Marcin Maziarz, Anthony Federico, Jingyi Zhao, Lorena Dujmusic, Zhiming Zhao, Stefano Monti, Xaralabos Varelas, Mikel Garcia-Marcos
Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs , Gi/o , Gq/11 , and G12/13 . Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs , Gi/o , or Gq/11 proteins have also been identified in patient tumor samples. In contrast, patient tumor-associated G12/13 mutations characterized to date lead to inactivation rather than activation...
December 4, 2020: Journal of Biological Chemistry
Zhizhou Xia, Xiuli Zhang, Ping Liu, Ruihong Zhang, Zhangsen Huang, Donghe Li, Xinhua Xiao, Min Wu, Nannan Ning, Qianqian Zhang, Jianmin Zhang, Mingzhu Liu, Bo Jiao, Ruibao Ren
GNA13, encoding one of the G protein alpha subunits of heterotrimeric G proteins that transduce signals of G protein-coupled receptors (GPCR), is frequently mutated in germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) with poor prognostic outcomes. Due to the "undruggable" nature of GNA13, targeted therapy for these patients is not available. In this study, we found that palmitoylation of GNA13 not only regulates its plasma membrane localization, but also regulates GNA13's stability...
January 9, 2021: Cell Death & Disease
Marcin Maziarz, Anthony Federico, Jingyi Zhao, Lorena Dujmusic, Zhiming Zhao, Stefano Monti, Xaralabos Varelas, Mikel Garcia-Marcos
<s></s>Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs, Gi/o, Gq/11 and G12/13. Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs, Gi/o or Gq/11 proteins have also been identified in patient tumor samples...
October 27, 2020: Journal of Biological Chemistry
Clementine Sarkozy, Stacy S Hung, Elizabeth A Chavez, Gerben Duns, Katsuyoshi Takata, Lauren C Chong, Tomohiro Aoki, Aixiang Jiang, Tomoko Miyata-Takata, Adèle Telenius, Graham W Slack, Thierry Jo Molina, Susana Ben-Neriah, Pedro Farinha, Peggy Dartigues, Diane Damotte, Anja Mottok, Gilles Andre Salles, Rene-Olivier Casasnovas, Kerry J Savage, Camille Laurent, David W Scott, Alexandra Traverse-Glehen, Christian Steidl
The mutational landscape of grey zone lymphoma (GZL) has not yet been established and differences to related entities are largely unknown. Here, we studied coding sequence mutations of 50 EBV-negative GZL and 20 polymorphic EBV-positive DLBCL NOS (poly-EBV-L) in comparison to classical Hodgkin lymphoma (cHL), primary mediastinal large B cell lymphoma (PMBCL), and diffuse large B cell lymphoma (DLBCL). Exomes of 21 GZL and 7 poly-EBV-L cases along with paired normals were analyzed as a discovery cohort followed by targeted sequencing of 217 genes in an extension cohort of 29 GZL and 13 poly-EBV-L cases...
September 22, 2020: Blood
Yuchen Hu, Shan Ye, Qian Li, Tiantian Yin, Jing Wu, Jie He
Purpose: Glioblastoma (GBM) is an aggressive central nervous system (CNS) cancer and a serious threat to human health. The long noncoding RNA (lncRNA) HULC has been implicated in GBM, but the molecular mechanism is uncertain. This study used quantitative proteomic analysis for global identification of HULC-regulated proteins in glioblastoma cells and identification of potential biomarkers. Materials and Methods: qRT-PCR was used to determine the expression of HULC in U87 cells stably transfected with HULC or an empty vector (control)...
2020: OncoTargets and Therapy
Juming Li, Lingxiang Liu, Qi Zhang, Yumin Huang, Yihong Zhang, Xiaoyan Gan, Siqin Liu, Zhen Yue, Yongzhong Wei
RATIONALE: Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma. Owing to the lack of specific histological criteria, immunohistochemical, and molecular diagnostic markers, several differential diagnoses must be considered. Advances in molecular testing can provide significant insights for management of rare tumor. PATIENT CONCERNS: The patient was a 50-year-old man with a history of lumpectomy on the right back 30 years ago. He felt a stabbing pain at the right iliac fossa and went to the local hospital...
June 26, 2020: Medicine (Baltimore)
Yanquan Liu, Jianzhen Shen, M Awal Issah, Tingbo Liu, Huarong Zhou, Haiying Fu
Diffuse large B-cell lymphoma (DLBCL) is the most common adult non-Hodgkin lymphoma (NHL) and is highly invasive, with a poor prognosis. The main clinical treatment for DLBCL involves chemotherapy or a combination of chemotherapy and targeted drugs. CD56 expression is considered as an indicator of poor prognosis in patients with acute myeloid leukemia and anaplastic large cell lymphoma; however, its role in DLBCL remains unclear. We report on a patient with CD56-positive DLBCL/leukemia with BCL6 / MYC double-hit, and DDX3X , LRP1B , SIN3A , and GNA13 gene mutations (stage IVA, prognostic index aaIPI = 2 points)...
May 2020: Journal of International Medical Research
Esther van den Bos, Benjamin Ambrosy, Markus Horsthemke, Stefan Walbaum, Anne C Bachg, Nina Wettschureck, Giulio Innamorati, Thomas M Wilkie, Peter J Hanley
G protein-coupled receptor (GPCR) signaling is required for the navigation of immune cells along chemoattractant gradients. However, chemoattractant receptors may couple to more than one type of heterotrimeric G protein, each of which consists of a Gα, Gβ, and Gγ subunit, making it difficult to delineate the critical signaling pathways. Here we used knockout mouse models and time-lapse microscopy to elucidate Gα and Gβ subunits contributing to complement C5a receptor-mediated chemotaxis. Complement C5a-mediated chemokinesis and chemotaxis were almost completely abolished in macrophages lacking Gnai2 (encoding Gαi2 ), consistent with a reduced leukocyte recruitment previously observed in Gnai2 -/- mice, whereas cells lacking Gnai3 (Gαi3 ) exhibited only a slight decrease in cell velocity...
April 24, 2020: Journal of Biological Chemistry
Vincent Camus, Mathieu Viennot, Justine Lequesne, Pierre-Julien Viailly, Elodie Bohers, Lucile Bessi, Bénédicte Marcq, Pascaline Etancelin, Sydney Dubois, Jean-Michel Picquenot, Elena-Liana Veresezan, Marie Cornic, Lucie Burel, Justine Loret, Stéphanie Becker, Pierre Decazes, Pascal Lenain, Stéphane Lepretre, Emilie Lemasle, Hélène Lanic, Anne-Lise Ménard, Nathalie Contentin, Hervé Tilly, Aspasia Stamatoullas, Fabrice Jardin
The relevance of circulating tumor DNA (ctDNA) analysis as a liquid biopsy and minimal residual disease tool in the management of classical Hodgkin Lymphoma (cHL) patients was demonstrated in retrospective settings and remains to be confirmed in a prospective setting. We developed a targeted Next-Generation sequencing (NGS) panel for fast analysis (AmpliSeq technology) of nine commonly mutated genes in biopies and ctDNA of cHL patients. We then conducted a prospective trial to assess ctDNA follow up at diagnosis and after 2 cycles of chemotherapy (C2)...
February 20, 2020: Haematologica
Kirsty Wienand, Bjoern Chapuy, Chip Stewart, Andrew J Dunford, David Wu, Jaegil Kim, Atanas Kamburov, Timothy R Wood, Fathima Zumla Cader, Matthew D Ducar, Aaron R Thorner, Anwesha Nag, Alexander T Heubeck, Michael J Buonopane, Robert A Redd, Kamil Bojarczuk, Lee N Lawton, Philippe Armand, Scott J Rodig, Jonathan R Fromm, Gad Getz, Margaret A Shipp
Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands. To define genetic mechanisms of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole-exome sequencing of flow cytometry-sorted HRS cells from 23 excisional biopsies of newly diagnosed cHLs, including 8 Epstein-Barr virus-positive (EBV+) tumors...
December 10, 2019: Blood Advances
Bo Xiang, Juanjuan Yang, Jin Zhang, Minglan Yu, Chaohua Huang, Wenying He, Wei Lei, Jing Chen, Kezhi Liu
Numerous variants associated with increased risk for SCZ have undergone positive selection and were associated with human brain development, but which brain regions and developmental stages were influenced by the positive selection for SCZ risk alleles are unclear. We analyzed SCZ using summary statistics from a genome-wide association study (GWAS) from the Psychiatric Genomics Consortium (PGC). Machine-learning scores were used to investigate two natural-selection scenarios: complete selection (loci where a selected allele has reached fixation) and incomplete selection (loci where a selected allele has not yet reached fixation)...
October 30, 2019: Progress in Neuro-psychopharmacology & Biological Psychiatry
Wei Kiang Lim, Xiaoran Chai, Sujoy Ghosh, Debleena Ray, Mei Wang, Suhail Ahmed Kabeer Rasheed, Patrick J Casey
GNA13, the alpha subunit of a heterotrimeric G protein, mediates signaling through G protein-coupled-receptors (GPCRs). GNA13 is up-regulated in many solid tumors, including prostate cancers, where it contributes to tumor initiation, drug resistance and metastasis. To better understand how GNA13 contributes to tumorigenesis and tumor progression,  we compared the entire transcriptome of PC3 prostate cancer cells with those cells in which GNA13 expression had been silenced. This analysis revealed that GNA13 levels affected multiple CXC-family chemokines...
October 21, 2019: Journal of Biological Chemistry
Tae Hyun Kim, Ja Hyun Koo, Mi Jeong Heo, Chang Yeob Han, Yong-In Kim, Shi-Young Park, Il Je Cho, Chang Ho Lee, Cheol Soo Choi, Jung Weon Lee, Won Kim, Je-Yoel Cho, Sang Geon Kim
The impact of liver disease on whole-body glucose homeostasis is largely attributed to dysregulated release of secretory proteins in response to metabolic stress. The molecular cues linking liver to whole-body glucose metabolism remain elusive. We found that expression of G protein α-13 (Gα13 ) was decreased in the liver of mice and humans with diabetes. Liver-specific deletion of the Gna13 gene in mice resulted in systemic glucose intolerance. Comparative secretome analysis identified inter-α-trypsin inhibitor heavy chain 1 (ITIH1) as a protein secreted by liver that was responsible for systemic insulin resistance in Gna13- deficient mice...
October 9, 2019: Science Translational Medicine
Hai-Xia Gao, Aijiang Nuerlan, Gulinaer Abulajiang, Wen-Li Cui, Jing Xue, Wei Sang, Si-Jing Li, Jing Niu, Zhi-Ping Ma, Wei Zhang, Xin-Xia Li
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with unclear pathogenesis. DLBCL accounts for 30%-35% of all non-Hodgkin lymphomas (NHLs) and is an aggressive subtype of mature B-cell neoplasm. At present, half of DLBCL cases can be cured, although one-third of patients experience recurrence after treatment and enter advanced tumor stage. This study aimed to investigate the differentially expressed proteins in activated B-cell-like-DLBCL (ABC-DLBCL) through quantitative proteomics (iTRAQ). Seven ABC-DLBCL experimental samples and eight control samples (reactive hyperplasia of the lymph node) were obtained from fresh tissues...
September 2019: Pathology, Research and Practice
Julia González-Rincón, Miriam Méndez, Sagrario Gómez, Juan F García, Paloma Martín, Carmen Bellas, Lucía Pedrosa, Socorro M Rodríguez-Pinilla, Francisca I Camacho, Cristina Quero, David Pérez-Callejo, Antonio Rueda, Marta Llanos, José Gómez-Codina, Miguel A Piris, Santiago Montes-Moreno, Carmen Bárcena, Delvys Rodríguez-Abreu, Javier Menárguez, Luis de la Cruz-Merino, Silvia Monsalvo, Consuelo Parejo, Ana Royuela, Ivo Kwee, Luciano Cascione, Alberto Arribas, Francesco Bertoni, Manuela Mollejo, Mariano Provencio, Margarita Sánchez-Beato
Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients...
2019: PloS One
Blanca Gonzalez-Farre, Joan Enric Ramis-Zaldivar, Julia Salmeron-Villalobos, Olga Balagué, Verónica Celis, Jaime Verdu-Amoros, Ferran Nadeu, Constantino Sábado, Antonio Ferrández, Marta Garrido, Federico García-Bragado, María Dolores de la Maya, José Manuel Vagace, Carlos Manuel Panizo, Itziar Astigarraga, Mara Andrés, Elaine S Jaffe, Elias Campo, Itziar Salaverria
Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases...
September 2019: Haematologica
Shan Muhammad, Qingchao Tang, Liu Wei, Qian Zhang, Guiyu Wang, Bilal Umar Muhammad, Kavanjit Kaur, Tatiana Kamchedalova, Zhao Gang, Zheng Jiang, Zheng Liu, Xishan Wang
MicroRNAs (miRNAs or miRs) are reported to be dysregulated in the progression and invasion of various human cancer types, including colorectal cancer (CRC). They are also reported to be molecular biomarkers and therapeutic targets in CRC. miRNAs serve functions in a plethora of biological processes, including proliferation, migration, invasion and apoptosis, and several miRNAs have been demonstrated to be involved in CRC carcinogenesis, invasion and metastasis. Aberrant miR-30d expression and its effects have been reported in certain cancer types...
January 2019: Experimental and Therapeutic Medicine
Rabea Wagener, Julian Seufert, Francesco Raimondi, Susanne Bens, Kortine Kleinheinz, Inga Nagel, Janine Altmüller, Holger Thiele, Daniel Hübschmann, Christian W Kohler, Peter Nürnberg, Rex Au-Yeung, Birgit Burkhardt, Heike Horn, Lorenzo Leoncini, Elaine S Jaffe, German Ott, Grzegorz Rymkiewicz, Matthias Schlesner, Robert B Russell, Wolfram Klapper, Reiner Siebert
The new recently described provisional lymphoma category Burkitt-like lymphoma with 11q aberration comprises cases similar to Burkitt lymphoma (BL) on morphological, immunophenotypic and gene-expression levels but lacking the IG- MYC translocation. They are characterized by a peculiar imbalance pattern on chromosome 11, but the landscape of mutations is not yet described. Thus, we investigated 15 MYC -negative Burkitt-like lymphoma with 11q aberration (mnBLL,11q,) cases by copy-number analysis and whole-exome sequencing...
February 28, 2019: Blood
Joji Shimono, Hiroaki Miyoshi, Noriaki Yoshida, Takeharu Kato, Kensaku Sato, Takeshi Sugio, Kohta Miyawaki, Daisuke Kurita, Yuya Sasaki, Keisuke Kawamoto, Yoshitaka Imaizumi, Koji Kato, Koji Nagafuji, Koichi Akashi, Masao Seto, Takanori Teshima, Koichi Ohshima
GNA13 is a G protein involved in modulating tumor proliferative capacity, infiltration, metastasis, and migration. Genomic alteration of GNA13 was frequently observed in follicular lymphoma (FL). In this study, we examined 167 cases of FL by immunostaining of GNA13 using tissue microarray to evaluate the clinical significance. There were 26 GNA13-positive cases (15.6%) and 141 GNA13-negative cases (84.4%). GNA13-positive cases had a higher incidence of early progression of disease for which disease progression was recognized within 2 years compared with GNA13-negative cases (P=0...
November 2018: American Journal of Surgical Pathology
Zhongqiang Zhang, Xiao Tan, Jing Luo, Beibei Cui, Sanlin Lei, Zhongzhou Si, Liangfang Shen, Hongliang Yao
GNA13 has been found overexpressed in various types of cancer, which is related to tumor metastasis and progression. However, the biological functions of GNA13 in colorectal cancer (CRC) progression remain unclear. This study aimed to explore the role of GNA13 in CRC and investigate the mechanism of how GNA13 promotes tumor growth. Interestingly, our findings showed that GNA13 is commonly upregulated in CRC, where these events are associated with a worse histologic grade and poor survival. Increased expression levels of GNA13 promoted cell growth, migration, invasion, and epithelial-mesenchymal transition, whereas GNA13 silencing abrogated these malignant phenotypes...
November 2018: Cancer Medicine
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