bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from S1P Stimulates Proliferation by Upregulating CTGF Expression through S1PR2-Mediated YAP Activation
Authors: Cheng Jung-Chien , Wang Evan Y. , Yi Yuyin , Thakur Avinash , Tsai Shu-Huei , Hoodless Pamela A.
Published: March 2024

Abstract
Dysregulation of the Hippo pathway in the liver results in overgrowth and eventually tumorigenesis. To date, several upstream mechanisms have been identified that affect the Hippo pathway, which ultimately regulate YAP, the major downstream effector of the pathway. However, upstream regulators of the Hippo pathway in the liver remain poorly defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that has been shown to stimulate hepatocellular carcinoma (HCC) cell proliferation, but whether the Hippo pathway is involved in S1P-stimulated HCC cell proliferation remains to be determined. Here it is demonstrated that S1P activates YAP and that the S1P receptor 2 (S1PR2/S1P2) mediates S1P-induced YAP activation in both human and mouse HCC cells. S1P promotes YAP-mediated upregulation of cysteine-rich protein 61 and connective tissue growth factor (CTGF), and stimulates HCC cell proliferation. By using siRNA-mediated knockdown approaches, only CTGF was required for S1P-stimulated cell proliferation. Of note, S1P activates YAP in a MST1/2-independent manner suggesting that the canonical Hippo kinase is not required for S1P-mediated proliferation in liver. The upregulation of CTGF and S1P2 were also observed in liver-specific YAP overexpression transgenic mouse hepatocytes. Moreover, YAP regulated liver differentiation–dependent gene expression by influencing the chromatin binding of HNF4α based on ChIP-seq analysis. Finally, results using gain- and loss-of-function approaches demonstrate that HNF4α negatively regulated S1P-induced CTGF expression.

Implications: These findings reveal a role for S1P in stimulating HCC cell proliferation by upregulating CTGF expression through S1P2-mediated YAP activation. Mol Cancer Res; 16(10); 1543–55. ©2018 AACR.
Data from Cancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma
Authors: Pankova Daniela , Chen Yulong , Terajima Masahiko , Schliekelman Mark J. , Baird Brandi N. , Fahrenholtz Monica , Sun Li , Gill Bartley J. , Vadakkan Tegy J. , Kim Min P. , Ahn Young-Ho , Roybal Jonathon D. , Liu Xin , Parra Cuentas Edwin Roger , Rodriguez Jaime , Wistuba Ignacio I. , Creighton Chad J. , Gibbons Don L. , Hicks John M. , Dickinson Mary E. , West Jennifer L. , Grande-Allen K. Jane , Hanash Samir M. , Yamauchi Mitsuo , Kurie Jonathan M.
Published: March 2024

Abstract
Intratumoral collagen cross-links heighten stromal stiffness and stimulate tumor cell invasion, but it is unclear how collagen cross-linking is regulated in epithelial tumors. To address this question, we used KrasLA1 mice, which develop lung adenocarcinomas from somatic activation of a KrasG12D allele. The lung tumors in KrasLA1 mice were highly fibrotic and contained cancer-associated fibroblasts (CAF) that produced collagen and generated stiffness in collagen gels. In xenograft tumors generated by injection of wild-type mice with lung adenocarcinoma cells alone or in combination with CAFs, the total concentration of collagen cross-links was the same in tumors generated with or without CAFs, but coinjected tumors had higher hydroxylysine aldehyde–derived collagen cross-links (HLCC) and lower lysine-aldehyde–derived collagen cross-links (LCCs). Therefore, we postulated that an LCC-to-HLCC switch induced by CAFs promotes the migratory and invasive properties of lung adenocarcinoma cells. To test this hypothesis, we created coculture models in which CAFs are positioned interstitially or peripherally in tumor cell aggregates, mimicking distinct spatial orientations of CAFs in human lung cancer. In both contexts, CAFs enhanced the invasive properties of tumor cells in three-dimensional (3D) collagen gels. Tumor cell aggregates that attached to CAF networks on a Matrigel surface dissociated and migrated on the networks. Lysyl hydroxylase 2 (PLOD2/LH2), which drives HLCC formation, was expressed in CAFs, and LH2 depletion abrogated the ability of CAFs to promote tumor cell invasion and migration.

Implications: CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells. Mol Cancer Res; 14(3); 287–95. ©2015 AACR.
Data from A Functional Screen Identifies miRs That Induce Radioresistance in Glioblastomas
Authors: Moskwa Patryk , Zinn Pascal O. , Choi Young Eun , Shukla Sachet A. , Fendler Wojciech , Chen Clark C. , Lu Jun , Golub Todd R. , Hjelmeland Anita , Chowdhury Dipanjan
Published: March 2024

Abstract
The efficacy of radiotherapy in many tumor types is limited by normal tissue toxicity and by intrinsic or acquired radioresistance. Therefore, it is essential to understand the molecular network responsible for regulating radiosensitivity/resistance. Here, an unbiased functional screen identified four microRNAs (miR1, miR125a, miR150, and miR425) that induce radioresistance. Considering the clinical importance of radiotherapy for patients with glioblastoma, the impact of these miRNAs on glioblastoma radioresistance was investigated. Overexpression of miR1, miR125a, miR150, and/or miR425 in glioblastoma promotes radioresistance through upregulation of the cell-cycle checkpoint response. Conversely, antagonizing with antagomiRs sensitizes glioblastoma cells to irradiation, suggesting their potential as targets for inhibiting therapeutic resistance. Analysis of glioblastoma datasets from The Cancer Genome Atlas (TCGA) revealed that these miRNAs are expressed in glioblastoma patient specimens and correlate with TGFβ signaling. Finally, it is demonstrated that expression of miR1 and miR125a can be induced by TGFβ and antagonized by a TGFβ receptor inhibitor. Together, these results identify and characterize a new role for miR425, miR1, miR125, and miR150 in promoting radioresistance in glioblastomas and provide insight into the therapeutic application of TGFβ inhibitors in radiotherapy.

Implications: Systematic identification of miRs that cause radioresistance in gliomas is important for uncovering predictive markers for radiotherapy or targets for overcoming radioresistance. Mol Cancer Res; 12(12); 1767–78. ©2014 AACR.
Data from Targeting IDH1 as a Prosenescent Therapy in High-grade Serous Ovarian Cancer
Authors: Dahl Erika S. , Buj Raquel , Leon Kelly E. , Newell Jordan M. , Imamura Yuka , Bitler Benjamin G. , Snyder Nathaniel W. , Aird Katherine M.
Published: March 2024

Abstract
Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. High-grade serous carcinoma (HGSC) is the most frequently diagnosed and lethal histosubtype of EOC. A significant proportion of patients with HGSC relapse with chemoresistant disease. Therefore, there is an urgent need for novel therapeutic strategies for HGSC. Metabolic reprogramming is a hallmark of cancer cells, and targeting metabolism for cancer therapy may be beneficial. Here, we found that in comparison with normal fallopian tube epithelial cells, HGSC cells preferentially utilize glucose in the TCA cycle and not for aerobic glycolysis. This correlated with universally increased TCA cycle enzyme expression in HGSC cells under adherent conditions. HGSC disseminates as tumor cell spheroids within the peritoneal cavity. We found that wild-type isocitrate dehydrogenase I (IDH1) is the only TCA cycle enzyme upregulated in both adherent and spheroid conditions and is associated with reduced progression-free survival. IDH1 protein expression is also increased in patients with primary HGSC tumors. Pharmacologic inhibition or knockdown of IDH1 decreased proliferation of multiple HGSC cell lines by inducing senescence. Mechanistically, suppression of IDH1 increased the repressive histone mark H3K9me2 at multiple E2F target gene loci, which led to decreased expression of these genes. Altogether, these data suggest that increased IDH1 activity is an important metabolic adaptation in HGSC and that targeting wild-type IDH1 in HGSC alters the repressive histone epigenetic landscape to induce senescence.
Implications:
Inhibition of IDH1 may act as a novel therapeutic approach to alter both the metabolism and epigenetics of HGSC as a prosenescent therapy.
Data from Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity
Authors: Aggarwal Rahul R. , Quigley David A. , Huang Jiaoti , Zhang Li , Beer Tomasz M. , Rettig Matthew B. , Reiter Rob E. , Gleave Martin E. , Thomas George V. , Foye Adam , Playdle Denise , Lloyd Paul , Chi Kim N. , Evans Christopher P. , Lara Primo N. , Feng Felix Y. , Alumkal Joshi J. , Small Eric J.
Published: March 2024

Abstract
Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary.
Implications:
The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.
Data from Inhibition of Discoidin Domain Receptor 1 Prevents Stroma-Induced Peritoneal Metastasis in Gastric Carcinoma
Authors: Jin Hyejin , Ham In-Hye , Oh Hye Jeong , Bae Cheong A , Lee Dakeun , Kim Young-Bae , Son Sang-Yong , Chwae Yong-Joon , Han Sang-Uk , Brekken Rolf A. , Hur Hoon
Published: March 2024

Abstract
Discoidin domain receptor 1 (DDR1) is activated by fibrillar (triple-helical) collagens and collagen IV, which are major components of tumor stroma; thus, DDR1 might be a critical mediator of communication between cancer cells and stroma. The aim of this study was to investigate the effect of DDR1 inhibition on stroma-induced peritoneal metastasis in gastric carcinoma. We analyzed by immunohistochemistry the correlation between DDR1 expression and the pattern of recurrence in gastric carcinoma tissues from a previously characterized and established gastric carcinoma patient cohort. We also cocultured human gastric carcinoma cell lines with gastric cancer–associated fibroblasts (CAF) and investigated DDR1 expression and activation. We evaluated CAF-induced tumorigenic properties of gastric carcinoma cell lines and the effect of a DDR1-specific inhibitor in organotypic cultures and in a peritoneal seeding xenograft animal model. The expression of DDR1 in gastric cancer tissues was positively associated with early recurrence (P = 0.043) and a high incidence of peritoneal recurrence (P = 0.036). We confirmed that coculturing with CAFs elevated DDR1 protein expression in gastric carcinoma cell lines and enhanced gastric carcinoma cell line spheroid formation in organotypic cultures in a tumor cell DDR1-dependent manner. Coimplantation of CAFs with gastric carcinoma cells enhanced peritoneal tumor formation in vivo, an effect that was sensitive to pharmacologic inhibition of DDR1.

Implications: This study highlights that CAF-induced elevation of DDR1 expression in gastric carcinoma cells enhances peritoneal tumorigenesis, and that inhibition of DDR1 is an attractive strategy for the treatment of gastric carcinoma peritoneal metastasis. Mol Cancer Res; 16(10); 1590–600. ©2018 AACR.
Data from Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance
Authors: Aronchik Ida , Dai Yumin , Labenski Matt , Barnes Carmen , Jones Terri , Qiao Lixin , Beebe Lisa , Malek Mehnaz , Elis Winfried , Shi Tao , Mavrommatis Konstantinos , Bray Gordon L. , Filvaroff Ellen H.
Published: March 2024

Abstract
As a critical signaling node, ERK1/2 are attractive drug targets, particularly in tumors driven by activation of the MAPK pathway. Utility of targeting the MAPK pathway has been demonstrated by clinical responses to inhibitors of MEK1/2 or RAF kinases in some mutant BRAF-activated malignancies. Unlike tumors with mutations in BRAF, those with mutations in KRAS (>30% of all cancers and >90% of certain cancer types) are generally not responsive to inhibitors of MEK1/2 or RAF. Here, a covalent ERK1/2 inhibitor, CC-90003, was characterized and shown to be active in preclinical models of KRAS-mutant tumors. A unique occupancy assay was used to understand the mechanism of resistance in a KRAS-mutant patient-derived xenograft (PDX) model of colorectal cancer. Finally, combination of CC-90003 with docetaxel achieved full tumor regression and prevented tumor regrowth after cessation of treatment in a PDX model of lung cancer. This effect corresponded to changes in a stemness gene network, revealing a potential effect on tumor stem cell reprograming.
Implications:
Here, a covalent ERK1/2 inhibitor (CC-90003) is demonstrated to have preclinical efficacy in models of KRAS-mutant tumors, which present a therapeutic challenge for currently available therapies.
Data from Potent Antineoplastic Effects of Combined PI3Kα–MNK Inhibition in Medulloblastoma
Authors: Eckerdt Frank , Bell Jonathan B. , Beauchamp Elspeth M. , Clymer Jessica , Blyth Gavin T. , Kosciuczuk Ewa M. , Ma Quanhong , Chen David Z. , Horbinski Craig , Goldman Stewart , Munshi Hidayatullah G. , Hashizume Rintaro , Platanias Leonidas C.
Published: March 2024

Abstract
Medulloblastoma is a highly malignant pediatric brain tumor associated with poor outcome. Developing treatments that target the cancer stem cell (CSC) population in medulloblastoma are important to prevent tumor relapse and induce long-lasting clinical responses. We utilized medulloblastoma neurospheres that display CSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. Of all class IA PI3Ks, only the PI3Kα isoform was required for sphere formation by medulloblastoma cells. Knockdown of p110α, but not p110β or p110δ, significantly disrupted cancer stem cell frequencies as determined by extreme limiting dilution analysis (ELDA), indicating an essential role for the PI3Kα catalytic isoform in medulloblastoma CSCs. Importantly, pharmacologic inhibition of the MAPK-interacting kinase (MNK) enhanced the antineoplastic effects of targeted PI3Kα inhibition in medulloblastoma. This indicates that MNK signaling promotes survival in medulloblastoma, suggesting dual PI3Kα and MNK inhibition may provide a novel approach to target and eliminate medulloblastoma CSCs. We also observed a significant reduction in tumor formation in subcutaneous and intracranial mouse xenograft models, which further suggests that this combinatorial approach may represent an efficient therapeutic strategy for medulloblastoma.
Implications:
These findings raise the possibility of a unique therapeutic approach for medulloblastoma, involving MNK targeting to sensitize medulloblastoma CSCs to PI3Kα inhibition.
Data from Cancer Stem Cell Phenotypes in ER+ Breast Cancer Models Are Promoted by PELP1/AIB1 Complexes
Authors: Truong Thu H. , Hu Hsiangyu , Temiz Nuri A. , Hagen Kyla M. , Girard Brian J. , Brady Nicholas J. , Schwertfeger Kathryn L. , Lange Carol A. , Ostrander Julie H.
Published: March 2024

Abstract
Proline, glutamic acid, leucine-rich protein 1 (PELP1) is overexpressed in approximately 80% of invasive breast tumors. PELP1 dynamically shuttles between the nucleus and cytoplasm, but is primarily nuclear in normal breast tissue. However, altered localization of PELP1 to the cytoplasm is an oncogenic event that promotes breast cancer initiation and progression. Herein, interacting partners unique to cytoplasmic PELP1 and the mechanisms by which these interactions promote oncogenic PELP1 signaling were sought. AIB1 (amplified in breast cancer 1; also known as SRC-3 or NCOA3) was identified as a novel binding partner of cytoplasmic PELP1 in both estrogen receptor–positive (ER+) and ER-negative cell lines. Cytoplasmic PELP1 expression elevated basal phosphorylation levels (i.e., activation) of AIB1 at Thr24, enhanced ALDH+ tumorsphere formation, and upregulated specific target genes independently of hormone stimulation. Direct manipulation of AIB1 levels using shRNA abrogated cytoplasmic PELP1-induced tumorsphere formation and downregulated cytoplasmic PELP1-specific target genes. SI-2, an AIB1 inhibitor, limited the PELP1/AIB1 interaction and decreased cytoplasmic PELP1-induced tumorsphere formation. Similar results were observed in a murine-derived MMTV-AIB1 tumor cell line. Furthermore, in vivo syngeneic tumor studies revealed that PELP1 knockdown resulted in increased survival of tumor-bearing mice as compared with mice injected with control cells.

Implications: These data demonstrate that cytoplasmic PELP1/AIB1–containing complexes function to promote advanced cancer phenotypes, including outgrowth of stem-like cells, associated with estrogen-independent breast cancer progression. Mol Cancer Res; 16(4); 707–19. ©2018 AACR.
Data from Novel Oral mTORC1/2 Inhibitor TAK-228 Has Synergistic Antitumor Effects When Combined with Paclitaxel or PI3Kα Inhibitor TAK-117 in Preclinical Bladder Cancer Models
Authors: Hernández-Prat Anna , Rodriguez-Vida Alejo , Juanpere-Rodero Nuria , Arpi Oriol , Menéndez Silvia , Soria-Jiménez Luis , Martínez Alejandro , Iarchouk Natalia , Rojo Federico , Albanell Joan , Brake Rachael , Rovira Ana , Bellmunt Joaquim
Published: March 2024

Abstract
Advanced bladder cancer is associated with a poor prognosis and limited treatment options. The PI3K/AKT/mTOR pathway is frequently activated in this disease and can be a potential therapeutic target for treatment intervention. We studied the antitumor efficacy of a new targeted therapy, TAK-228 (oral mTORC1/2 inhibitor), in preclinical models of bladder cancer. We evaluated the effects of TAK-228 in combination with a PI3Kα inhibitor (TAK-117) or with chemotherapy (paclitaxel). We used six bladder cancer cell lines and in vivo xenografts models. TAK-228 strongly inhibited cell proliferation in vitro, and reduced tumor growth and angiogenesis in vivo. Three possible biomarkers of response to TAK-228 (basal levels of 4E-BP1, p-4E-BP1/4E-BP1 ratio, or eIF4E/4E-BP1 ratio) were identified. The combination of TAK-228 and TAK-117 had synergistic effects in vitro and in vivo. Furthermore, TAK-228 demonstrated greater efficiency when combined with paclitaxel. TAK-228 also showed ex vivo activity in tumor tissue from patients with treatment-naïve bladder cancer. TAK-228 is a promising investigational agent that induces a strong effect on cell proliferation, tumor growth, and angiogenesis in bladder cancer models. High synergistic effects were observed with TAK-228 combined with a PI3K inhibitor or with chemotherapy. These results are currently being investigated in a clinic trial of TAK-228 plus paclitaxel in patients with metastatic bladder cancer (NCT03745911).
Implications:
Strong synergistic effects were observed when combining TAK-228 with TAK-117 (a PI3Kα inhibitor) or with paclitaxel chemotherapy. A phase II study at our institution is currently evaluating the efficacy of TAK-228 combined with paclitaxel in patients with metastatic bladder cancer.
Data from Pattern-Specific Transcriptomics Identifies ASGR2 as a Predictor of Hematogenous Recurrence of Gastric Cancer
Authors: Tanaka Haruyoshi , Kanda Mitsuro , Miwa Takashi , Tanaka Chie , Kobayashi Daisuke , Umeda Shinichi , Shibata Masahiro , Suenaga Masaya , Hattori Norifumi , Hayashi Masamichi , Iwata Naoki , Yamada Suguru , Nakayama Goro , Fujiwara Michitaka , Kodera Yasuhiro
Published: March 2024

Abstract
Hematogenous recurrence is a challenging clinical finding that often leads to fatalities of patients with gastric cancer. Therefore, the identification of specific biomarkers and potential therapeutic target molecules for hematogenous recurrence is required to improve the outcomes of these patients. Here, transcriptome and bioinformatics analyses were conducted to uncover candidate molecules differentially expressed in patients with hematogenous recurrence of gastric cancer. One potential candidate identified was asialoglycoprotein receptor 2 (ASGR2), and siRNA experiments were conducted to determine the effect of manipulating ASGR2 expression has on cell phenotypes. ASGR2 mRNA expression analysis using quantitative real-time reverse-transcription PCR was conducted with stage II/III gastric cancer clinical specimens (n = 95). Transcript levels were increased in gastric cancer cells as compared with a control nontumorigenic epithelial cell line. Knockdown of ASGR2 decreased the adhesion and migration potential. Thus, although gastric cancer cell–invasive activity was significantly decreased by knockdown, forced expression of ASGR2 promoted invasive activity. Using a mouse hepatic metastasis model, knockdown of ASGR2 resulted in the absence of hepatic metastasis formation. High ASGR2 expression in primary gastric cancer tissues was an independent predictor of shorter disease-free and overall survival. Finally, patients with high ASGR2 expression were more likely to have a high cumulative rate of hematogenous recurrence but not peritoneal or nodal recurrence.

Implications: ASGR2 expression is associated with the malignant phenotypes in gastric cancer and represents a specific biomarker of hematogenous recurrences after curative resection for gastric cancer. Mol Cancer Res; 16(9); 1420–9. ©2018 AACR.
Data from PARP1 Trapping and DNA Replication Stress Enhance Radiosensitization with Combined WEE1 and PARP Inhibitors
Authors: Parsels Leslie A. , Karnak David , Parsels Joshua D. , Zhang Qiang , Vélez-Padilla Jonathan , Reichert Zachery R. , Wahl Daniel R. , Maybaum Jonathan , O'Connor Mark J. , Lawrence Theodore S. , Morgan Meredith A.
Published: March 2024

Abstract
KRAS mutations in non–small cell lung cancer (NSCLC) cause increased levels of DNA damage and replication stress, suggesting that inhibition of the DNA damage response (DDR) is a promising strategy for radiosensitization of NSCLC. This study investigates the ability of a WEE1 inhibitor (AZD1775) and a PARP inhibitor (olaparib) to radiosensitize KRAS-mutant NSCLC cells and tumors. In addition to inhibiting the DDR, these small-molecule inhibitors of WEE1 and PARP induce DNA replication stress via nucleotide exhaustion and PARP trapping, respectively. As monotherapy, AZD1775 or olaparib alone modestly radiosensitized a panel of KRAS-mutant NSCLC lines. The combination of agents, however, significantly increased radiosensitization. Furthermore, AZD1775-mediated radiosensitization was rescued by nucleotide repletion, suggesting a mechanism involving AZD1775-mediated replication stress. In contrast, radiosensitization by the combination of AZD1775 and olaparib was not rescued by nucleosides. Whereas both veliparib, a PARP inhibitor that does not efficiently trap PARP1 to chromatin, and PARP1 depletion radiosensitized NSCLC cells as effectively as olaparib, which does efficiently trap PARP, only olaparib potentiated AZD1775-mediated radiosensitization. Taken together, these mechanistic data demonstrate that although nucleotide depletion is sufficient for radiosensitization by WEE1 inhibition alone, and inhibition of PARP catalytic activity is sufficient for radiosensitization by olaparib alone, PARP1 trapping is required for enhanced radiosensitization by the combination of WEE1 and PARP inhibitors.

Implications: This study highlights DNA replication stress caused by nucleotide depletion and PARP1 trapping as an important mechanism of radiosensitization in KRAS-mutant tumors and supports further development of DNA replication as a therapeutic target. Mol Cancer Res; 16(2); 222–32. ©2017 AACR.
Data from LINC00152 Promotes Invasion through a 3′-Hairpin Structure and Associates with Prognosis in Glioblastoma
Authors: Reon Brian J. , Takao Real Karia Bruno , Kiran Manjari , Dutta Anindya
Published: March 2024

Abstract
Long noncoding RNAs (lncRNA) are increasingly implicated in oncogenesis. Here, it is determined that LINC00152/CYTOR is upregulated in glioblastoma multiforme (GBM) and aggressive wild-type IDH1/2 grade 2/3 gliomas and upregulation associates with poor patient outcomes. LINC00152 is similarly upregulated in over 10 other cancer types and associates with a poor prognosis in 7 other cancer types. Inhibition of the mostly cytoplasmic LINC00152 decreases, and overexpression increases cellular invasion. LINC00152 knockdown alters the transcription of genes important to epithelial-to-mesenchymal transition (EMT). PARIS and Ribo-seq data, together with secondary structure prediction, identified a protein-bound 121-bp stem-loop structure at the 3′ end of LINC00152 whose overexpression is sufficient to increase invasion of GBM cells. Point mutations in the stem-loop suggest that stem formation in the hairpin is essential for LINC00152 function. LINC00152 has a nearly identical homolog, MIR4435-2HG, which encodes a near identical hairpin, is equally expressed in low-grade glioma (LGG) and GBM, predicts poor patient survival in these tumors, and is also reduced by LINC00152 knockdown. Together, these data reveal that LINC00152 and its homolog MIR4435-2HG associate with aggressive tumors and promote cellular invasion through a mechanism that requires the structural integrity of a hairpin structure.

Implications: Frequent upregulation of the lncRNA, LINC00152, in glioblastoma and other tumor types combined with its prognostic potential and ability to promote invasion suggests LINC00152 as a potential biomarker and therapeutic target. Mol Cancer Res; 16(10); 1470–82. ©2018 AACR.
Data from Breast Cancer Risk–Associated SNPs in the mTOR Promoter Form De Novo KLF5- and ZEB1-Binding Sites that Influence the Cellular Response to Paclitaxel
Authors: Chen Qiuchen , Deng Xiaolan , Hu Xiaoyun , Guan Shu , He Miao , Wang Yilin , Wei Binbin , Zhang Jing , Zhao Haishan , Yao Weifan , Jin Feng , Liu Yong , Chen Jianjun , Olapade Olufunmilayo I. , Wu Huizhe , Wei Minjie
Published: March 2024

Abstract
ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5–mTOR–CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5–mTOR–CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis.
Implications:
This study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5–mTOR–CCND1/ABCB1 axis.
Data from SPHK1 Is a Novel Target of Metformin in Ovarian Cancer
Authors: Hart Peter C. , Chiyoda Tatsuyuki , Liu Xiaojing , Weigert Melanie , Curtis Marion , Chiang Chun-Yi , Loth Rachel , Lastra Ricardo , McGregor Stephanie M. , Locasale Jason W. , Lengyel Ernst , Romero Iris L.
Published: March 2024

Abstract
The role of phospholipid signaling in ovarian cancer is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion, and stem-like phenotypes in ovarian cancer cell lines. Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of ovarian cancer, which was associated with elevation of key markers of proliferation and stemness. The diabetes drug, metformin, has been shown to have anticancer effects. Here, we found that ovarian cancer patients taking metformin had significantly reduced serum S1P levels, a finding that was recapitulated when ovarian cancer cells were treated with metformin and analyzed by lipidomics. These findings suggested that in cancer the sphingolipid rheostat may be a novel metabolic target of metformin. In support of this, metformin blocked hypoxia-induced SPHK1, which was associated with inhibited nuclear translocation and transcriptional activity of hypoxia-inducible factors (HIF1α and HIF2α). Further, ovarian cancer cells with high SPHK1 were found to be highly sensitive to the cytotoxic effects of metformin, whereas ovarian cancer cells with low SPHK1 were resistant. Together, the findings reported here show that hypoxia-induced SPHK1 expression and downstream S1P signaling promote ovarian cancer progression and that tumors with high expression of SPHK1 or S1P levels might have increased sensitivity to the cytotoxic effects of metformin.
Implications:
Metformin targets sphingolipid metabolism through inhibiting SPHK1, thereby impeding ovarian cancer cell migration, proliferation, and self-renewal.
Data from TRPM7 Regulates AKT/FOXO1–Dependent Tumor Growth and Is an Independent Prognostic Indicator in Renal Cell Carcinoma
Authors: Zhao Zhijian , Zhang Mengping , Duan Xiaolu , Chen Yiwen , Li Ermao , Luo Lianmin , Wu Wenqi , Peng Zhenwei , Qiu Huijuan , Zeng Guohua
Published: March 2024

Abstract
Transient receptor potential melastatin 7 (TRPM7) is important for the tumorigenesis and progression of several cancers. However, little is known about TRPM7 expression and its clinical significance in clear cell renal cell carcinoma (ccRCC). The expression dynamics of TRPM7 was examined in a clinical cohort of RCC specimens by qPCR, immunoblotting, and IHC staining. A series of in vitro and in vivo assays were performed to elucidate the function of TRPM7 in RCC and the underlying mechanisms. For the first time, results demonstrate that TRPM7 expression is markedly higher in RCC cell lines and clinical samples and had a positive correlation with T status, tumor size, and poor patients' overall survival and progression-free survival. Preclinical studies using multiple RCC cells and a mouse model indicate that TRPM7 promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Mechanistically, TRPM7 promotes AKT phosphorylation, leading to repression of the FOXO1 expression and transcriptional activity. Moreover, luciferase reporter assays demonstrate that miR-129-3p directly targets the 3′-UTR of TRPM7 and acts as a negative regulator of TRPM7. These findings reveal an important role for TRPM7 in the regulation of RCC growth and represent a novel prognostic biomarker for this disease.

Implications: TRPM7 is an independent prognostic indicator in RCC, and targeting the TRPM7 signaling pathway may be a novel therapeutic approach for the treatment of RCC. Mol Cancer Res; 16(6); 1013–23. ©2018 AACR.
Data from Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models
Authors: Bowers Laura W. , Rossi Emily L. , McDonell Shannon B. , Doerstling Steven S. , Khatib Subreen A. , Lineberger Claire G. , Albright Jody E. , Tang Xiaohu , deGraffenried Linda A. , Hursting Stephen D.
Published: March 2024

Abstract
Obesity is associated with poor prognosis in triple-negative breast cancer (TNBC). Preclinical models of TNBC were used to test the hypothesis that increased leptin signaling drives obesity-associated TNBC development by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). MMTV-Wnt-1 transgenic mice, which develop spontaneous basal-like, triple-negative mammary tumors, received either a control diet (10% kcal from fat) or a diet-induced obesity regimen (DIO, 60% kcal from fat) for up to 42 weeks (n = 15/group). Mice were monitored for tumor development and euthanized when tumor diameter reached 1.5 cm. Tumoral gene expression was assessed via RNA sequencing (RNA-seq). DIO mice had greater body weight and percent body fat at termination than controls. DIO mice, versus controls, demonstrated reduced survival, increased systemic metabolic and inflammatory perturbations, upregulated tumoral CSC/EMT gene signature, elevated tumoral aldehyde dehydrogenase activity (a CSC marker), and greater leptin signaling. In cell culture experiments using TNBC cells (murine: E-Wnt and M-Wnt; human: MDA-MB-231), leptin enhanced mammosphere formation, and media supplemented with serum from DIO versus control mice increased cell viability, migration, invasion, and CSC- and EMT-related gene expression, including Foxc2, Twist2, Vim, Akt3, and Sox2. In E-Wnt cells, knockdown of leptin receptor ablated these procancer effects induced by DIO mouse serum. These findings indicate that increased leptin signaling is causally linked to obesity-associated TNBC development by promoting CSC enrichment and EMT.

Implications: Leptin-associated signals impacting CSC and EMT may provide new targets and intervention strategies for decreasing TNBC burden in obese women. Mol Cancer Res; 16(5); 869–79. ©2018 AACR.
Data from Association of USP10 with G3BP2 Inhibits p53 Signaling and Contributes to Poor Outcome in Prostate Cancer
Authors: Takayama Ken-ichi , Suzuki Takashi , Fujimura Tetsuya , Takahashi Satoru , Inoue Satoshi
Published: March 2024

Abstract
Ubiquitin-specific protease 10 (USP10) is known to deubiquitylate its target proteins, mainly to enhance their stabilities. USP10 maintains p53 protein levels and controls epigenetic changes induced by the androgen receptor (AR). GTPase-activating protein-binding protein 2 (G3BP2), an androgen-responsive gene, is known as the main component of stress granules (SG) that interacts with USP10 in SGs. This study explores the roles of USP10 in prostate cancer progression in p53, G3BP2, and AR signaling. Using chromatin immunoprecipitation (ChIP) and sequence analysis, it was found that USP10 is transcriptionally induced with AR recruitment to an intronic region. Furthermore, USP10 regulates androgen-mediated signaling and cell growth. USP10 maintained G3BP2 protein stability by reducing polyubiquitylation. G3BP2-dependent growth activation and p53 nuclear export that reduced p53 signaling were repressed by USP10 knockdown. Clinically, USP10 was expressed primarily in the cytoplasm of prostate cancer tissues. High levels of USP10 expression were strongly correlated with high levels of AR, G3BP2, and p53 in the cytoplasm. High expression of USP10 was significantly associated with poor prognosis of patients with prostate cancer. Taken together, USP10 has a repressive effect on p53 signaling for cell growth by regulating G3BP2 expression. These findings highlight an important oncogenic aspect of USP10 through its modulation of the p53–G3BP2 complex and AR signaling in prostate cancer.

Implications: These findings elucidate the oncogenic role of USP10 in prostate cancer through an increase in G3BP2 protein that inhibits p53 activity, in addition to the promotion of AR signaling. Mol Cancer Res; 16(5); 846–56. ©2018 AACR.
Data from Recognition of Recurrent Protein Expression Patterns in Pediatric Acute Myeloid Leukemia Identified New Therapeutic Targets
Authors: Hoff Fieke W. , Hu Chenyue W. , Qiu Yihua , Ligeralde Andrew , Yoo Suk-Young , Mahmud Hasan , de Bont Eveline S.J.M. , Qutub Amina A. , Horton Terzah M. , Kornblau Steven M.
Published: March 2024

Abstract
Heterogeneity in the genetic landscape of pediatric acute myeloid leukemia (AML) makes personalized medicine challenging. As genetic events are mediated by the expression and function of proteins, recognition of recurrent protein patterns could enable classification of pediatric AML patients and could reveal crucial protein dependencies. This could help to rationally select combinations of therapeutic targets. To determine whether protein expression levels could be clustered into functionally relevant groups, custom reverse-phase protein arrays were performed on pediatric AML (n = 95) and CD34+ normal bone marrow (n = 10) clinical specimens using 194 validated antibodies. To analyze proteins in the context of other proteins, all proteins were assembled into 31 protein functional groups (PFG). For each PFG, an optimal number of protein clusters was defined that represented distinct transition states. Block clustering analysis revealed strong correlations between various protein clusters and identified the existence of 12 protein constellations stratifying patients into 8 protein signatures. Signatures were correlated with therapeutic outcome, as well as certain laboratory and demographic characteristics. Comparison of acute lymphoblastic leukemia specimens from the same array and AML pediatric patient specimens demonstrated disease-specific signatures, but also identified the existence of shared constellations, suggesting joint protein deregulation between the diseases.

Implication: Recognition of altered proteins in particular signatures suggests rational combinations of targets that could facilitate stratified targeted therapy. Mol Cancer Res; 16(8); 1275–86. ©2018 AACR.

See related article by Hoff et al., p. 1263
Data from Functional Toll-like Receptor 4 Overexpression in Papillary Thyroid Cancer by MAPK/ERK–Induced ETS1 Transcriptional Activity
Authors: Peyret Victoria , Nazar Magalí , Martín Mariano , Quintar Amado A. , Fernandez Elmer A. , Geysels Romina C. , Fuziwara Cesar S. , Montesinos María M. , Maldonado Cristina A. , Santisteban Pilar , Kimura Edna T. , Pellizas Claudia G. , Nicola Juan P. , Masini-Repiso Ana M.
Published: March 2024

Abstract
Emerging evidence suggests that unregulated Toll-like receptor (TLR) signaling promotes tumor survival signals, thus favoring tumor progression. Here, the mechanism underlying TLR4 overexpression in papillary thyroid carcinomas (PTC) mainly harboring the BRAFV600E mutation was studied. TLR4 was overexpressed in PTC compared with nonneoplastic thyroid tissue. Moreover, paired clinical specimens of primary PTC and its lymph node metastasis showed a significant upregulation of TLR4 levels in the metastatic tissues. In agreement, conditional BRAFV600E expression in normal rat thyroid cells and mouse thyroid tissue upregulated TLR4 expression levels. Furthermore, functional TLR4 expression was demonstrated in PTC cells by increased NF-κB transcriptional activity in response to the exogenous TLR4-agonist lipopolysaccharide. Of note, The Cancer Genome Atlas data analysis revealed that BRAFV600E-positive tumors with high TLR4 expression were associated with shorter disease-free survival. Transcriptomic data analysis indicated a positive correlation between TLR4 expression levels and MAPK/ERK signaling activation. Consistently, chemical blockade of MAPK/ERK signaling abrogated BRAFV600E-induced TLR4 expression. A detailed study of the TLR4 promoter revealed a critical MAPK/ERK–sensitive Ets-binding site involved in BRAFV600E responsiveness. Subsequent investigation revealed that the Ets-binding factor ETS1 is critical for BRAFV600E-induced MAPK/ERK signaling-dependent TLR4 gene expression. Together, these data indicate that functional TLR4 overexpression in PTCs is a consequence of thyroid tumor-oncogenic driver dysregulation of MAPK/ERK/ETS1 signaling.

Implications: Considering the participation of aberrant NF-κB signaling activation in the promotion of thyroid tumor growth and the association of high TLR4 expression with more aggressive tumors, this study suggests a prooncogenic potential of TLR4 downstream signaling in thyroid tumorigenesis. Mol Cancer Res; 16(5); 833–45. ©2018 AACR.
Data from MST1 Suppresses Pancreatic Cancer Progression via ROS-Induced Pyroptosis
Authors: Cui Jiujie , Zhou Zhuqing , Yang Haiyan , Jiao Feng , Li Ning , Gao Yong , Wang Liwei , Chen Jingde , Quan Ming
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, and its incidence is increasing annually. It is critical to reveal and delineate the molecular mechanism promoting PDAC development and progression. Mammalian STE20-like kinase 1 (MST1) is a proapoptotic cytoplasmic kinase and also one of the core components of the Hippo pathway. Here, we showed that MST1 expression was decreased in PDAC, and restored expression of MST1 promoted PDAC cell death and suppressed the proliferation, migration, invasion, and cell spheroid formation of PDAC via caspase-1–induced pyroptosis. Further studies demonstrated that pyroptosis induced by MST1 was independent of the Hippo pathway, but mediated by reactive oxygen species (ROS). And ROS scavenger N-acetyl-cysteine attenuated the activation of caspase-1 induced by MST1 and the effect of MST1 in PDAC cell death, proliferation, migration, and invasion. Collectively, our study demonstrated that MST1 suppressed the progression of PDAC cells at least partly through ROS-induced pyroptosis.
Implications:
In this study, we identified a new mechanism of MST1 in inhibiting PDAC development and progression and revealed that MST1 would be a potential prognostic and therapeutic target for PDAC.
Data from AP-1 Signaling by Fra-1 Directly Regulates HMGA1 Oncogene Transcription in Triple-Negative Breast Cancers
Authors: Tolza Claire , Bejjani Fabienne , Evanno Emilie , Mahfoud Samantha , Moquet-Torcy Gabriel , Gostan Thierry , Maqbool Muhammad Ahmad , Kirsh Olivier , Piechaczyk Marc , Jariel-Encontre Isabelle
Published: March 2024

Abstract
The architectural chromatin protein HMGA1 and the transcription factor Fra-1 are both overexpressed in aggressive triple-negative breast cancers (TNBC), where they both favor epithelial-to-mesenchymal transition, invasion, and metastasis. We therefore explored the possibility that Fra-1 might be involved in enhanced transcription of the HMGA1 gene in TNBCs by exploiting cancer transcriptome datasets and resorting to functional studies combining RNA interference, mRNA and transcriptional run-on assays, chromatin immunoprecipitation, and chromosome conformation capture approaches in TNBC model cell lines. Our bioinformatic analysis indicated that Fra-1 and HMGA1 expressions positively correlate in primary samples of patients with TNBC. Our functional studies showed that Fra-1 regulates HMGA1 mRNA expression at the transcriptional level via binding to enhancer elements located in the last two introns of the gene. Although Fra-1 binding is required for p300/CBP recruitment at the enhancer domain, this recruitment did not appear essential for Fra-1–stimulated HMGA1 gene expression. Strikingly, Fra-1 binding is required for efficient recruitment of RNA Polymerase II at the HMGA1 promoter. This is permitted owing to chromatin interactions bringing about the intragenic Fra-1–binding enhancers and the gene promoter region. Fra-1 is, however, not instrumental for chromatin loop formation at the HMGA1 locus but rather exerts its transcriptional activity by exploiting chromatin interactions preexisting to its binding.
Implications:
We demonstrate that Fra-1 bound to an intragenic enhancer region is required for RNA Pol II recruitement at the HMGA1 promoter. Thereby, we provide novel insights into the mechanisms whereby Fra-1 exerts its prooncogenic transcriptional actions in the TNBC pathologic context.
Data from High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer
Authors: Garinet Simon , Pignot Géraldine , Vacher Sophie , Le Goux Constance , Schnitzler Anne , Chemlali Walid , Sirab Nanor , Barry Delongchamps Nicolas , Zerbib Marc , Sibony Mathilde , Allory Yves , Damotte Diane , Bieche Ivan
Published: March 2024

Abstract
Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, noncoding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of GPR126 gene in 2.7% of a large breast cancer series. As GPR126 is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 nonmuscle-invasive bladder cancers (NMIBC) and 59 muscle-invasive bladder cancers (MIBC). GPR126 mutations were analyzed by high-resolution melting and Sanger sequencing, and GPR126 expression levels were assessed using real-time quantitative RT-PCR. In NMIBC, somatic GPR126 noncoding mutations occurred in 47.7% of samples and were negatively associated with GPR126 mRNA levels. GPR126 mutations had higher frequencies in nonsmoker patients and were associated with a prior history of NMIBC. GPR126 overexpression was detected in 70.5% of samples. GPR126 mutation and overexpression status were not associated with outcome. In MIBC, somatic GPR126 mutations occurred in 44.1% of samples. Mutations were more frequent in females. GPR126 overexpression was detected in 27.1% of the sample. A trend toward significance was observed between GPR126 overexpression and better outcome. We identified the second most frequent mutational hotspot after TERT promoter (∼70%) in bladder cancer, with a mutation rate of approximately 50%.
Implications:
The GPR126 intronic mutational hotspot could be a promising clinical biomarker candidate to monitor tumor burden using circulating tumor DNA in bladder cancer.
Data from TGFβ-Induced Lung Cancer Cell Migration Is NR4A1-Dependent
Authors: Hedrick Erik , Mohankumar Kumaravel , Safe Stephen
Published: March 2024

Abstract
TGFβ induces migration of lung cancer cells (A549, H460, and H1299), dependent on activation of c-Jun N-terminal kinase (JNK1), and is inhibited by the JNK1 inhibitor SP600125. Moreover, TGFβ-induced migration of the cells is also blocked by the nuclear export inhibitor leptomycin B (LMB) and the orphan nuclear receptor 4A1 (NR4A1) ligand 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (CDIM8), which retains NR4A1 in the nucleus. Subsequent analysis showed that the TGFβ/TGFβ receptor/PKA/MKK4 and -7/JNK pathway cascade phosphorylates and induces nuclear export of NR4A1, which in turn forms an active complex with Axin2, Arkadia (RNF111), and RNF12 (RLIM) to induce proteasome-dependent degradation of SMAD7 and enhance lung cancer cell migration. Thus, NR4A1 also plays an integral role in mediating TGFβ-induced lung cancer invasion, and the NR4A1 ligand CDIM8, which binds nuclear NR4A1, represents a novel therapeutic approach for TGFβ-induced blocking of lung cancer migration/invasion.
Implications:
Effective treatment of TGFβ-induced lung cancer progression could involve a number of agents including the CDIM/NR4A1 antagonists that block not only TGFβ-induced migration, but several other NR4A1-regulated prooncogenic genes/pathways in lung cancer cell lines.