IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor

Kim, Hye-Youn,Ha Thi, Huyen Trang,Hong, Suntaek Elsevier 2018 Cancer letters Vol.415 No.-

<P><B>Abstract</B></P> <P>Triple-negative breast cancer (TNBC) is one of the most aggressive malignancies and is associated with high mortality rates due to the lack of effective therapeutic targets. In this study, we demonstrated that insulin-like growth factor-II mRNA-binding protein 2 and 3 (IMP2 and IMP3) are specifically overexpressed in TNBC and cooperate to promote cell migration and invasion. Downregulation of both IMP2 and IMP3 in TNBC cells was found to produce a synergistic effect in suppressing cell invasion and invadopodia formation, whereas overexpression of IMP2 and IMP3 in luminal subtype cells enhanced epithelial-mesenchymal transition and metastasis. We also showed that IMP2 and IMP3 are direct targets of microRNA-200a (miR-200a), which is downregulated in TNBC. Conversely, IMP2 and IMP3 suppressed the transcription of miR-200a by destabilizing progesterone receptor (PR) mRNA through recruitment of the CCR4-NOT transcription complex subunit 1 (CNOT1) complex. Together, our findings suggest that IMP2 and IMP3 partially determine the characteristic phenotype and synergistically promote the metastasis of TNBC by downregulating PR. The identified IMP2/3-miR-200a-PR axis represents a novel double-negative feedback loop and serves as a new potential therapeutic target for the treatment of TNBC.</P> <P><B>Highlights</B></P> <P> <UL> <LI> IMP2 and IMP3 synergistically promote the migration and metastasis of TNBC. </LI> <LI> miR-200a directly regulates the expression of IMP2 and IMP3. </LI> <LI> IMP2 and IMP3 negatively regulate the expression of miR-200a at transcriptional level. </LI> <LI> IMP2 and IMP3 reduce the stability of PR mRNA by recruiting the CNOT1 complex. </LI> <LI> IMP2/3-miR-200a-PR axis can be a novel therapeutic target against metastasis of TNBC. </LI> </UL> </P>

IMP3, a Promising Prognostic Marker in Clear Cell Renal Cell Carcinoma

박지영,최미선,강유나,이상숙 대한병리학회 2014 Journal of Pathology and Translational Medicine Vol.48 No.2

Background: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) has been reported as a prognostic biomarker in various cancers. To validate IMP3 as a prognostic biomarker in renal cell carcinoma (RCC), we investigated the expression of IMP3, p53, and Ki-67, and their associations with clinicopathologic outcomes. Methods: We studied 148 clear cell RCCs (CCRCCs) from patients who underwent radical nephrectomy. The expression levels of IMP3, p53, and Ki-67 were assessed by immunohistochemical staining and the clinical and pathologic parameters were retrospectively reviewed. Results: Twenty-nine percent of CCRCCs expressed IMP3. Forty-one percent of IMP3-immunopositive tumors developed metastases, while only 11.4% of IMP3-negative tumors developed metastases (p<.001). A Kaplan-Meier curve showed that patients with IMP3-immunopositive tumors had lower metastasis-free survival and cancer-specific survival than did those with IMP3-immunonegative tumors (p<.001 and p<.001, respectively). Expression of high Ki-67 proliferation index was also associated with a higher metastatic rate. In the multivariate Cox regression analysis, pT stage and IMP3-positivity were independently associated with diseasespecific survival. Conclusions: IMP3 is an independent prognostic biomarker for patients with CCRCC to predict metastasis and poor outcome.

참다랑어(Thunnus orientalis) 치어에 있어서 전갱이(Trachrus japonicus) 근육 엑기스 중의 섭이촉진물질 검색

지승철,타카오카오사무,세오카마나부,코오바라준,호소카와히테츠요,시메노사다오,정관식,이시우,타키이켄지,Ji, Seung-Cheol,Takaoka, Osamu,Seoka, Manabu,Kohbara, Jun,Hosokawa, Hidetuyo,Shimeno, Sadao,Jeong, Gwan-Sik,Lee, Si-Woo,Takii, Kenji 한국양식학회 2007 韓國養殖學會誌 Vol.20 No.1

참다랑어(Thunnus orientalis)의 배합사료 개발을 위해 전갱이(Trachrus japonicus) 근육 합성 엑기스(SE)를 사용하여 omission test를 통해 섭이촉진물질을 검색하였다. 인공종묘 생산된 참다랑어 치어(평균체중 $9.0{\pm}0.91\;g$: 실험 1, 2, 3; $1.6{\pm}0.23\;g$: 실험 4)를 사용하여 전갱이 근육 100 g 상당 함량의 각각의 섭이촉진 물질을 카제인 기초 사료에 첨가하여 총 4회의 사육실험을 실시하였다. 실험 1에서 인공합성엑기스(SE)와 SE로부터 아미노산 관련 화합물(SE-A), 핵산관련물질(SE-N) 그리고 유기염기화합물(SE-O)을 각각 제외한 시험액을 제조하여 천연 전갱이 근육 엑기스(NE)와 비교한 결과, SE-A와 SE-N구는 SE보다 낮은 섭이활성을 보였으나, SE-O구는 SE와 유사한 섭이활성을 보였다. 실험 2에서는 IMP가 섭이 촉진에 가장 많은 영향을 미치는 것이 인정되었으며, 실험 3에서는 L-alanine, L-glutamic acid, L-histidine, L-lysine, taurine 그리고 IMP의 혼합물이 SE와 섭이활성의 차이를 보이지 않았다. 실험 4에서는 L-histidine, L-glutamine 그리고 IMP 혼합물이 가장 높은 섭이활성을 보였으며, 그 다음으로는 SE, L-lysine, L-alanine and IMP 혼합물, L-histidine, L-glutamic acid, L-lysine and L-alanine과 IMP의 혼합물이 높은 섭이활성을 보였다. 본 연구결과 참다랑어 치어의 유효 섭이촉진물질은 L-histidine, L-glutamic acid 그리고 IMP로 판단되었다. For establishing a basal diet for the Pacific bluefin tuna Thunnus orientalis (PBT), feeding stimulants were initially identified by omission test using the synthetic extract of horse mackerel, Trachurus japonicus. Four feeding trials were conducted using juvenile PBT weighing $9.0{\pm}0.91\;g$ (trial 1, 2 and 3) and $1.6{\pm}0.23\;g$ (trial 4), which were originated from an artificial seedling production. The fish fed the casein diet with each test solution were added at the ratio of 100 g casein diet to 100 g jack mackerel muscle. A complete synthetic extract of jack mackerel containing all 3 fractions, amino acid, nucleotide and organic nitrogenous base, exhibited a comparable feeding stimulant activity compared to that of natural extract. The omission of nucleotide or amino acid fraction showed lower feeding activity, but the omission of other nitrogenous fraction maintained a similar feeding stimulant activity compared to that of the synthetic extract (trial 1). Inosine-5' monophosphate $Na_2$ (IMP) was identified as a major constituent for maintaining feeding activity. The mixture of L-alanine, L-glutamic acid, L-histidine, L-lysine, taurine and IMP induced a similar feeding activity compared to that of the synthetic extract (trial 2 and 3). In trial 4, the highest feeding activity was finally obtained in the mixture of L-histidine, L-glutamine and IMP, followed by the synthetic extract, the mixture of L-lysine, L-alanine and IMP, IMP and the mixture of L-histidine, L-glutamic acid, L-lysine and L-alanine. These results revealed that the mixture of L-histidine, L-glutamic acid and IMP for the proper feeding stimulant of PBT in this study.

FCP 13 : Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3) expression as a novel prognostic biomarker in malignant melanoma

( Seung Min Ha ),( Seung Hwan Choi ),( Dong Yeob Ko ),( Ki Ho Kim ),( Ki Hoon Song ) 대한피부과학회 2013 대한피부과학회 학술발표대회집 Vol.65 No.2

Background: Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3), a member of the insulin-like growth factor mRNA-binding protein family, is expressed in several human malignancies including malignant melanoma(MM). Recent studies reported that IMP-3 overexpression correlates with poor prognosis in various malignancies such as pancreatic cancer, lung cancer, thyroid cancer, breast cancer and urinary bladder carcinoma. However, the correlation between IMP-3 expression and prognosis in MM has not yet been investigated. Objectives: We sought to investigate the clinical relevance and long-term survival analysis according to IMP-3 expression in MM. Methods: IMP3 expression in total of 98 samples among 72 patients diagnosed as MM was analyzed by immunohistochemistry and Western blotting. Expression level was measured by clinicopathologic features and clinical follow-up data of using logistic regression model and Kaplan-Meier methods. Results: IMP3 expression was significantly higher in metastatic cases than in non-metastatic MM. Increased IMP3 levels significantly correlated with higher T classification (p<0.001), lymph node metastasis (p<0.003) and distant metastasis (p<0.037). Multivariate survival analysis showed that IMP3 expression is an independent prognostic marker for overall survival (HR 4.68; 95% CI 2.07-10.61; P <0.001) Conclusion: Our data suggests that IMP-3 expression can be an independent prognostic factor in MM.

세포병리검사에서 쓸개관암종의 IMP3 발현과 진단적 가치

이정희,양정욱,이종실,김동출,송대현,고경혁 대한병리학회 2010 Journal of Pathology and Translational Medicine Vol.44 No.6

Background : Pathologists occasionally have difficulty in distinguishing cholangiocarcinoma from benign reactive cells on the biliary cytology. We estimated the diagnostic value of insulinlike growth factor II mRNA binding protein 3 (IMP3) on biliary cytology specimens. Methods : We selected 40 patients who had undergone a biliary cytology examination and whose diagnoses were confirmed by biopsy. The IMP3 expression was evaluated by immunohistochemical staining in both the tissue and the cytology specimens. Their histologic diagnoses were cholangiocarcinoma (n = 34), high grade dysplasia (n = 2), low grade dysplasia (n = 1) and non-biliary tumor or no tumor (n = 3). Results : On the histology, all the cases of cholangiocarcinoma or high grade dysplasia were positive for IMP3 (36/36). The low grade dysplasia or the normal bile ducts in the other 4 cases were negative for IMP3 (0/4). Of the 36 cases diagnosed as cholangiocarcinoma or high grade dysplasia histologically, 29 cases were positive for IMP3 on the cytology (29/36; sensitivity, 80.6%). Of the 4 cases without cholangiocarcinoma or high grade dysplasia, 1 case was weakly positive for IMP3 on the cytology. The histologic diagnosis of this case was hepatocellular carcinoma. Except for this hepatocellular carcinoma case, the specificity of IMP3 on the cytology was 100%. Conclusions : IMP3 is a useful diagnostic marker for cholangiocarcinoma on cytology.

Insulin‐like growth factor II mRNA‐binding protein 3: A novel prognostic biomarker for oral squamous cell carcinoma

Li, Shengjin,Cha, JeongDan,Kim, Jin,Kim, Ki‐,Yeol,Kim, Hyung‐,Jun,Nam, Woong,Cha, In‐,Ho Wiley Subscription Services, Inc., A Wiley Company 2011 Head & neck Vol.33 No.3

<P><B>Abstract</B></P><P><B>Background.</B></P><P>Oral squamous cell carcinoma (OSCC) is caused by multiple factors, including carcinogen exposure. Insulin‐like growth factor II mRNA‐binding protein 3 (IMP3) is highly expressed in various cancer cells but is rarely expressed in normal cells. We investigated whether IMP3 can be used as a prognostic biomarker for OSCC.</P><P><B>Methods.</B></P><P>We performed immunohistochemistry and Western blotting to examine IMP3 expression in human tissues. We also investigated correlations among IMP3 expression, clinicopathologic factors, and overall survival.</P><P><B>Results.</B></P><P>IMP3 was overexpressed in OSCC cells. The expression was correlated with high histologic grade, lymph node metastasis, and advanced tumor and clinical stages. Univariate analysis indicated that advanced clinical stages, lymph node metastases, and IMP3 expression were predictive factors for OSCC. Multivariate analysis showed that IMP3 expression was an independent prognostic indicator for OSCC.</P><P><B>Conclusions.</B></P><P>IMP3 expression was related to various clinicopathologic factors. IMP3 expression was an independent prognostic factor in patients with OSCC. © 2010 Wiley Periodicals, Inc. Head Neck, 2010</P>

Insulin-like Growth Factor II mRNA-Binding Protein 3 Expression in Benign and Premalignant Lesions and Carcinomas of the Stomach

송대현,양정욱,김동출,이종실,이정희,정상호,고경혁 대한병리학회 2011 Journal of Pathology and Translational Medicine Vol.45 No.4

Background: Recent studies have demonstrated that insulin-like growth factor II mRNA-binding protein 3 (IMP3) is expressed in malignant tumors of various organs but not in normal tissue. We investigated IMP3 expression in various benign lesions, premalignant lesions and carcinomas of the stomach. Methods: IMP3 immunohistochemical staining was performed on 24 benign gastric lesions, 24 gastric adenomas, and 322 gastric carcinomas. Results: IMP3 was not expressed in benign gastric lesions including adenomas with low-grade dysplasia, but was expressed in 17% of adenomas with high-grade dysplasia, and in 44% of carcinomas. As the carcinomas were in the advanced stage, they expressed IMP3 more frequently and strongly. Patients with IMP3-positive tumors had poorer survival than those with negative tumors. Conclusions: IMP3 expression in gastric carcinoma may be related to tumor invasion and metastasis, and is an independent risk factor for poor prognosis.

OXA-23 혹은 IMP-1 β-Lactamase 생성 Acinetobacter baumannii에 의한 감염의 분자 역학

박광옥,손한철,배일권,정석훈 대한임상미생물학회 2005 Annals of clinical microbiology Vol.8 No.2

Background: The purposes of this study were to investigate the prevalence of imipenem-resistant clinical Acinetobacter baumanniiisolates and to determine the mechanism of the resistance. Methods: During the period of June to September 2004, susceptibility to imipenem of A. baumannii isolates from a hospital in Busan, Korea were investigated. The isolates were screened for the production of carbapenemase and metallo-β-lactamase by Modified-Hodge and EDTA-disk synergy tests, respectively; minimum inhibitory concentrations (MICs) were determined by agar dilution method. Genes coding for GES, IMP, VIM, SMP-1, GIM-1 and OXA type β-lactamases were searched by PCR amplification, and the PCR products were subjected to direct sequencing. Isoelectric points of β-lactamases were estimated by isoelectric focusing and the epidemiological relationships of isolates were investigated by enterobacterial repetitive intergenic consensus (ERIC) PCR. Results: Fifty eight strains of A. baumannii were isolated from clinical specimens during the surveillance period, and 14 isolates (24.1%) were resistant to imipenem. Of the 14 isolates, 9 were tested positive in Modified-Hodge test and 2 were also positive in EDTA-disk synergy test. Genes encoding OXA-23 and IMP-1 were detected in 7 and 2 isolates, respectively. In IEF studies, OXA-23 and IMP-1 enzymes had corresponding pIs at 6.7 and 9.0, respectively. Seven OXA-23-producing and 2 IMP-1-producing isolates showed the same ERIC PCR patterns. Conclusion: It is concluded that 7 and 2 A. baumannii isolates from the patients in a hospital in Busan acquired resistance to imipenem by producing OXA-23 and IMP-1 β-lactamases, respectively. The isolates producing these β-lactamases might be originated from a common source.

대전지역의 입원환자에서 분리된 Carbapenem 내성 Pseudomonas aeruginosa의 분자역학조사(2008년에서 2014년까지)

조혜현 대한임상검사과학회 2018 대한임상검사과학회지(KJCLS) Vol.50 No.4

The emergence of carbapenem resistance among Pseudomonas aeruginosa has become an increasing problem worldwide. In particular, metallo-β-lactamases (MBLs) are responsible for the high-level resistance to carbapenem. Sequence type 235 (ST235) has been found internationally in a multidrug-resistant clone and is involved in the dissemination of genes encoding IMP-6 and VIM-2. This study examined the prevalence of MBLs and the epidemiological relationship in carbapenem-resistant P. aeruginosa (CRPA) isolates obtained from a tertiary hospital in Daejeon, Korea, between March 2008 and June 2014. The antimicrobial susceptibilities were determined using the disk-diffusion method and PCR and DNA sequencing were used to identify the MBL genes. In addition, an epidemiological relationship was investigated by multilocus sequence typing (MLST). Among the 110 CRPA isolates, 32 isolates (29.1%) were MBL-producers; the major type was IMP-6 (29 isolates, 90.6%). VIM-2 was identified in 3 isolates (9.4%) of ST357. IMP-6-producing isolates were multidrug-resistant (MDR) and belonged to ST235. ST235 (55 isolates, 50.0%) was the clone most frequently detected and has gradually emerged during a seven-year period. To prevent the spread of MDR ST235 P. aeruginosa isolates, the current widespread use of carbapenems needs to be curtailed, and novel continuous monitoring strategies should be developed as soon as possible. 최근 P. aeruginosa의 carbapenem에 대한 내성은 전 세계적으로 증가하고 있는 실정이다. 특히 metallo--lactamases (MBLs)는 carbapenem의 고도 내성에 관여하고 있는 것으로보고되고 있다. 한편, Sequence type 235 (ST235)는 다제내성클론으로써 국제적으로 보고되고 있으며, IMP-6와 VIM-2 유전자의 확산에도 관여하는 것으로 알려져 있다. 본 연구에서는2008년 3월부터 2014년 6월까지, 대전지역의 3차 병원에서 분리된 carbapenem 내성 P. aeruginosa에서 MBL 유전자를 분석하고 이에 대한 역학관계를 조사하고자 하였다. 항균제 감수성 양상은 디스크 확산법으로 확인하였고, MBL 유전자의 분석을 위해 PCR과 염기서열분석을 수행하였다. 더불어, 역학 관계를 조사하기 위해 multilocus sequence typing (MLST)를 실시하였다. 110 균주의 carbapenem 내성 P. aeruginosa 중, 32균주(29.1%)가 MBL를 생성하였고, IMP-6 (29균주, 90.6%)가 주요하게 확인되었다. VIM-2는 3균주(9.4%)에서 확인되었으며, 모두 ST357로 확인되었다. IMP-6를 생성하는 P. aeruginosa 는 모두 다제내성을 보였고, ST235로 확인되었다. ST235 (55 균주, 50.0%)는 가장 높은 비율로 확인된 클론이며 7년 동안 지속적으로 확인되었다. 이러한 다제내성 ST235의 확산을 방지하기 위해, carbapenem의 과도한 사용을 제한하고, 지속적으로 모니터링하는 전략이 개발되어야 할 것으로 사료된다.

Lin28 and Imp are Required for Stability of Bowl Transcripts in Hub Cells of the Drosophila Testis

Van To,Hyun Ju Kim,장위정,Perinthottathil Sreejith,김창수 한국발생생물학회 2021 발생과 생식 Vol.25 No.4

Hub cells comprise a niche for germline stem cells and cyst stem cells in the Drosophila testis. Hub cells arise from common somatic gonadal precursors in embryos, but the mechanism of their specification is still poorly understood. Here we find that RNA binding proteins Lin28 and Imp mediate transcript stability of Bowl, a known hub specification factor; Bowl transcripts were reduced in the testis of Lin28 and Imp mutants, and also when RNAmediated interference against Lin28 or Imp was expressed in hub cells. In tissue culture Luciferase assays involving the Bowl 3’UTR, stability of Luc reporter transcripts depended on the Bowl 3’UTR and required Lin28 and Imp. Our findings suggest that proper Bowl function during hub cell specification requires Lin28 and Imp in the testis hub cells.