bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S2 from A Human Genome-Wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1α–XBP1 Activation
Authors: Yang Zhifen , Zhang Jing , Jiang Dadi , Khatri Purvesh , Solow-Cordero David E. , Toesca Diego A.S. , Koumenis Constantinos , Denko Nicholas C. , Giaccia Amato J. , Le Quynh-Thu , Koong Albert C.
Published: April 2023

Validation of the screen hits.
Supplementary Figure 2 from Circular RNA ciRS-7 Maintains Metastatic Phenotypes as a ceRNA of miR-1299 to Target MMPs
Authors: Sang Meixiang , Meng Lingjiao , Liu Sihua , Ding Pingan , Chang Sheng , Ju Yingchao , Liu Fei , Gu Lina , Lian Yishui , Geng Cuizhi
Published: April 2023

Down-regulation of ciRS-7 had no significant effect on proliferation of TNBC cells.
Supplementary Table 3 from The Pioneering Role of GATA2 in Androgen Receptor Variant Regulation Is Controlled by Bromodomain and Extraterminal Proteins in Castrate-Resistant Prostate Cancer
Authors: Chaytor Lewis , Simcock Matthew , Nakjang Sirintra , Heath Richard , Walker Laura , Robson Craig , Jones Dominic , Gaughan Luke
Published: April 2023

ChIP primers
Supplementary Figures from Serine Threonine Kinase 17A Maintains the Epithelial State in Colorectal Cancer Cells
Authors: Short Sarah P. , Thompson Joshua J. , Bilotta Anthony J. , Chen Xi , Revetta Frank L. , Washington M. Kay , Williams Christopher S.
Published: April 2023

Supplemental Figure 1. STK17A expression does not correlate with CRC patient survival. Supplemental Figure 2. Attenuated morphological characteristics observed with decreased STK17A KD. Supplemental Figure 3. STK17A does not affect proliferation or viability of CRC cells. Supplemental Figure 4. STK17A expression KD human tumor organoid lines. Supplemental Figure 5. No phenotype induced by STK17A loss in HTO3.
Table S3 from Identification of Genes Regulating Breast Cancer Dormancy in 3D Bone Endosteal Niche Cultures
Authors: McGrath Julie , Panzica Louis , Ransom Ryan , Withers Henry G. , Gelman Irwin H.
Published: April 2023

PCR Primer sequences
Table S1 from Identification of Genes Regulating Breast Cancer Dormancy in 3D Bone Endosteal Niche Cultures
Authors: McGrath Julie , Panzica Louis , Ransom Ryan , Withers Henry G. , Gelman Irwin H.
Published: April 2023

DSRG candidates from modules 2 and 3
Figure S5 from Dual TGFβ/BMP Pathway Inhibition Enables Expansion and Characterization of Multiple Epithelial Cell Types of the Normal and Cancerous Breast
Authors: Prasad Mayuri , Kumar Brijesh , Bhat-Nakshatri Poornima , Anjanappa Manjushree , Sandusky George , Miller Kathy D. , Storniolo Anna Maria , Nakshatri Harikrishna
Published: April 2023

Characteristics of cells grown from metastases
Supplementary Table 7 from BORIS Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through GALNT14
Authors: Hillman Joanna C. , Pugacheva Elena M. , Barger Carter J. , Sribenja Sirinapa , Rosario Spencer , Albahrani Mustafa , Truskinovsky Alexander M. , Stablewski Aimee , Liu Song , Loukinov Dmitri I. , Zentner Gabriel E. , Lobanenkov Victor V. , Karpf Adam R. , Higgins Michael J.
Published: April 2023

Primers used for RT-qPCR
Figure S1 from Dual TGFβ/BMP Pathway Inhibition Enables Expansion and Characterization of Multiple Epithelial Cell Types of the Normal and Cancerous Breast
Authors: Prasad Mayuri , Kumar Brijesh , Bhat-Nakshatri Poornima , Anjanappa Manjushree , Sandusky George , Miller Kathy D. , Storniolo Anna Maria , Nakshatri Harikrishna
Published: April 2023

Breast epithelial cells from the normal breast show inter-individual heterogeneity
Supplementary Table 4 from BORIS Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through GALNT14
Authors: Hillman Joanna C. , Pugacheva Elena M. , Barger Carter J. , Sribenja Sirinapa , Rosario Spencer , Albahrani Mustafa , Truskinovsky Alexander M. , Stablewski Aimee , Liu Song , Loukinov Dmitri I. , Zentner Gabriel E. , Lobanenkov Victor V. , Karpf Adam R. , Higgins Michael J.
Published: April 2023

Reactome pathways
Supplementary Table 3 from BORIS Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through GALNT14
Authors: Hillman Joanna C. , Pugacheva Elena M. , Barger Carter J. , Sribenja Sirinapa , Rosario Spencer , Albahrani Mustafa , Truskinovsky Alexander M. , Stablewski Aimee , Liu Song , Loukinov Dmitri I. , Zentner Gabriel E. , Lobanenkov Victor V. , Karpf Adam R. , Higgins Michael J.
Published: April 2023

KEGG Pathways
Supplementary Data from Establishment and Characterization of Four Novel Thyroid Cancer Cell Lines and PDX Models Expressing the RET/PTC1 Rearrangement, BRAFV600E, or RASQ61R as Drivers
Authors: Schweppe Rebecca E. , Pozdeyev Nikita , Pike Laura A. , Korch Christopher , Zhou Qiong , Sams Sharon B. , Sharma Vibha , Pugazhenthi Umarani , Raeburn Christopher , Albuja-Cruz Maria B. , Reigan Philip , LaBarbera Daniel V. , Landa Iñigo , Knauf Jeffrey A. , Fagin James A. , Haugen Bryan R.
Published: April 2023

Figure S1 legend
Supplementary Table 1 from BORIS Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through GALNT14
Authors: Hillman Joanna C. , Pugacheva Elena M. , Barger Carter J. , Sribenja Sirinapa , Rosario Spencer , Albahrani Mustafa , Truskinovsky Alexander M. , Stablewski Aimee , Liu Song , Loukinov Dmitri I. , Zentner Gabriel E. , Lobanenkov Victor V. , Karpf Adam R. , Higgins Michael J.
Published: April 2023

Differentially expressed genes between EV and BORIS
Supplementary Data from BORIS Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through GALNT14
Authors: Hillman Joanna C. , Pugacheva Elena M. , Barger Carter J. , Sribenja Sirinapa , Rosario Spencer , Albahrani Mustafa , Truskinovsky Alexander M. , Stablewski Aimee , Liu Song , Loukinov Dmitri I. , Zentner Gabriel E. , Lobanenkov Victor V. , Karpf Adam R. , Higgins Michael J.
Published: April 2023

Supplementary Figures 1-9
Supplementary Table S2 from TP53 Mutation by CRISPR System Enhances the Malignant Potential of Colon Cancer
Authors: Watanabe Sho , Tsuchiya Kiichiro , Nishimura Ryu , Shirasaki Tomoaki , Katsukura Nobuhiro , Hibiya Shuji , Okamoto Ryuichi , Nakamura Tetsuya , Watanabe Mamoru
Published: April 2023

A microarray analysis-based comparison of TP53 mutant and TP53WT cells
Figure S5 from Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis
Authors: Neelakantan Deepika , Dogra Samrita , Devapatla Bharat , Jaiprasart Pharavee , Mukashyaka Marie Claire , Janknecht Ralf , Dwivedi Shailendra Kumar Dhar , Bhattacharya Resham , Husain Sanam , Ding Kai , Woo Sukyung
Published: April 2023

Various pro-metastatic pathways are upregulated downstream of APJ in OvCa cells.
Supplementary Table S1 from TP53 Mutation by CRISPR System Enhances the Malignant Potential of Colon Cancer
Authors: Watanabe Sho , Tsuchiya Kiichiro , Nishimura Ryu , Shirasaki Tomoaki , Katsukura Nobuhiro , Hibiya Shuji , Okamoto Ryuichi , Nakamura Tetsuya , Watanabe Mamoru
Published: April 2023

List of primers used for RT-PCR, guide RNAs used for CRISPR-mediated mutagenesis and primers used for promoter analysis of REG1A
Figure S4 from Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis
Authors: Neelakantan Deepika , Dogra Samrita , Devapatla Bharat , Jaiprasart Pharavee , Mukashyaka Marie Claire , Janknecht Ralf , Dwivedi Shailendra Kumar Dhar , Bhattacharya Resham , Husain Sanam , Ding Kai , Woo Sukyung
Published: April 2023

Increased APJ expression influences anoikis resistance and cell adhesion.
Supplementary FigureS5 from TP53 Mutation by CRISPR System Enhances the Malignant Potential of Colon Cancer
Authors: Watanabe Sho , Tsuchiya Kiichiro , Nishimura Ryu , Shirasaki Tomoaki , Katsukura Nobuhiro , Hibiya Shuji , Okamoto Ryuichi , Nakamura Tetsuya , Watanabe Mamoru
Published: April 2023

The regulation of REG1A by TP53
Figure S1 from Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis
Authors: Neelakantan Deepika , Dogra Samrita , Devapatla Bharat , Jaiprasart Pharavee , Mukashyaka Marie Claire , Janknecht Ralf , Dwivedi Shailendra Kumar Dhar , Bhattacharya Resham , Husain Sanam , Ding Kai , Woo Sukyung
Published: April 2023

APJ/Apelin pathway is pathologically relevant in ovarian cancer and correlates with worsened prognosis in OvCa patients.
Supplemental Figures 1-3 and Table 1 from Foxo-dependent Par-4 Upregulation Prevents Long-term Survival of Residual Cells Following PI3K–Akt Inhibition
Authors: Damrauer Jeffrey S. , Phelps Stephanie N. , Amuchastegui Katie , Lupo Ryan , Mabe Nathaniel W. , Walens Andrea , Kroger Benjamin R. , Alvarez James V.
Published: April 2023

Figures S1-3 show regulation of Par-4 by PI3K-Akt-Foxo pathway. Table 1 shows primer sequences.
Supplementary Table 5 from Sophoridine Inhibits Human Colorectal Cancer Progression via Targeting MAPKAPK2
Authors: Wang Rui , Liu Hongwei , Shao Yingying , Wang Kailong , Yin Shuangshuang , Qiu Yuling , Wu Honghua , Liu Erwei , Wang Tao , Gao Xiumei , Yu Haiyang
Published: April 2023

Main serum biochemical index of Sophoridine
Supplementary materials from Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non–Small Cell Lung Cancer Cells
Authors: Day Timothy F. , Kallakury Bhaskar V.S. , Ross Jeffrey S. , Voronel Olga , Vaidya Shantashri , Sheehan Christine E. , Kasid Usha N.
Published: April 2023

Supplementary methods, references and figure legends
Figure S6 from Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non–Small Cell Lung Cancer Cells
Authors: Day Timothy F. , Kallakury Bhaskar V.S. , Ross Jeffrey S. , Voronel Olga , Vaidya Shantashri , Sheehan Christine E. , Kasid Usha N.
Published: April 2023

Increased expression of IGFBP3 mRNA
Figure S5(A,B) from Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non–Small Cell Lung Cancer Cells
Authors: Day Timothy F. , Kallakury Bhaskar V.S. , Ross Jeffrey S. , Voronel Olga , Vaidya Shantashri , Sheehan Christine E. , Kasid Usha N.
Published: April 2023

Suppression of pIGF1R
Figure S3(A-C) from Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non–Small Cell Lung Cancer Cells
Authors: Day Timothy F. , Kallakury Bhaskar V.S. , Ross Jeffrey S. , Voronel Olga , Vaidya Shantashri , Sheehan Christine E. , Kasid Usha N.
Published: April 2023

Increased expression of SNX1
Supplemental Figure 7 from Centriole Overduplication is the Predominant Mechanism Leading to Centrosome Amplification in Melanoma
Authors: Denu Ryan A. , Shabbir Maria , Nihal Minakshi , Singh Chandra K. , Longley B. Jack , Burkard Mark E. , Ahmad Nihal
Published: April 2023

Centrosome amplification does not sensitize to centrinone B.
Supplemental Figure 6 from Centriole Overduplication is the Predominant Mechanism Leading to Centrosome Amplification in Melanoma
Authors: Denu Ryan A. , Shabbir Maria , Nihal Minakshi , Singh Chandra K. , Longley B. Jack , Burkard Mark E. , Ahmad Nihal
Published: April 2023

Effects of centrinone B on melanoma cell lines are dependent on PLK4 inhibition.
Figure S1 from Ubiquitin-Specific Protease 3 Promotes Glioblastoma Cell Invasion and Epithelial–Mesenchymal Transition via Stabilizing Snail
Authors: Fan Ligang , Chen Zhengxin , Wu Xiaoting , Cai Xiaomin , Feng Shuang , Lu Jiacheng , Wang Huibo , Liu Ning
Published: April 2023

USP3 maintains the stability of Snail
Supplemental Figure 2 from Centriole Overduplication is the Predominant Mechanism Leading to Centrosome Amplification in Melanoma
Authors: Denu Ryan A. , Shabbir Maria , Nihal Minakshi , Singh Chandra K. , Longley B. Jack , Burkard Mark E. , Ahmad Nihal
Published: April 2023

Validation of tyrosinase staining to identify melanocytes.
Supp. Figure 5 from Targeted AKT Inhibition in Prostate Cancer Cells and Spheroids Reduces Aerobic Glycolysis and Generation of Hyperpolarized [1-13C] Lactate
Authors: Tee Sui Seng , Suster Izabela , Truong Steven , Jeong Sangmoo , Eskandari Roozbeh , DiGialleonardo Valentina , Alvarez Julio A. , Aldeborgh Hannah N. , Keshari Kayvan R.
Published: April 2023

Time-lapse images of spheroid formation. LnCAP cells were grown on a 1:1 mixture of sodium alginate and matrigel in ultra-low adhesion 96-well plates. Time-lapse images were acquired using a 10X objective on the Incucyte cell imager platform located in a humidified cell culture chamber. Scale bar = 1mm
Supplementary Data containing Supplementary Methods, 10 Supplementary Figures and 5 Supplementary Tables from Autophagy Governs Protumorigenic Effects of Mitotic Slippage–induced Senescence
Authors: Jakhar Rekha , Luijten Monique N.H. , Wong Alex X.F. , Cheng Bing , Guo Ke , Neo Suat P. , Au Bijin , Kulkarni Madhura , Lim Kah J. , Maimaiti Jiamila , Chong Han C. , Lim Elaine H. , Tan Tee B.K. , Ong Kong W. , Sim Yirong , Wong Jill S.L. , Khoo James B.K. , Ho Juliana T.S. , Chua Boon T. , Sinha Indrajit , Wang Xiaomeng , Connolly John E. , Gunaratne Jayantha , Crasta Karen C.
Published: April 2023

S1. Post-slippage cells arrest at G1 as tetraploid multinucleated cells. S2. Correlation of multinucleation and senescence post-slippage in response to various anti-mitotic drugs. S3. In vivo association of senescence and anti-mitotic drug treatment. S4. Post-slippage cells increase expression of factors associated with senescence and SASP. S5. SASP factors from post-slippage cells do not affect proliferation of neighbouring cells. S6. Autophagy mediates senescence. S7. Autophagy does not modulate cell fate during prolonged mitotic arrest. S8. Autophagy-dependent IL-1β and IL-8 expression mediate cell invasiveness in a paracrine manner. S9. Silencing of p53 increases post-slippage cell death. S10. p53 status determines synergistic effect of microtubule poisons and autophagy inhibition. Table S1. List of differentially regulated proteins after 48 h Noc treatment detected by SILAC mass spectrometry. Table S2. List of antibodies. Table S3. List of chemicals. Table S4. List of primers. Table S5. Quantitative H scoring method
Supplementary Methods from Combined AURKA and H3K9 Methyltransferase Targeting Inhibits Cell Growth By Inducing Mitotic Catastrophe
Authors: Mathison Angela , Salmonson Ann , Missfeldt Mckenna , Bintz Jennifer , Williams Monique , Kossak Sarah , Nair Asha , de Assuncao Thiago M. , Christensen Trace , Buttar Navtej , Iovanna Juan , Huebert Robert , Lomberk Gwen
Published: April 2023

Detailed extended description of key methods.
Figure S4 from Satellite RNA Increases DNA Damage and Accelerates Tumor Formation in Mouse Models of Pancreatic Cancer
Authors: Kishikawa Takahiro , Otsuka Motoyuki , Suzuki Tatsunori , Seimiya Takahiro , Sekiba Kazuma , Ishibashi Rei , Tanaka Eri , Ohno Motoko , Yamagami Mari , Koike Kazuhiko
Published: April 2023

Chronic pancreatitis and skin tumors in PKM mice.
Figure S2 from Satellite RNA Increases DNA Damage and Accelerates Tumor Formation in Mouse Models of Pancreatic Cancer
Authors: Kishikawa Takahiro , Otsuka Motoyuki , Suzuki Tatsunori , Seimiya Takahiro , Sekiba Kazuma , Ishibashi Rei , Tanaka Eri , Ohno Motoko , Yamagami Mari , Koike Kazuhiko
Published: April 2023

Pancreatic pathological changes after caerulein treatment.
Supplementary Figures from Phosphatase 1 Nuclear Targeting Subunit (PNUTS) Regulates Aurora Kinases and Mitotic Progression
Authors: Wang Feifei , Wang Ling , Fisher Laura A. , Li Chunling , Wang Weidong , Peng Aimin
Published: April 2023

S1. PNUTS knockdown reduced mitotic phosphorylation of Aurora B.1. PNUTS knockdown reduced mitotic phosphorylation of Aurora B. S2. The subcellular localization of PNUTS. S3. PNUTS targeting renders cancer cells sensitive to Aurora inhibition.
Supplementary Figures 1-6, Supplemental Table 1 from Repurposing of mTOR Complex Inhibitors Attenuates MCL-1 and Sensitizes to PARP Inhibition
Authors: Mattoo Abid R. , Joun Alex , Jessup J. Milburn
Published: April 2023

S1. Immuno-staining of Clone A for MCL-1 S2. Autophagy is not involved in enhanced killing of Clone A and SF-539 cell lines by combination treatments S3. Combination treatment of Everolimus or AZD2014 and Olaparib fails to increase PARP cleavage in Clone A and SF-539 cells respectively S4. Pre-treatment of Clone A (A) and SF-539 (B) cells with Everolimus or AZD2014 decrease the frequency of cells with >10 RPA foci when exposed to 10μM of Olaparib compared to treatment with Olaparib alone S5. Pre-treatment of Clone A (A) and SF-539 (B) cells with Everolimus or AZD2014 decrease the frequency of cells with > 10 Rad51 foci when exposed to 10μM of Olaparib compared to treatment with Olaparib alone. S6. Tumor size of Clone A xenografts Table S1. IC50 values of cancer cells treated with Everolimus and AZD2014.
Table S1 from HPV Integration in HNSCC Correlates with Survival Outcomes, Immune Response Signatures, and Candidate Drivers
Authors: Koneva Lada A. , Zhang Yanxiao , Virani Shama , Hall Pelle B. , McHugh Jonathan B. , Chepeha Douglas B. , Wolf Gregory T. , Carey Thomas E. , Rozek Laura S. , Sartor Maureen A.
Published: April 2023

List of the human and HPV genomic locations for the 320 identified integration events.
Supplementary Figure Legends from Loss of Uracil DNA Glycosylase Selectively Resensitizes p53-Mutant and -Deficient Cells to 5-FdU
Authors: Yan Yan , Qing Yulan , Pink John J. , Gerson Stanton L.
Published: April 2023

Supplementary Figure Legends
Supplementary Figures 1-3 from SOX9/FXYD3/Src Axis Is Critical for ER+ Breast Cancer Stem Cell Function
Authors: Xue Yue , Lai Lihua , Lian Wenwen , Tu Xintao , Zhou Jiaojiao , Dong Ping , Su Dan , Wang Xiaojia , Cao Xuetao , Chen Yiding , Wang Qingqing
Published: April 2023

S1. FXYD3 is required for the maintenance of the ER+ cancer stem cells. S2. A) Immunohistochemistry of FXYD3 in a tissue microarray (TMA) of human breast cancers showed representative examples of strong (score 4), moderate (score 3), weak (score 2), and negative (score 1) staining. Scale bar, 100 Î¼m (upper), 20 Î¼m (lower). B) Bioinformatics analysis of the public dataset (GEO: GSE75688) for the expression of FXYD3 based on the indicated stratifications (unpaired t test, *p<0.05, **p<0.01, ***p<0.001). ER+ breast cancer, N=85; triple-negative breast cancer (TNBC), N=166. C) Bioinformatics analysis of the public dataset (GEO: GSE4057) of FXYD3 expression in ER+ and ERï�¡- breast cancer. P=0.0169; ER+ breast cancer patients, N=42; ER- breast cancer patients, N=56 (unpaired t-test, *p<0.05, **p< 0.01, ***p<0.001). D) GFP images and DPAI staining of spontaneous breast tumors in MMTV-PyMT mice injected with shNC or shFXYD3-containing lentivirus. Scale bar, 100 Î¼m. E) Representative pictures and tumor volumes of spontaneous breast tumors in MMTV-PyMT mice injected with shNC or shFXYD3 lentivirus in mammary fat pad (unpaired t-test, **p<0.01). S3. FXYD3 potently promotes Src activation in non-genomic estrogen signaling.
Supplemental Table 1 from The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice
Authors: Tracey Lauren J. , Brooke-Bisschop Travis , Jansen Pascal W.T.C. , Campos Eric I. , Vermeulen Michiel , Justice Monica J.
Published: April 2023

Mass spectrometry results listing LFQs, significance values and gene names.
Supplemental Figure 1 from The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice
Authors: Tracey Lauren J. , Brooke-Bisschop Travis , Jansen Pascal W.T.C. , Campos Eric I. , Vermeulen Michiel , Justice Monica J.
Published: April 2023

Western blot results of 2.5% input from transfected HA-CBFA2T3 constructs shown at two exposures.
Figure S5 from FLYWCH1, a Novel Suppressor of Nuclear β-Catenin, Regulates Migration and Morphology in Colorectal Cancer
Authors: Muhammad Belal A. , Almozyan Sheema , Babaei-Jadidi Roya , Onyido Emenike K. , Saadeddin Anas , Kashfi Seyed Hossein , Spencer-Dene Bradley , Ilyas Mohammad , Lourdusamy Anbarasu , Behrens Axel , Nateri Abdolrahman S.
Published: April 2023

S5. Nonsense and deletion mutations spontaneously arise in stable cell lines with putative expression of full-length FLYWCH1
Figure S2 from FLYWCH1, a Novel Suppressor of Nuclear β-Catenin, Regulates Migration and Morphology in Colorectal Cancer
Authors: Muhammad Belal A. , Almozyan Sheema , Babaei-Jadidi Roya , Onyido Emenike K. , Saadeddin Anas , Kashfi Seyed Hossein , Spencer-Dene Bradley , Ilyas Mohammad , Lourdusamy Anbarasu , Behrens Axel , Nateri Abdolrahman S.
Published: April 2023

S2. Functional interaction sites of FLYWCH1 and Î²-catenin
Supplementary Data from Microenvironment-Derived Regulation of HIF Signaling Drives Transcriptional Heterogeneity in Glioblastoma Multiforme
Authors: Heiland Dieter Henrik , Gaebelein Annette , Börries Melanie , Wörner Jakob , Pompe Nils , Franco Pamela , Heynckes Sabrina , Bartholomae Mark , hAilín Darren Ó. , Carro Maria Stella , Prinz Marco , Weber Stefan , Mader Irina , Delev Daniel , Schnell Oliver
Published: April 2023

The supplementary data contains a table of used chemicals and reagents, additional experimental procedures
Supplementary Figures 1 - 6 from Metabolic Alterations in Lung Cancer–Associated Fibroblasts Correlated with Increased Glycolytic Metabolism of the Tumor
Authors: Chaudhri Virendra K. , Salzler Gregory G. , Dick Salihah A. , Buckman Melanie S. , Sordella Raffaella , Karoly Edward D. , Mohney Robert , Stiles Brendon M. , Elemento Olivier , Altorki Nasser K. , McGraw Timothy E.
Published: April 2023

PDF file - 403K, Supplemental Figure 1. Heat map of 203 metabolites in 21 pairs of CAFs and NFs. Supplemental Figure 2. The distributions of "relative" t-scores for the 203 metabolites categorized into 46 biochemical subgroupings. Supplemental Figure 3. Total LAMP 2A expression in 8 NF/CAF pairs determined by quantitative Western blotting. Supplemental Figure 4: Alteration in glucose concentration has no consistent effect on NF or CAF growth. Supplemental Figure 5. pH calibration curve constructed for rhodamine-fluorescein (R/F)dextran labeled lysosomes in human fibroblasts. Supplemental Figure 6 (A,B,C,D) Rhodamine-fluorescein (R/F) ratios in arbitrary fluorescent units histograms of ROIs of 4 example CAF/NF pairs.
Supplementary Figures 1 - 5 from CXCR4, but not CXCR7, Discriminates Metastatic Behavior in Non–Small Cell Lung Cancer Cells
Authors: Choi Young H. , Burdick Marie D. , Strieter Brett A. , Mehrad Borna , Strieter Robert M.
Published: April 2023

PDF file - 6067K, S1. Characterization of NSCLC cells with stable knock-down of CXCR4, CXCR7 or both CXCR4 and CXCR7. S2. CXCR7 does not mediate chemotaxis of NSCLC cells. S3. CXCR4 and CXCR7 expression does not influence NSCLC proliferation, apoptosis or adhesion. S4. CXCL12 mediates increased tumor size and vascularity only in the absence of CXCR4 expression by cancer cells. S5. Immunohistochemical demonstration of brain metastases in vivo.
Supplementary Figure 1 from The Novel miR-7515 Decreases the Proliferation and Migration of Human Lung Cancer Cells by Targeting c-Met
Authors: Lee Ji Min , Yoo Jung Ki , Yoo Hanna , Jung Ho Yong , Lee Dong Ryul , Jeong Hye Cheol , Oh Seoung Hun , Chung Hyung Min , Kim Jin Kyeoung
Published: April 2023

PDF file - 80K, The expression of hc-smR-S2-5 in Dicer knock-down cells: (A) Dicer mRNA expression in Dicer knock-down cells was determined by RT-PCR analysis. (B) The expression of hc-smR-S2-5 in Dicer knock-down cells was determined by TaqMan miRNA Assay. let-7a, a known miRNA, was used as a positive control. Experiments were repeated three times. (bars, SD; *, P < 0.05)
Supplementary Figure Legends 1-5, References from Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia
Authors: DeSalvo Joanna , Kuznetsov Jeffim N. , Du Jianfeng , Leclerc Gilles M. , Leclerc Guy J. , Lampidis Theodore J. , Barredo Julio C.
Published: April 2023

PDF file - 114K
Supplementary Figure 5 from Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia
Authors: DeSalvo Joanna , Kuznetsov Jeffim N. , Du Jianfeng , Leclerc Gilles M. , Leclerc Guy J. , Lampidis Theodore J. , Barredo Julio C.
Published: April 2023

PDF file - 240K, Effects of D-mannose on ALL cytotoxicity induced by equimolar concentrations of 2-DG and 2-FDG
Supplementary Figure 2 from Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia
Authors: DeSalvo Joanna , Kuznetsov Jeffim N. , Du Jianfeng , Leclerc Gilles M. , Leclerc Guy J. , Lampidis Theodore J. , Barredo Julio C.
Published: April 2023

PDF file - 385K, The AMP analogue AICAr does not significantly affect 2-DG-induced cytotoxicity in ALL cell lines
Supplementary Figure 1 from Macrophages Promote Fibroblast Growth Factor Receptor-Driven Tumor Cell Migration and Invasion in a Cxcr2-Dependent Manner
Authors: Bohrer Laura R. , Schwertfeger Kathryn L.
Published: April 2023

PDF file - 1.7MB, Isolation and characterization of mammary gland macrophages following iFGFR1 activation
Supplementary Table 2 from Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis
Authors: Pollari Sirkku , Käkönen Rami S. , Mohammad Khalid S. , Rissanen Jukka P. , Halleen Jussi M. , Wärri Anni , Nissinen Liisa , Pihlavisto Marjo , Marjamäki Anne , Perälä Merja , Guise Theresa A. , Kallioniemi Olli , Käkönen Sanna-Maria
Published: April 2023

XLS file - 49K, Supplementary Table 2. Effects of 196 siRNAs (including 2 siRNAs targeting IL11) on TGF-�-induced IL-11 production in MDA-MB-231(SA) cells. The relative IL-11 concentration values were obtained by dividing the IL-11 concentration by the amount of viable cells in the well (as determined by the CellTiter-Blue assay). The values are shown relative to the average values for the negative control siRNA.
Supplementary Table 1 from Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis
Authors: Pollari Sirkku , Käkönen Rami S. , Mohammad Khalid S. , Rissanen Jukka P. , Halleen Jussi M. , Wärri Anni , Nissinen Liisa , Pihlavisto Marjo , Marjamäki Anne , Perälä Merja , Guise Theresa A. , Kallioniemi Olli , Käkönen Sanna-Maria
Published: April 2023

PDF file - 6K, Supplementary Table 1. Primers and probes used for quantitative RT-PCR.
Supplementary Table S1 from Mitotic Arrest, Apoptosis, and Sensitization to Chemotherapy of Melanomas by Methionine Deprivation Stress
Authors: Kokkinakis Demetrius M. , Brickner Anthony G. , Kirkwood John M. , Liu XiaoYan , Goldwasser Jason E. , Kastrama Anastasiya , Sander Cindy , Bocangel Dora , Chada Sunil
Published: April 2023

Supplementary Table S1 from Mitotic Arrest, Apoptosis, and Sensitization to Chemotherapy of Melanomas by Methionine Deprivation Stress
Data from Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155
Authors: Nyquist Michael D. , Corella Alexandra , Burns John , Coleman Ilsa , Gao Shuai , Tharakan Robin , Riggan Luke , Cai Changmeng , Corey Eva , Nelson Peter S. , Mostaghel Elahe A.
Published: April 2023

Abstract
Androgen receptor (AR) signaling is fundamental to prostate cancer and is the dominant therapeutic target in metastatic disease. However, stringent androgen deprivation therapy regimens decrease quality of life and have been largely unsuccessful in curtailing mortality. Recent clinical and preclinical studies have taken advantage of the dichotomous ability of AR signaling to elicit growth-suppressive and differentiating effects by administering hyperphysiologic levels of testosterone. In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance transporter ABCB1. SLC35F2 expression was significantly correlated with intratumor androgen levels in four distinct patient-derived xenograft models, and with AR activity score in a large gene expression dataset of castration-resistant metastases. A subset of tumors had significantly elevated SLC35F2 expression and, therefore, may identify patients who are highly responsive to YM155 treatment.

Implications: The combination of androgen therapy with YM155 represents a novel drug synergy, and SLC35F2 may serve as a clinical biomarker of response to YM155. Mol Cancer Res; 15(5); 521–31. ©2017 AACR.
Data from miR-21 Targets 15-PGDH and Promotes Cholangiocarcinoma Growth
Authors: Lu Lu , Byrnes Kathleen , Han Chang , Wang Ying , Wu Tong
Published: April 2023

Abstract
miRNAs are a group of small, noncoding RNAs that modulate the translation of genes by binding to specific target sites in the target mRNA. This study investigated the biologic function and molecular mechanism of miR-21 in human cholangiocarcinoma. In situ hybridization analysis of human cholangiocarcinoma specimens showed increased miR-21 in cholangiocarcinoma tissue compared with the noncancerous biliary epithelium. Lentiviral transduction of miR-21 enhanced human cholangiocarcinoma cell growth and clonogenic efficiency in vitro, whereas inhibition of miR-21 decreased these parameters. Overexpression of miR-21 also promoted cholangiocarcinoma growth using an in vivo xenograft model system. The NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH/HPGD), a key enzyme that converts the protumorigenic prostaglandin E2 (PGE2) to its biologically inactive metabolite, was identified as a direct target of miR-21 in cholangiocarcinoma cells. In parallel, cyclooxygenase-2 (COX2) overexpression and PGE2 treatment increased miR-21 levels and enhanced miR-21 promoter activity in human cholangiocarcinoma cells.

Implications: Cholangiocarcinogenesis and tumor progression are regulated by a novel interplay between COX-2/PGE2 and miR-21 signaling, which converges at 15-PGDH. Mol Cancer Res; 12(6); 890–900. ©2014 AACR.
Data from IGF-1 Receptor Modulates FoxO1-Mediated Tamoxifen Response in Breast Cancer Cells
Authors: Vaziri-Gohar Ali , Zheng Yan , Houston Kevin D.
Published: April 2023

Abstract
Tamoxifen is a common adjuvant treatment for estrogen receptor (ER)α-positive patients with breast cancer; however, acquired resistance abrogates the efficacy of this therapeutic approach. We recently demonstrated that G protein–coupled estrogen receptor 1 (GPER1) mediates tamoxifen action in breast cancer cells by inducing insulin-like growth factor–binding protein-1 (IGFBP-1) to inhibit IGF-1–dependent signaling. To determine whether dysregulation of IGFBP-1 induction is associated with tamoxifen resistance, IGFBP-1 transcription was measured in tamoxifen-resistant MCF-7 cells (TamR) after tamoxifen (Tam) treatment. IGFBP-1 transcription was not stimulated in tamoxifen-treated TamR cells whereas decreased expression of FoxO1, a known modulator of IGFBP-1, was observed. Exogenous expression of FoxO1 rescued the ability of tamoxifen to induce IGFBP-1 transcription in TamR cells. As decreased IGF-1R expression is observed in tamoxifen-resistant cells, the requirement for IGF-1R expression on tamoxifen-stimulated IGFBP-1 transcription was investigated. In TamR and SK-BR-3 cells, both characterized by low IGF-1R levels, exogenous IGF-1R expression increased FoxO1 levels and IGFBP-1 expression, whereas IGF-1R knockdown in MCF-7 cells decreased tamoxifen-stimulated IGFBP-1 transcription. Interestingly, both 17β-estradiol (E2)-stimulated ERα phosphorylation and progesterone receptor (PR) expression were altered in TamR. PR is a transcription factor known to modulate FoxO1 transcription. In addition, IGF-1R knockdown decreased FoxO1 protein levels in MCF-7 cells. Furthermore, IGF-1R or FoxO1 knockdown inhibited the ability of tamoxifen to induce IGFBP-1 transcription and tamoxifen sensitivity in MCF-7 cells. These data provide a molecular mechanistic connection between IGF-1R expression and the FoxO1-mediated mechanism of tamoxifen action in breast cancer cells.

Implications: Loss of IGF-1R expression is associated with decreased tamoxifen efficacy in patients with breast cancer and the development of tamoxifen resistance. This contribution identifies potential molecular mechanisms of altered tamoxifen sensitivity in breast cancer cells resulting from decreased IGF-1R expression. Mol Cancer Res; 15(4); 489–97. ©2017 AACR.
Data from Abituzumab Targeting of αV-Class Integrins Inhibits Prostate Cancer Progression
Authors: Jiang Yuan , Dai Jinlu , Yao Zhi , Shelley Greg , Keller Evan T.
Published: April 2023

Abstract
Integrins that contain an integrin αV subunit contribute to multiple functions that promote cancer progression. The goal of this study was to determine whether abituzumab (DI17E6, EMD 525797), a humanized monoclonal antibody (mAb) against integrin αV impacts, prostate cancer progression. To evaluate this, prostate cancer cells were treated with DI17E6 and its effects on proliferation, apoptosis, cell-cycle, adhesion, detachment, migration, invasion and phosphorylation of downstream targets, including FAK, Akt, and ERK, were determined. DI17E6 promoted detachment and inhibited adhesion of prostate cancer cells to several extracellular matrix (ECM) proteins and cells found in the bone microenvironment but had no impact on cell viability, cell-cycle, and caspase-3/7 activity. DI17E6 inhibited migration and invasion of prostate cancer cells. In addition, DI7E6 decreased phosphorylation of FAK, Akt, and ERK. These results indicate that inhibition of integrin αV with DI17E6 inhibits several prometastatic phenotypes of prostate cancer cells and therefore provide a rationale for further evaluation of DI17E6 for diminishing prostate cancer progression.

Implications: This work identifies that therapeutic targeting of integrins containing an αV integrin unit inhibits cancer progression and thus may be of clinical benefit. Mol Cancer Res; 15(7); 875–83. ©2017 AACR.
Data from Therapeutic Efficacy of p53 Restoration in Mdm2-Overexpressing Tumors
Authors: Li Qin , Zhang Yun , El-Naggar Adel K. , Xiong Shunbin , Yang Peirong , Jackson James G. , Chau Gilda , Lozano Guillermina
Published: April 2023

Abstract
The p53 (TP53) tumor suppressor is the most frequently mutated gene in human cancers. Restoring expression of wild-type p53 has led to tumor growth suppression in a variety of tumor models that are p53 deficient. Other mechanisms, for example, upregulation of Mdm2, exist in tumors to inactivate the p53 pathway. Mdm2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation, is present at high levels in many tumors with wild-type p53. In this study, the effects of restoring p53 activity were probed in Mdm2-overexpressing tumors genetically using animal models. Here, it was demonstrated that elevated levels of Mdm2 and decreased levels of p53 act additively to dampen p53 activity in DNA damage response and tumor development. Our data further indicate that restoration of wild-type p53 expression in Mdm2-overexpressing angiosarcomas results in tumor stasis and regression in some cases. Finally, it was determined that restored p53 suppressed cell proliferation but did not elicit apoptosis in the Mdm2-overexpressing angiosarcomas.

Implications: Restoration of wild-type p53 expression in Mdm2-overexpressing tumors suppresses tumor growth, which represents a potential clinical strategy to treat tumors with high levels of Mdm2.

Visual Overview: http://mcr.aacrjournals.org/content/12/6/901/F1.large.jpg.

Mol Cancer Res; 12(6); 901–11. ©2014 AACR.
Data from Astrocyte Elevated Gene-1 Regulates β-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal
Authors: Hu Bin , Emdad Luni , Kegelman Timothy P. , Shen Xue-Ning , Das Swadesh K. , Sarkar Devanand , Fisher Paul B.
Published: April 2023

Abstract
Glioblastoma multiforme is a common malignant brain tumor that portends extremely poor patient survival. Recent studies reveal that glioma stem-like cells (GSC) are responsible for glioblastoma multiforme escape from chemo-radiotherapy and mediators of tumor relapse. Previous studies suggest that AEG-1 (MTDH), an oncogene upregulated in most types of cancers, including glioblastoma multiforme, plays a focal role linking multiple signaling pathways in tumorigenesis. We now report a crucial role of AEG-1 in glioma stem cell biology. Primary glioblastoma multiforme cells were isolated from tumor specimens and cultured as neurospheres. Using the surface marker CD133, negative and positive cells were separated as nonstem and stem populations by cell sorting. Tissue samples and low passage cells were characterized and compared with normal controls. Functional biological assays were performed to measure stemness, self-renewal, differentiation, adhesion, protein–protein interactions, and cell signaling. AEG-1 was upregulated in all glioblastoma multiforme neurospheres compared with normal neural stem cells. Expression of AEG-1 was strongly associated with stem cell markers CD133 and SOX2. AEG-1 facilitated β-catenin translocation into the nucleus by forming a complex with LEF1 and β-catenin, subsequently activating Wnt signaling downstream genes. Through an AEG-1/Akt/GSK3β signaling axis, AEG-1 controlled phosphorylation levels of β-catenin that stabilized the protein.

Implications: This study discovers a previously unrecognized role of AEG-1 in GSC biology and supports the significance of this gene as a potential therapeutic target for glioblastoma multiforme. Mol Cancer Res; 15(2); 225–33. ©2016 AACR.
Data from HDAC Inhibition for the Treatment of Epithelioid Sarcoma: Novel Cross Talk Between Epigenetic Components
Authors: Lopez Gonzalo , Song Yechun , Lam Ryan , Ruder Dennis , Creighton Chad J. , Bid Hemant Kumar , Bill Kate Lynn , Bolshakov Svetlana , Zhang Xiaoli , Lev Dina , Pollock Raphael E.
Published: April 2023

Abstract
Epithelioid sarcoma is a rare neoplasm uniquely comprised of cells exhibiting both mesenchymal and epithelial features. Having propensity for local and distant recurrence, it poses a diagnostic dilemma secondary to pathologic complexity. Patients have dismal prognosis due to lack of effective therapy. HDAC inhibitors (HDACi) exhibit marked antitumor effects in various malignancies. The studies here demonstrate that pan-HDAC inhibitors constitute novel therapeutics versus epithelioid sarcoma. Human ES cells (VAESBJ, HS-ES, Epi-544) were studied in preclinical models to evaluate HDACi effects. Immunoblot and RT-PCR were used to evaluate expression of acetylated tubulin, histones H3/H4, EZH2 upon HDACi. MTS and clonogenic assays were used to assess the impact of HDACi on cell growth. Cell culture assays were used to evaluate the impact of HDACi and EZH2-specific siRNA inhibition on cell-cycle progression and survival. Unbiased gene array analysis was used to identify the impact of HDACi on epithelioid sarcoma gene expression. Xenografts were used to evaluate epithelioid sarcoma tumor growth in response to HDACi. HDAC inhibition increased target protein acetylation and abrogated cell growth and colony formation in epithelioid sarcoma cells. HDACi induced G2 cell-cycle arrest and marked apoptosis, and reduced tumor growth in xenograft models. HDACi induced widespread gene expression changes, and EZH2 was significantly downregulated. EZH2 knockdown resulted in abrogated cell growth in vitro.

Implications: The current study suggests a clinical role for HDACi in human epithelioid sarcoma, which, when combined with EZH2 inhibitors, could serve as a novel therapeutic strategy for epithelioid sarcoma patients. Future investigations targeting specific HDAC isoforms along with EZH2 may potentially maximizing treatment efficacy. Mol Cancer Res; 14(1); 35–43. ©2015 AACR.
Data from EGFR Signals through a DOCK180-MLK3 Axis to Drive Glioblastoma Cell Invasion
Authors: Misek Sean A. , Chen Jian , Schroeder Laura , Rattanasinchai Chotirat , Sample Ashley , Sarkaria Jann N. , Gallo Kathleen A.
Published: April 2023

Abstract
A hallmark of glioblastoma (GBM) tumors is their highly invasive behavior. Tumor dissemination into surrounding brain tissue is responsible for incomplete surgical resection, and subsequent tumor recurrence. Identification of targets that control GBM cell dissemination is critical for developing effective therapies to treat GBM. A majority of GBM tumors have dysregulated EGFR signaling, due most frequently to EGFR amplification or the presence of a constitutively active EGFRvIII mutant. Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that can activate multiple MAPK pathways. In this study, evidence is provided that MLK3 is essential for GBM cell migration and invasion, and that an MLK inhibitor blocks EGF-induced migration and invasion. MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation, suggesting that MLK3-JNK signaling promotes invasion of GBM cells. Mechanistically, it is demonstrated that DOCK180, a RAC1 guanine nucleotide exchange factor (GEF) overexpressed in invasive GBM cells, activates the MLK3-JNK signaling axis in a RAC1-dependent manner. In summary, this investigation identifies an EGFR–DOCK180–RAC1–MLK3–JNK signaling axis that drives glioblastoma cell migration and dissemination.

Implications: On the basis of these findings, MLK3 emerges as a potential therapeutic target for the treatment of glioblastoma. Mol Cancer Res; 15(8); 1085–95. ©2017 AACR.
Data from miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis
Authors: Sun Xiaojuan , Charbonneau Cherie , Wei Lei , Chen Qian , Terek Richard M.
Published: April 2023

Abstract
Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis; however, its role in chondrosarcoma is undetermined. miR-181a is overexpressed in high-grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine whether miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is a regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondrosarcoma, its expression is also increased by hypoxia, and is associated with angiogenesis and metastasis; however, receptor blockade is only partially effective. RGS16 expression is restored after miR-181a inhibition and partially accounts for the antiangiogenic and antimetastatic effects of miR-181a inhibition. These data establish miR-181a as an oncomiR that promotes chondrosarcoma progression through a new mechanism involving enhancement of CXCR4 signaling by inhibition of RGS16.

Implications: Targeting miR-181a can inhibit tumor angiogenesis, growth, and metastasis, thus suggesting the possibility of antagomir-based therapy in chondrosarcoma. Mol Cancer Res; 13(9); 1347–57. ©2015 AACR.
Data from The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling
Authors: Yu Ling , Xia Kezhou , Gao Tian , Chen Jingteng , Zhang Zhengpei , Sun Xiangran , Simões Bruno M. , Eyre Rachel , Fan Zhengfu , Guo Weichun , Clarke Robert B.
Published: April 2023

Abstract
Despite significant advancements in the diagnosis and treatment of osteosarcoma, the molecular mechanisms underpinning disease progression remain unclear. This work presents strong clinical and experimental evidence demonstrating that Notch signaling contributes to osteosarcoma progression. First, using a cohort of 12 patients, Notch genes were upregulated in tumors compared with adjacent normal tissue, and high tumor expression of Notch1 intercellular domain (NICD1) and the Notch target gene Hes1 correlated with poor chemotherapy response. Data mining of publicly available datasets confirmed that expression of Notch pathway genes is related to poor prognosis in osteosarcoma. On the basis of in vitro analysis, Notch signaling promoted osteosarcoma proliferation, enhanced chemoresistance, facilitated both migration and invasion, and upregulated stem cell–like characteristics. Xenograft models demonstrated that Notch signaling promotes primary tumor growth and pulmonary metastasis, and Notch inhibition is effective in reducing tumor size and preventing metastasis. Mechanistically, activated Notch signaling induces the expression of ephrinB1 and enhances the tumor-promoting ephrin reverse signaling. Overall, these findings provide functional evidence for Notch pathway genes as candidate biomarkers to predict prognosis in patients with osteosarcoma, and suggest a mechanistic rationale for the use of Notch inhibitors to treat osteosarcoma.
Implications:
The study provides preclinical evidence for Notch pathway as a molecular marker to predict osteosarcoma prognosis and as a therapeutic target against osteosarcoma. In addition, we identified a novel mechanism that ephrin reverse signaling acts as a key mediator of Notch pathway.
Data from Reprogramming of Glucose Metabolism by Zerumbone Suppresses Hepatocarcinogenesis
Authors: Wani Nissar Ahmad , Zhang Bo , Teng Kun-yu , Barajas Juan M. , Motiwala Tasneem , Hu Peng , Yu Lianbo , Brüschweiler Rafael , Ghoshal Kalpana , Jacob Samson T.
Published: April 2023

Abstract
Hepatocellular carcinoma (HCC) is the most prevalent and highly aggressive liver malignancy with limited therapeutic options. Here, the therapeutic potential of zerumbone, a sesquiterpene derived from the ginger plant Zingiber zerumbet, against HCC was explored. Zerumbone inhibited proliferation and clonogenic survival of HCC cells in a dose-dependent manner by arresting cells at the G2–M phase and inducing apoptosis. To elucidate the underlying molecular mechanisms, a phosphokinase array was performed that showed significant inhibition of the PI3K/AKT/mTOR and STAT3 signaling pathways in zerumbone-treated HCC cells. Gene expression profiling using microarray and analysis of microarray data by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) revealed that zerumbone treatment resulted in significant deregulation of genes regulating apoptosis, cell cycle, and metabolism. Indeed, tracing glucose metabolic pathways by growing HCC cells with 13C6-glucose and measuring extracellular and intracellular metabolites by 2D nuclear magnetic resonance (NMR) spectroscopy showed a reduction in glucose consumption and reduced lactate production, suggesting glycolytic inhibition. In addition, zerumbone impeded shunting of glucose-6-phosphate through the pentose phosphate pathway, thereby forcing tumor cells to undergo cell-cycle arrest and apoptosis. Importantly, zerumbone treatment suppressed subcutaneous and orthotopic growth and lung metastasis of HCC xenografts in immunocompromised mice. In conclusion, these findings reveal a novel and potentially effective therapeutic strategy for HCC using a natural product that targets cancer cell metabolism.

Implications: Dietary compounds, like zerumbone, that impact cell cycle, apoptosis, and metabolic processes may have therapeutic benefits for HCC patients. Mol Cancer Res; 16(2); 256–68. ©2017 AACR.