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Hidejiro Torigoe, Hiromasa Yamamoto, Masakiyo Sakaguchi, Chen Youyi, Kei Namba, Hiroki Sato, Kazuhiko Shien, Junichi Soh, Ken Suzawa, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations, and have been targeted for treatment in non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues...
March 13, 2018: Carcinogenesis
S Hayano, Y Fukui, N Kawanabe, K Kono, M Nakamura, Y Ishihara, H Kamioka
In developing teeth, the sequential and reciprocal interactions between epithelial and mesenchymal tissues promote stem/progenitor cell differentiation. However, the origin of the stem/progenitor cells has been the subject of considerable debate. According to recent studies, mesenchymal stem cells originate from periarterial cells and are regulated by neurons in various organs. The present study examined the role of innervation in tooth development and rodent incisor stem/progenitor cell homeostasis. Rodent incisors continuously grow throughout their lives, and the lower incisors are innervated by the inferior alveolar nerve (IAN)...
March 1, 2018: Journal of Dental Research
Lin Zhou, Xiaowei Li, Fan Zhou, Zhi'an Jin, Di Chen, Pin Wang, Shu Zhang, Yuzheng Zhuge, Yulong Shang, Xiaoping Zou
Multidrug resistance (MDR) significantly restricts the clinical efficacy of gastric cancer (GC) chemotherapy, and it is critical to search novel targets to predict and overcome MDR. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) has been proved to be correlated with drug resistance in several cancers. The present study revealed that LRIG1 was overexpressed in chemo-sensitive GC tissues and decreased expression of LRIG1 predicted poor survival in GC patients. We observed that up-regulation of LRIG1 enhanced chemo-sensitivity in GC cells...
February 16, 2018: Cancer Science
David Lindquist, Fernando C Alsina, Carl Herdenberg, Catharina Larsson, Jo Höppener, Na Wang, Gustavo Paratcha, Miklós Tarján, Tibor Tot, Roger Henriksson, Håkan Hedman
Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are characterized by genomic rearrangements and point mutations in the proto-oncogene RET. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a suppressor of various receptor tyrosine kinases, including RET. LRIG1 expression levels are associated with patient survival in many cancer types. In the present study, we investigated whether the oncogenic RET mutants RET2A (C634R) and RET2B (M918T) were regulated by LRIG1, and the possible effects of LRIG1 expression in thyroid cancer were investigated in three different clinical cohorts and in a RET2B-driven mouse model of MTC...
February 9, 2018: International Journal of Oncology
Feng Mao, Camilla Holmlund, Mahmood Faraz, Wanzhong Wang, Tommy Bergenheim, Samuel Kvarnbrink, Mikael Johansson, Roger Henriksson, Håkan Hedman
Recently, a genome-wide association study showed that a single nucleotide polymorphism (SNP) -rs11706832-in intron 2 of the human LRIG1 (Leucine-rich repeats and immunoglobulin-like domains 1) gene is associated with susceptibility to glioma. However, the mechanism by which rs11706832 affects glioma risk remains unknown; additionally, it is unknown whether the expression levels of LRIG1 are a relevant determinant of gliomagenesis. Here, we investigated the role of Lrig1 in platelet-derived growth factor (PDGF)-induced experimental glioma in mice by introducing mono-allelic and bi-allelic deletions of Lrig1 followed by inducing gliomagenesis via intracranial retroviral transduction of PDGFB in neural progenitor cells...
February 2, 2018: Oncogenesis
Mahmood Faraz, Carl Herdenberg, Camilla Holmlund, Roger Henriksson, Håkan Hedman
Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a tumor suppressor and a negative regulator of several receptor tyrosine kinases (RTKs). The molecular mechanisms by which LRIG1 mediates its tumor suppressor effects and regulates RTKs remain incompletely understood. Here, we performed a yeast two-hybrid screen to identify novel LRIG1-interacting proteins and mined data from the BioPlex (biophysical interactions of ORFeome-based complexes) protein interaction data repository. The putative LRIG1 interactors identified in the screen were functionally evaluated using a triple co-transfection system in which HEK293 cells were co-transfected with platelet-derived growth factor receptor alpha (PDGFRA), LRIG1, and shRNAs against the identified LRIG1 interactors...
January 9, 2018: Journal of Biological Chemistry
Feng Mao, Baofeng Wang, Qungen Xiao, Fangling Cheng, Ting Lei, Dongsheng Guo
Gliomas are the most common intracranial tumors of the nervous system. These tumors are characterized by unlimited cell proliferation and excessive invasiveness. Despite the advances in diagnostic imaging, microneurosurgical techniques, radiation therapy, and chemotherapy, significant increases in the progression free survival of glioma patients have not been achieved. Improvements in our understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways may impact both the diagnosis and the treatment strategies for patients with gliomas...
December 15, 2017: Journal of the Neurological Sciences
Leon Raskin, Yan Guo, Liping Du, Mark Clendenning, Christophe Rosty, Noralane M Lindor, Stephen B Gruber, Daniel D Buchanan
The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation sequencing (NGS) can be prohibitively expensive for studies requiring large samples sizes. The aim of the study was to identify rare single nucleotide variants and small indels in 40 established or candidate CRC susceptibility genes in 1,046 familial CRC cases (including both MSS and MSI-H tumor subtypes) and 1,006 unrelated controls from the Colon Cancer Family Registry Cohort using a robust and cost-effective DNA pooling NGS strategy...
November 7, 2017: Oncotarget
Mariela F Trinchero, Karina A Buttner, Jessica N Sulkes Cuevas, Silvio G Temprana, Paula A Fontanet, M Cristina Monzón-Salinas, Fernanda Ledda, Gustavo Paratcha, Alejandro F Schinder
During aging, the brain undergoes changes that impair cognitive capacity and circuit plasticity, including a marked decrease in production of adult-born hippocampal neurons. It is unclear whether development and integration of those new neurons are also affected by age. Here, we show that adult-born granule cells (GCs) in aging mice are scarce and exhibit slow development, but they display a remarkable potential for structural plasticity. Retrovirally labeled 3-week-old GCs in middle-aged mice were small, underdeveloped, and disconnected...
October 31, 2017: Cell Reports
Fabienne Fontao, Laurent Barnes, Guerkan Kaya, Jean-Hilaire Saurat, Olivier Sorg
We have previously shown that cytochrome P450 1A1 (CYP1A1) was highly induced for a long period of time in a patient who had been poisoned by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound known to activate the aryl hydrocarbon receptor (AhR). During that period of time, no sebaceous glands could be observed in the skin of this patient. In this study, starting from observations in the patient exposed to TCDD, we analyzed the seboatrophy induced by dioxins in mice. We observed a very different pattern of AhR and CYP1A1 immunostaining in skin biopsies of the patient...
December 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Yaqi Zhang, Zhizhen Liu, Shunrui Yu
We investigated the role of leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 in ovarian cancer cell line and VP16 drug-resistant cell line to explore the possible mechanism of action. Human ovarian cancer cell line SKOV3 and the VP16 drug-resistant cell line SKOV3/VP16 were used to investigate whether LRIG1 affects the sensitivity of SKOV3 to drugs. RT-qPCR was used to detect the difference in LRIG1 expression between drug-resistant and wild-type cell lines. siRNA LRIG1 was designed and transfected to silence LRIG1 to investigate the mechanism by which LRIG1 affects the sensitivity of SKOV3 to drugs...
October 2017: Oncology Letters
Cecilia Ranhem, Gabriella Lillsunde Larsson, Håkan Hedman, David Lindquist, Mats G Karlsson, Ann-Cathrin Hellström, Ellinor Östensson, Bengt Sorbe, Kristina Hellman, Sonia Andersson
BACKGROUND: Primary vaginal carcinoma (PVC) is a rare malignancy. Established prognostic factors include tumour stage and age at diagnosis. The leucine-rich repeats and immunoglobuline-like domains (LRIG)-1 protein functions as a tumour suppressor, but less is known about the functions of LRIG2 and LRIG3. The present study aimed to evaluate the expression of LRIG proteins and analyse their possible associations with clinical characteristics and survival in a cohort of PVC patients. METHODS: We used immunohistochemistry to investigate LRIG1, LRIG2, and LRIG3 expression in tumour samples from a consecutive cohort of 70 PVC patients...
2017: PloS One
Eunyoung Choi, Tyler L Lantz, Gregory Vlacich, Theresa M Keeley, Linda C Samuelson, Robert J Coffey, James R Goldenring, Anne E Powell
OBJECTIVE: Lrig1 is a marker of proliferative and quiescent stem cells in the skin and intestine. We examined whether Lrig1-expressing cells are long-lived gastric progenitors in gastric glands in the mouse stomach. We also investigated how the Lrig1-expressing progenitor cells contribute to the regeneration of normal gastric mucosa by lineage commitment to parietal cells after acute gastric injury in mice. DESIGN: We performed lineage labelling using Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) or R26R-LacZ/+ (Lrig1/LacZ) mice to examine whether the Lrig1-YFP-marked cells are gastric progenitor cells...
August 16, 2017: Gut
Long Chen, Wenhua Wang, Shengqiang Zhu, Xuegang Jin, Jian Wang, Jianfang Zhu, Youxin Zhou
microRNA (miR)-590 has been found to serve potential roles in cancer development; however, the expression and function of miR-590 in human gliomas remains to be elucidated. The present study aimed to investigate the expression of miR-590 in human glioma tissues and radioresistant human glioblastoma cells (U251R), and to determine the effect and related molecular mechanism of miR-590-3p on the radiosensitivity of U251R cells in vitro. The results from reverse transcription-quantitative polymerase chain reaction indicated that miR-590-3p was upregulated in human glioma tissues and radioresistant human glioblastoma cells, and that miR-590-3p expression was higher in high grade than in low grade gliomas...
August 2017: Experimental and Therapeutic Medicine
Simone Lanfredini, Carlotta Olivero, Cinzia Borgogna, Federica Calati, Kathryn Powell, Kelli-Jo Davies, Marco De Andrea, Sarah Harries, Hiu Kwan Carolyn Tang, Herbert Pfister, Marisa Gariglio, Girish K Patel
β-Human papillomaviruses (HPVs) cause near ubiquitous latent skin infection within long-lived hair follicle (HF) keratinocyte stem cells. In patients with epidermodysplasia verruciformis, β-HPV viral replication is associated with skin keratosis and cutaneous squamous cell carcinoma. To determine the role of HF keratinocyte stem cells in β-HPV-induced skin carcinogenesis, we utilized a transgenic mouse model in which the keratin 14 promoter drives expression of the entire HPV8 early region (HPV8tg). HPV8tg mice developed thicker skin in comparison with wild-type littermates consistent with a hyperproliferative epidermis...
October 2017: Journal of Investigative Dermatology
Kerstin Seidel, Pauline Marangoni, Cynthia Tang, Bahar Houshmand, Wen Du, Richard L Maas, Steven Murray, Michael C Oldham, Ophir D Klein
Investigations into stem cell-fueled renewal of an organ benefit from an inventory of cell type-specific markers and a deep understanding of the cellular diversity within stem cell niches. Using the adult mouse incisor as a model for a continuously renewing organ, we performed an unbiased analysis of gene co-expression relationships to identify modules of co-expressed genes that represent differentiated cells, transit-amplifying cells, and residents of stem cell niches. Through in vivo lineage tracing, we demonstrated the power of this approach by showing that co-expression module members Lrig1 and Igfbp5 define populations of incisor epithelial and mesenchymal stem cells...
May 5, 2017: ELife
Virginie Neirinckx, Hakan Hedman, Simone P Niclou
Leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) is an endogenous feedback regulator of receptor tyrosine kinases (RTKs) and was recently shown to inhibit growth of different types of malignancies. Additionally, this multifaceted RTK inhibitor was reported to be a tumor suppressor, a stem cell regulator, and a modulator of different cellular phenotypes. This mini-review provides a concise and up-to-date summary about the known functions of LRIG1 and its related family members, with a special emphasis on underlying molecular mechanisms and the opportunities for harnessing its therapeutic potential against cancer...
August 2017: Biochimica et Biophysica Acta
Juanjuan Zhang, Xiaoyan Wang, Yijie Zhang, Jingcan Wu, Nannan Zhou
OBJECTIVE: To assess the clinical significance of leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) and fascin actin-bundling protein 1 (Fascin-1) expression in nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Six-one NSCLC patients were included in this study. The expression of LRIG1 and Fascin-1 was assayed in the tumor tissue and relative normal lung tissue of the 61 NSCLC patients by immunohistochemistry. The relationship between LRIG1, Fascin-1 expression pattern and lung cancer patients' clinical pathology characteristics was evaluated...
December 2016: Journal of Cancer Research and Therapeutics
Laurent Barnes, Jean-Hilaire Saurat, Gürkan Kaya
Lrig1 is known to repress the epidermal growth through its inhibitory activity on EGFR, while CD44 promotes it. We analyzed the expression of these molecules in senescent atrophic human epidermis and in the epidermis of CD44KO mice. In normal human epidermis, Lrig1+ cells form clusters located in the basal layer in which CD44 expression is downregulated and Lef1 expression reflects an active Wnt signaling. In senescent atrophic human epidermis, we found retention of Lrig1high+ cells all along the basal layer, forming no clusters, with decrease of CD44 and lef1 expression...
2017: PloS One
Raquel López-Mejías, Alfonso Corrales, Esther Vicente, Montserrat Robustillo-Villarino, Carlos González-Juanatey, Javier Llorca, Fernanda Genre, Sara Remuzgo-Martínez, Trinidad Dierssen-Sotos, José A Miranda-Filloy, Marco A Ramírez Huaranga, Trinitario Pina, Ricardo Blanco, Juan J Alegre-Sancho, Enrique Raya, Verónica Mijares, Begoña Ubilla, Iván Ferraz-Amaro, Carmen Gómez-Vaquero, Alejandro Balsa, Francisco J López-Longo, Patricia Carreira, Isidoro González-Álvaro, J Gonzalo Ocejo-Vinyals, Luis Rodríguez-Rodríguez, Benjamín Fernández-Gutiérrez, Santos Castañeda, Javier Martín, Miguel A González-Gay
A genetic component influences the development of atherosclerosis in the general population and also in rheumatoid arthritis (RA). However, genetic polymorphisms associated with atherosclerosis in the general population are not always involved in the development of cardiovascular disease (CVD) in RA. Accordingly, a study in North-American RA patients did not show the association reported in the general population of coronary artery disease with a series of relevant polymorphisms (TCF21, LPA, HHIPL1, RASD1-PEMT, MRPS6, CYP17A1-CNNM2-NT5C2, SMG6-SRR, PHACTR1, WDR12 and COL4A1-COL4A2)...
January 6, 2017: Scientific Reports
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