasis. CDH6 gene is frequently overexpressed in late stages of some types of ovarian carcinoma, clear cell renal carcinoma, renal papillary carcinoma and thyroid cancers. Therefore, as reported for CDH17 and CDH5, we hypothesized that CDH6 might be a potential therapeutic target for metastatic ovarian cancer. Indeed, an “in silico” analysis revealed a significant association between CDH6 expression, tumour stage and poor survival in renal and ovarian cancer patients.
We confirmed a high CDH6 expression in ovarian cancer cell lines, although with significant differences in cell surface availability, as determined by flow cytometry. In addition, we noticed a variable α2β1 integrin expression in the same cell lines. Indeed, CDH6 RGD peptide caused β1 integrin activation in OVCAR3 cells but not in SKOV-3, suggesting the existence of alternative mechanisms. In this regard, as CDH6 has been reported to be a αIIbβ3 integrin ligand in platelets, we investigated and confirmed the expression of αIIbβ3 integrin in SKOV3 but not in OVCAR3 cells. Remarkably, CDH6 was able to activate αIIbβ3 integrin in SKOV3 cells. Moreover, silencing of CDH6 or β3 integrin triggered a significant loss of prometastatic traits in ovarian cells, such as cell adhesion, migration, invasion and proliferation. Signalling pathway analysis demonstrated that β3 integrin activation was triggering the phosphorylation of AKT and SRC, but not FAK, promoting cell invasion. Finally, treatment with monoclonal antibodies against the cadherin RGD motif inhibited the metastatic behaviour in ovarian cancer cell lines “in vitro”. Experiments with metastatic mouse models to confirm the inhibitory capacity of cadherin RGD-specific monoclonal antibodies are in progress.
In summary, these findings suggest that CDH6 RGD motif could activate α2β1 or αIIbβ3 integrins, according to the cell context, and be targeted to avoid metastatic dissemination and cancer progression in those ovarian tumours overexpressing CDH6.
Citation Format: Miranda Burdiel, Ruben Bartolomé, Marta Jaén, Ignacio Casal. Characterization of cadherin 6 as a novel therapeutic target in metastatic ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2850.
Abstract 2851: The effects of nidogen-1 on proliferation and migration in claudin-low mammary tumor cells
Authors: Jagroop Rebecca , Moorehead Roger 
Published: August 2019

Abstract
Breast cancer is the most common type of cancer among women, with one subset of the triple-negative subtype, claudin-low, known to be very aggressive and metastatic. For invasion and metastasis to occur, cancer cells must cross basement membranes, which contain structural proteins such as laminin and collagen IV and linking proteins such as perlecan and nidogen, to colonize distant tissues. Nidogen is a glycoprotein that makes up 2-3% of basement membranes and has two types: nidogen-1 (NID1) and nidogen-2 (NID2). There have been limited studies on NID1 in cancer, with results demonstrating decreased invasiveness and metastatic capabilities in Nid1 silenced cells of various cancer types. In previous work, a murine cell line representative of the claudin-low subtype, known as RJ423, was developed; it demonstrated a 5000-fold increase in Nid1 expression compared to the luminal subtypes. To test whether high Nid1 expression contributes to the aggressive, metastatic nature of claudin-low tumors, Nid1 levels were knocked down in RJ423 cells and proliferation and migratory capabilities were assessed. Phospho-histone H3 immunofluorescence demonstrated that suppressing NID1 reduced RJ423 cell proliferation significantly. Also, proliferation was explored using flow cytometry to obtain cell cycle profiles, and it was observed that there was a reduction in the G2 phase of NID1-suppressed cells. Additionally, apoptosis was assessed through flow cytometry to determine annexin V levels, but suppression of NID1 levels did not alter apoptosis. Furthermore, invasion assays demonstrated a reduction in migration through collagen IV-coated wells using NID1-suppressed cells. Knockdown of Nid1 expression in RJ423 cells reduced the level of NID1 in conditioned media, and preliminary studies suggest that the levels of NID1 in conditioned media can influence tumor cell growth. These findings suggest that NID1 could be targeted to lessen the metastatic nature of claudin-low breast cancer.
Citation Format: Rebecca Jagroop, Roger Moorehead. The effects of nidogen-1 on proliferation and migration in claudin-low mammary tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2851.
Abstract 2855: Oleic acid-induced ANGPTL4 facilitates metastasis of human colorectal cancer via up-regulation of NOX4 expression
Authors: Shen Chih-Jie , Liao Yu-Han , Tsai Jhih-Peng , Hung Liang-Yi , Chang Wen-Chang , Chen Ben-Kuen 
Published: August 2019

Abstract
Colorectal cancer (CRC) is highly associated with metabolic diseases, such as obesity and diabetes. Elevated free fatty acids (FFAs) in cancer patients with metabolic disorders may be associated with cancer progression. In addition, increased levels of reactive oxygen species (ROS) are also observed in dyslipidemia which induces expression of NADPH oxidase 4 (NOX4) by FFAs in aorta, kidney, and white adipocyte in physiology condition. Although the expression of NOX4 has been also up-regulated in various cancer cell types, the correlation between up-regulation of NOX4 and dyslipidemia-regulated CRC metastasis remains unclear. Here, we found that oleic acid (OA) induced-angiopoietin-like 4 (ANGPTL4) expression was through the activation of PPARs pathways, resulting in promoting the metastasis of CRC. The recombinant protein of human ANGPTL4 rescued the OA-induced invasive ability in ANGPTL4 knockdown cells. It is worthy to note that the knockdown of ANGPTL4 not only significantly inhibited OA-induced NOX4 expression, but also reduced ROS production. In addition, the depletion of ROS by using NAC or knockdown of NOX4 inhibited OA-induced extravasation of CRC cells in vivo. OA-induced MMP1 and MMP9 expressions were also dependent on the expression of ANGPTL4 and NOX4 in CRC cells. The transcriptional activation of NOX4 gene by OA-induced ANGPTL4 was regulated by activation of c-Jun and dependent on AP-1 site of NOX4 promoter. These results reveal that OA-promoted CRC metastasis was through the activation of ANGPTL4/NOX4 axis, suggesting that ANGPTL4 and NOX4 may be potential therapeutic targets and diagnostic markers to improving outcomes for patients with CRC.
Citation Format: Chih-Jie Shen, Yu-Han Liao, Jhih-Peng Tsai, Liang-Yi Hung, Wen-Chang Chang, Ben-Kuen Chen. Oleic acid-induced ANGPTL4 facilitates metastasis of human colorectal cancer via up-regulation of NOX4 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2855.
Abstract 2857: Vimentin is a novel PKC-ι target facilitating migration and invasion in melanoma
Authors: Ratnayake Wishrawana Sarathi , Breedy Sloan , Apostolatos Christopher , Hill Robert , Dennison Clare , Acevedo-Duncan Mildred 
Published: August 2019

Abstract
Vimentin plays an important role in gaining rear-to-front polarity for mesenchymal cells, making it a hallmark of cancer metastasis. Epithelial-mesenchymal transition (EMT) is a vital process in tumor progression that converts stationary epithelial cells into motile mesenchymal phenotype by downregulating E-cadherin and upregulating Vimentin expression. Molecular dynamics of Vimentin intermediate filaments (VIFs) play several key roles in cancer metastasis. Vimentin is activated via phosphorylation through various kinases. Recently, we reported that Protein Kinase C-iota (PKC-ι), activates Vimentin in melanoma while inducing EMT. We also reported the effects of PKC-ι inhibition on mitigating EMT in melanoma based on PKC- ι specific inhibitors {Ratnayake, W.S., et al. Int. J. Oncol. 51(5), (2017), 1370-1382 https://doi.org/10.3892/ijo.2017.4131 and Ratnayake, W.S., et al. Cell Adhes. Migr. (2018) https://doi.org/10.1080/19336918.2018.1471323}. This novel finding is very important with respect to cancer progression since PKC-ι is a well-established oncogene in various tumor types. Here, we analyzed the VIF dynamic changes upon PKC-ι inhibition using specific inhibitors targeting multiple activation sites on Vimentin. In addition to siRNA knockdown of expression of PKC-ι, we also report the effects of siRNA knockdown of two transcription factors, Paired related homeobox1 (PRRX1) and Zinc finger protein SNAI1 (SNAIL1) on the expressions of Vimentin, PKC-ι and E-cadherin. Herein we show that inhibition of PKC-ι downregulate the transcriptional activities of PRRX1 and SNAIL1, which was demonstrated with diminished levels of Vimentin and elevated levels of E-cadherin. Western blot, confocal immunofluorescence and immune-gold electron microscopic results suggested that PKC-ι targets multiple activation sites (S33, S39 and S56) on Vimentin without having an effect on S6 and S71 phosphorylation sites. Results also suggest that PKC-ι inhibition leads to diminution of activities of PRRX1 and SNAIL1 thereby further downregulation of Vimentin while upregulating E-cadherin in order to continue retardation of EMT in-vitro. Overall results indicate that PKC-ι is essential for VIF dynamics regulation during the metastasis in-vitro and therefore can be used as a novel biomarker to assess and mitigate melanoma metastasis.
Citation Format: Wishrawana Sarathi Ratnayake, Sloan Breedy, Christopher Apostolatos, Robert Hill, Clare Dennison, Mildred Acevedo-Duncan. Vimentin is a novel PKC-ι target facilitating migration and invasion in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2857.
Abstract 2861: ACKR3 promotes cell metastasis via activating TGF-beta 1/Smad signaling in head and neck squamous cell carcinoma
Authors: Kim Nayoung , Kim Solbi , Joo Mina , Jeon Heung Jin , Lee Myung-Won , Ryu Hyewon , Lee Hyo Jin 
Published: August 2019

Abstract
Background: The atypical chemokine receptor, ACKR3, has been shown to play as a tumor promoter, which is upregulated in various types of cancer. However, the biological role of ACKR3 and its underlying mechanism in head and neck squamous cell carcinoma (HNSCC) is still unknown. In this study, we investigated the functional role of ACKR3 and the underlying molecular mechanism of tumor progression in HNSCC.
Methods: We examined the ACKR3 expression and its association with clinicopathological characteristics in 103 cases of HNSCC by immunohistochemical staining. The biological roles of ACKR3- and ACKR3-induced downstream signaling were investigated in HNSCC cell through ACKR3 overexpression and knockdown of ACKR3 in vitro and in vivo.
Results: We detected differential expression of ACKR3 in HNSCC cells and tissues. High ACKR3 expression was significantly associated with invasion depth of tumor (T status; P = 0.007), lymph node involvement (N status; P = 0.004), and higher stage III/IV (P = 0.02). Overexpression of ACKR3 dramatically enhanced cell migration and invasion in HNSCC cells in vitro, and promoted lymph node metastasis in vivo. ACKR3 overexpression also induced the epithelial-mesenchymal transition. Vimentin, Slug, and Twist were increased but E-cadherin and Ep-CAM were decreased by ACKR3 expression. Upregulation of TGF-β1 was observed in ACKR3 overexpression, and TGF-β1/Smad signaling activation and Akt phosphorylation were induced in HNSCC cells with ACKR3 overexpression. Treatment with a PI3K inhibitor reduced Slug and Twist levels while suppression of Smad2/3 signaling by siRNA reduced Akt phosphorylation, as well as Slug and Twist. Furthermore, inhibition of Smad2/3 decreased tumor cell migration and invasion in HNSCC. ACKR3 knockdown using siRNA in HNSCC cells reduced the secretion of TGF-β1 and also recovered the cell migratory and invasive behavior of HNSCC cells.
Conclusions: ACKR3 expression was associated with an aggressive tumor behavior in HNSCC. ACKR3 contributed to migration and invasion of HNSCC cell through the TGF-β1/Smad signaling axis and epithelial-mesenchymal transition in vitro, and was involved in lymph node metastasis in vivo, suggesting that ACKR3 plays an important role during HNSCC progression and metastasis.
Citation Format: Nayoung Kim, Solbi Kim, Mina Joo, Heung Jin Jeon, Myung-Won Lee, Hyewon Ryu, Hyo Jin Lee. ACKR3 promotes cell metastasis via activating TGF-beta 1/Smad signaling in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2861.
Abstract 2863: Long non-coding RNA LINC00152 plays an oncogenic role via targeting MET, STAT3 signaling in esophagus adenocarcinoma
Authors: Xiao Matthew , Wang Zhuwen , Lin Jules , Beer David G. , Chang Andrew C. , Chen Guoan 
Published: August 2019

Abstract
Esophageal cancer remains a threat to public health with an increasing incidence and low survival rate world wide. Long non-coding RNA, LINC00152 has been linked to several human cancers and promotes cell proliferation in lung, gastric, hepatocellular, colorectal, and clear cell renal carcinoma. The expression of LINC00152 and its roles in esophagus adenocarcinomas (EAC), however, are unknown. The objective of this study is to investigate the role of LINC00152 in EAC. We used the esophageal cancer cell lines Flo-1, OE19, and OE33 for in vitro study. siRNA of specific to LINC00152 was used to knockdown LINC00152 followed by cell proliferation, colony formation, invasion and migration assays. Real-time PCR assay was used for detecting mRNA expression and Western blot for examining altered proteins expression affected by LINC00152 knockdown. Data analysis were performed using excel and Prism. The difference of variables was analyzed using the Student’s T-test. We found that LINC00152 was increased in EAC as compared to Barrett, low-grad displasia or high-grad dysplasia. The LINC00152 expression was decreased more than 90% after LINC00152 knockdown with siRNA on Flo, OE19 and OE33 cells measured by RT-PCR. Cell proliferation, colony and invasion were decreased significantly after LINC00152 siRNA transfection on these EAC cell lines. Apoptosis was also induced. Mechanistic study indicated that MET protein was significantly decreased in OE33 cells after LINC00152 knockdown, while STAT3 decreased in Flo cells. P21, p27 and Myc was decreased in all 3 cell lines. In this study we found that LINC00152 knockdown could inhibit cell proliferation, colony formation, cell migration and invasion, as well as trigger apoptosis via targeting multiple oncogenic signaling. We also found LINC00152 was increased in EAC tumors. Our study indicates that LINC00152 plays an important role in EAC and is potentially a diagnostic marker. Further characterization of LINC00152 as a novel therapeutic target of EAC is warranted.
Citation Format: Matthew Xiao, Zhuwen Wang, Jules Lin, David G. Beer, Andrew C. Chang, Guoan Chen. Long non-coding RNA LINC00152 plays an oncogenic role via targeting MET, STAT3 signaling in esophagus adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2863.
Abstract 2913: Serpinb3a-/- mice are radioresistant
Authors: Thermozier Stephanie , Epperly Michael , Franicola Darcy , Zhang Xichen , Fisher Renee , Shields Donna , Wang Hong , Willis John , Luke Cliff , Silverman Gary , Greenberger Joel 
Published: August 2019

Abstract
Serpins are a superfamily of serine protease inhibitors that regulate proteolytic pathways by utilizing a conformational change to bind to and inhibit their target peptidases. Currently 36 human serpins have been identified, but the biological roles of most are not fully understood (Silverman et al., J Biol Chem. 285(32):24299-305, 2010). Serpinb3a (the mouse orthologue of human SERPINB3 and -B4) is an intracellular serpin and inhibits both serine and cysteine peptidases invitro. We now report radioresistance of Serpinb3a-/- mice and their hematopoietic progenitor cells. Serpinb3a-/- and control Balb/c mice were irradiated to a dose of 8.0 Gy total body irradiation and followed for the development of the hematopoietic syndrome. Long Term Bone Marrow Cultures (LTBMCs) were established from the bone marrow flushed from the femurs and tibias of Serpinb3a-/- and Balb/c mice. Irradiation survival curves were performed on bone marrow stromal cell lines established from the LTBMCs and on fresh bone marrow isolated from the femurs of sacrificed Serpinb3a-/- and Balb/c mice. Colony forming unit granulocyte-macrophage (CFU-GM) colonies of 50 cells or greater were counted. The data from 3 experiments were analyzed using linear quadratic and single-hit, multi-target models. Serpinb3a-/- mice showed increased survival following 8.0 Gy TBI compared to Balb/c mice (p &lt; 0.0001). CFU-GM from Serpinb3a-/- were radioresistant compared to Balb/c marrow (ň = 4.9 ± 1.4 and 1.4 ± 0.1, p = 0.0451, respectively). Serpinb3a-/- bone marrow stromal cells were radioresistant with an increased Do (1.97 + 0.11 Gy) compared to bone marrow stromal cells from Balb/c mice (Do = 1.45 + 0.03 Gy, p = 0.0113). Loss of Serpinb3a provides a radiation survival advantage, increases radioresistance of both hematopoietic progenitor cells and marrow stromal cells, and may lead to identification of new targets for design of radiation mitigator drugs.
This research was supported by grant NIAID/NIH U19-A168021.
Citation Format: Stephanie Thermozier, Michael Epperly, Darcy Franicola, Xichen Zhang, Renee Fisher, Donna Shields, Hong Wang, John Willis, Cliff Luke, Gary Silverman, Joel Greenberger. Serpinb3a-/- mice are radioresistant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2913.