Colorectal adenocarcinoma‐derived EGFR mutants are oncogenic and sensitive to EGFR‐targeted monoclonal antibodies, cetuximab and panitumumab

Kim, Nayoung,Cho, Daseul,Kim, Hyunjin,Kim, Sujin,Cha, Young‐,je,Greulich, Heidi,Bass, Adam,Cho, Hyun‐,Soo,Cho, Jeonghee Alan R. Liss, Inc 2020 International journal of cancer Vol.146 No.8

<P>Somatic mutations of epidermal growth factor receptor (EGFR) occur in ~3% of colorectal cancer (CRC) patients. Here, through systematic functional screening of 21 recurrent EGFR mutations selected from public data sets, we show that 11 colon cancer‐derived EGFR mutants (G63R, E114K, R165Q, R222C, S492R, P596L, K708R, E709K, G719S, G724S and L858R) are oncogenic and able to transform cells in a ligand‐independent manner. We demonstrate that cellular transformation by these mutants requires receptor dimerization. Importantly, the EGF‐induced and constitutive oncogenic potential of these EGFR mutants are inhibited by cetuximab or panitumumab <I>in vivo</I> and <I>in vitro</I>. Taken together, we propose that a subset of EGFR mutations can serve as genomic predictors for response to anti‐EGFR antibodies and that metastatic CRC patients with such mutations may benefit from these drugs as part of the first‐line therapy.</P>

Thyrocyte‐specific deletion of insulin and IGF‐1 receptors induces papillary thyroid carcinoma‐like lesions through EGFR pathway activation

Ock, Sangmi,Ahn, Jihyun,Lee, Seok Hong,Kim, Hyun Min,Kang, Hyun,Kim, Young‐,Kook,Kook, Hyun,Park, Woo Jin,Kim, Shin,Kimura, Shioko,Jung, Chan Kwon,Shong, Minho,Holzenberger, Martin,Abel, E. Dale Alan R. Liss, Inc 2018 International journal of cancer Vol.143 No.10

<P>Insulin and insulin‐like growth factor (IGF)‐1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid‐stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF‐1 receptor (IGF‐1R) in thyroid development and function has not been explored. Here, we generated thyrocyte‐specific IR and IGF‐1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid‐specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF‐1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR‐dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)‐like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF‐1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF‐1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.</P>

Whole genome analysis for liver metastasis gene signatures in colorectal cancer

Ki, Dong Hyuk,Jeung, Hei-Cheul,Park, Chan Hee,Kang, Seung Hee,Lee, Gui Youn,Lee, Won Suk,Kim, Nam Kyu,Chung, Hyun Chul,Rha, Sun Young Alan R. Liss, Inc 2007 International journal of cancer Vol.121 No.9

<P>Liver metastasis is one of the major causes of death in colorectal cancer (CRC) patients. To understand this process, we investigated whether the gene expression profiling of matched colorectal carcinomas and liver metastases could reveal key molecular events involved in tumor progression and metastasis. We performed experiments using a cDNA microarray containing 17,104 genes with the following tissue samples: paired tissues of 25 normal colorectal mucosa, 27 primary colorectal tumors, 13 normal liver and 27 liver metastasis, and 20 primary colorectal tumors without liver metastasis. To remove the effect of normal cell contamination, we selected 4,583 organ-specific genes with a false discovery rate (FDR) of 0.0067% by comparing normal colon and liver tissues using significant analysis of microarray, and these genes were excluded from further analysis. We then identified and validated 46 liver metastasis-specific genes with an accuracy of 83.3% by comparing the expression of paired primary colorectal tumors and liver metastases using prediction analysis of microarray. The 46 selected genes contained several known oncogenes and 2 ESTs. To confirm that the results correlated with the microarray expression patterns, we performed RT-PCR with WNT5A and carbonic anhydrase II. Additionally, we observed that 21 of the 46 genes were differentially expressed (FDR = 2.27%) in primary tumors with synchronous liver metastasis compared with primary tumors without liver metastasis. We scanned the human genome using a cDNA microarray and identified 46 genes that may play an important role in the progression of liver metastasis in CRC. © 2007 Wiley-Liss, Inc.</P>

Modulation of lung cancer growth arrest and apoptosis by Phellinus Linteus

Guo, Jinjin,Zhu, Tongbo,Collins, LeaAnn,Xiao, Zhi-Xiong J.,Kim, Sung-Hoon,Chen, Chang-Yan Alan R. Liss, Inc 2007 Molecular carcinogenesis Vol.46 No.2

<P>The Phellinus Linteus (PL) mushroom has been shown to possess anti-tumor properties. Through influencing lymphocytes, PL indirectly augments the host's immune system against cancer cells. PL has also been demonstrated to reduce tumor proliferation. However, the mechanisms of PL against malignant growth have not yet been fully explored. In this study, we report that PL mediates the following two activities in mouse and human lung cancer cells: cell-cycle arrest at a low concentration of PL and apoptosis in response to a high dose of PL. After exposure to a low dose of PL, G<SUB>1</SUB> growth arrest occurred in the lung cancer cells. The negative growth control mediated by PL is evidenced by the decrease of the activities of cyclin-dependent kinases CDK2, 4, and 6. In contrast, at high doses, PL-induced lung cancer cells to undergo apoptosis in a dose-dependent fashion. This was evidenced by DNA fragmentation, caspase activation, and loss of clonogenecity in the lung cancer cells, all of which were lacking in the lung cancer cells treated with low concentrations of PL as well as the normal mouse lung epithelial cells exposed to either low or high concentrations of PL. The addition of the caspase inhibitor Z-VADfmk completely suppressed PL-induced apoptosis. Furthermore, the low dose of PL was able to synergize with doxorubicin to induce apoptosis in the lung cancer cells. Thus, our findings suggest that PL regulates two responses in the lung cancer cells: cell-cycle arrest and apoptosis. © 2006 Wiley-Liss, Inc.</P>

Oncostatin M promotes osteogenesis and suppresses adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells

Song, Hae Young,Jeon, Eun Su,Kim, Jung Il,Jung, Jin Sup,Kim, Jae Ho ALAN R LISS INC 2007 Journal of Cellular Biochemistry Vol.101 No.5

<P>Oncostatin M (OSM) is a multifunctional cytokine of the interleukin-6 family and has been implicated in embryonic development, differentiation, inflammation, and regeneration of liver and bone. In the present study, we demonstrated that treatment of human adipose mesenchymal stem cells (hADSCs) with OSM-attenuated adipogenic differentiation, as indicated by decreased accumulation of intracellular lipid droplets and down-regulated expression of adipocytic markers, such as lipoprotein lipase and PPARγ. However, OSM treatment stimulated osteogenic differentiation, as demonstrated by the increase in matrix mineralization and expression levels of osteogenic differentiation markers, including alkaline phosphatase, Runx2, and osteocalcin. OSM treatment induced activation of JAK2, JAK3, and ERK in hADSCs, and pre-treatment of hADSCs with the JAK2 inhibitor, AG490, significantly restored the OSM-induced inhibition of adipogenic differentiation. Whereas, the JAK3 inhibitor, WHI-P131, and the MEK inhibitor, U0126, had no effects on the anti-adipogenic activity of OSM. On the other hand, the pro-osteogenic activity of OSM was prevented by treatment of the cells with WHI-P131 or U0126, but not with AG490. These results indicate that distinct signaling pathways, including JAK2, JAK3, and MEK-ERK, play specific roles in the OSM-induced anti-adipogenic and pro-osteogenic differentiation of hADSCs. J. Cell. Biochem. 101:1238–1251, 2007. © 2007 Wiley-Liss, Inc.</P>

Akt signaling regulates actin organization via modulation of MMP-2 activity during chondrogenesis of chick wing limb bud mesenchymal cells

Jin, Eun-Jung,Park, Kwang Sook,Bang, Ok-Sun,Kang, Shin-Sung ALAN R LISS INC 2007 Journal of Cellular Biochemistry Vol.102 No.1

<P>Endochondral ossification is initiated by the differentiation of mesenchymal precursor cells to chondrocytes. This process is characterized by a strong interdependence of cell shape and cytoskeletal organization accompanying the onset of chondrogenic gene expression, but the molecular mechanisms mediating these interactions are not known. In this study, we hypothesized that the activation of matrix metalloproteinase (MMP)-2 would be involved in the reorganization of the actin cytoskeleton and that this would require an Akt-dependent signaling pathway in chick wing bud mesenchymal cells. The pharmacological inhibition of Akt signaling resulted in decreased glycosaminoglycan synthesis and reduced the level of active MMP-2, leading to suppressed cortical actin organization which is characteristic of differentiated chondrocytes. In addition, the exposure of cells to bafilomycin A1 reversed these chondro-inhibitory effects induced by inhibition of Akt signaling. In conclusion, our data indicate that Akt signaling is involved in the activation of MMP-2 and that this Akt-induced activation of MMP-2 is responsible for reorganization of the actin cytoskeleton into a cortical pattern with parallel rounding of chondrogenic competent cells. J. Cell. Biochem. 102: 252–261, 2007. © 2007 Wiley-Liss, Inc.</P>

Genetic variability of the fusion protein and circulation patterns of genotypes of the respiratory syncytial virus

Kim, Yun-Kyung,Choi, Eun-Hwa,Lee, Hoan-Jong Alan R. Liss 2007 Journal of medical virology Vol.79 No.6

<P>Although antigenic and genetic variations were shown to occur both in the G and F protein of respiratory syncytial virus (RSV), few studies looked at the variation of F gene. The F genotypes were determined by the evaluation of clustering patterns, via the phylogenetic analysis of the nucleotide sequences of a variable region in the F gene. One hundred seventy-nine strains obtained from a children's hospital in Korea over nine consecutive epidemics were included. The relationship between the F and G genotypes was analyzed with the G genotypes previously published by the authors. The phylogenetic analysis of the variable region from the F gene revealed 9 genotypes among 129 group A RSVs and 4 genotypes among 50 group B RSVs. In each of the epidemics, the dominant genotypes were replaced with new genotypes in consecutive epidemics. In each of the epidemics of group B RSVs, the predominant genotype alternated between genotypes. Most of the strains which clustered to a particular F genotype were assigned to particular G genotype(s). By determining the nearly entire sequences of the F genes, we revealed the percentage of the nucleotide differences which resulted in amino acid coding changes was determined to be much great in two distinct variable regions of the F gene. Our results indicated that the F gene of the RSVs may be continuously evolving under selective pressure in a distinct pattern, and that the genetic variability of the F protein is associated with that of the G protein. J. Med. Virol. 79: 820–828, 2007. © 2007 Wiley-Liss, Inc.</P>

Dopamine neurotransmission is involved in the attenuating effects of 5-HT₃ receptor antagonist MDL 72222 on acute methamphetamine-induced locomotor hyperactivity in mice

Yoo, Ji-Hoon,Nam, Yun-Sun,Lee, Seok-Yong,Jang, Choon-Gon Alan R. Liss, Inc 2008 Synapse Vol.62 No.1

<P>We have previously shown that 5-HT<SUB>3</SUB> receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. In the present study, we further examined whether the dopaminergic system is involved in the attenuating effects of MDL 72222, a 5-HT<SUB>3</SUB> receptor antagonist, on acute MAP-induced locomotor hyperactivity. For this, we examined alterations of dopamine (DA) in the form of D<SUB>1</SUB> receptor, D<SUB>2</SUB> receptor, and dopamine transporter (DAT) binding labeled with [<SUP>3</SUP>H]SCH23390 for D<SUB>1</SUB>, [<SUP>3</SUP>H]raclopride for D<SUB>2</SUB>, and [<SUP>3</SUP>H]mazindol for DAT binding in the mouse brains with acute MAP exposure or pretreatment of MDL 72222 with MAP. No significant differences were detected in the D<SUB>1</SUB> receptor, D<SUB>2</SUB> receptor, or DAT binding between any of the groups studied. Interestingly, we found increased DA levels in the striatum following acute MAP exposure; these increased levels were reversed by pretreatment with MDL 72222, but did not affect 5-HT levels in the dorsal raphe. Overall, our results suggest that dopamine neurotransmission plays an important role in the attenuating effects of 5-HT<SUB>3</SUB> receptor antagonist MDL 72222 on acute MAP-induced locomotor hyperactivity in mice. Synapse 62:8–13, 2008. © 2007 Wiley-Liss, Inc.</P>

In-vivo measurements of the dielectric properties of breast carcinoma xenografted on nude mice

Cho, Jeiwon,Yoon, Jeonghoon,Cho, Sungjoon,Kwon, Kihyun,Lim, Sungkyu,Kim, Daeduk,Lee, Eun Sook,Kim, Chul Hwan,Choi, Jin Wook,Cheon, Changyul,Kwon, Youngwoo Alan R. Liss, Inc 2006 International journal of cancer Vol.119 No.3

<P>A developing method of cancer detection is to use electromagnetic waves to compare the dielectric properties of normal and cancerous tissue. Because most of the previous studies consisted of dielectric measurements taken ex-vivo, this study investigated the advantages of in-vivo measurements, obtained using the newly developed insertion-type planar probe, through the measurements of cancer (MDA MB 231), which was cultivated and implanted into the mammary fat pad of nude mice. Reflection coefficients were obtained in the broadband frequency range from 0.5 to 30 GHz, from which broadband complex permittivity data was extracted. Complex permittivity, in addition to other parameters such as conductivity and characteristic frequency, were used to make comparisons between cancerous tissue, normal muscle tissue and fat tissue, as well as comparisons between in-vivo and ex-vivo measurements. This study investigated the suitability of in-vivo cancer detection using microwaves with the newly developed insertion-type planar probe. Results showed that both sensitivity and specificity of the current method was 97%. In addition, predictive values were 99% for the positive and 94% for the negative, thus greatly enhancing the practicality of this method. In conclusion, it was demonstrated that in-vivo measurements are highly beneficial in studying the potential of microwaves as a diagnostic tool of breast cancer, especially in combination with the newly developed insertion-type planar probe. © 2006 Wiley-Liss, Inc.</P>

Inactivation of LLC1 gene in nonsmall cell lung cancer

Hong, Kyeong-Man,Yang, Sei-Hoon,Chowdhuri, Sinchita Roy,Player, Audrey,Hames, Megan,Fukuoka, Junya,Meerzaman, Daoud,Dracheva, Tatiana,Sun, Zhifu,Yang, Ping,Jen, Jin Alan R. Liss, Inc 2007 International journal of cancer Vol.120 No.11

<P>Serial analysis of gene expression studies led us to identify a previously unknown gene, c20orf85, that is present in the normal lung epithelium but absent or downregulated in most primary nonsmall cell lung cancers and lung cancer cell lines. We named this gene LLC1 for Low in Lung Cancer 1. LLC1 is located on chromosome 20q13.3 and has a 70% GC content in the promoter region. It has 4 exons and encodes a protein containing 137 amino acids. By in situ hybridization, we observed that LLC1 message is localized in normal lung bronchial epithelial cells but absent in 13 of 14 lung adenocarcinoma and 9 out of 10 lung squamous carcinoma samples. Methylation at CpG sites of the LLC1 promoter was frequently observed in lung cancer cell lines and in a fraction of primary lung cancer tissues. Treatment with 5-aza deoxycytidine resulted in a reduced methylation of the LLC1 promoter concomitant with the increase of LLC1 expression. These results suggest that inactivation of LLC1 by means of promoter methylation is a frequent event in nonsmall cell lung cancer and may play a role in lung tumorigenesis. © 2007 Wiley-Liss, Inc.</P>