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Richard I Gregory - One of the best experts on this subject based on the ideXlab platform.
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A Single Let-7 MicroRNA Bypasses LIN28-Mediated Repression
Cell reports, 2015Co-Authors: Robinson Triboulet, Mehdi Pirouz, Richard I GregoryAbstract:Let-7 microRNAs (miRNAs) are critical regulators of animal development, stem cell differentiation, glucose metabolism, and tumorigenesis. Mammalian genomes contain 12 let-7 isoforms that suppress expression of a common set of target mRNAs. LIN28 proteins selectively block let-7 biogenesis in undifferentiated cells and in cancer. The current model for coordinate let-7 repression involves the LIN28 cold-shock domain (CSD) binding the terminal loop and the two CCHC-type zinc fingers recognizing a GGAG sequence motif in precursor let-7 (pre-let-7) RNAs. Here, we perform a systematic analysis of all let-7 miRNAs and find that a single let-7 family member, human let-7a-3 (and its murine ortholog let-7c-2), escapes LIN28-mediated regulation. Mechanistically, we find that the pre-let-7c-2 loop precludes LIN28A binding and regulation. These findings refine the current model of let-7 regulation by LIN28 proteins and have important implications for understanding the LIN28/let-7 axis in development and disease.
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LIN28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7).
RNA (New York N.Y.), 2012Co-Authors: James E Thornton, Elena Piskounova, Hao-ming Chang, Richard I GregoryAbstract:The pluripotency factor LIN28 recruits a 39 terminal uridylyl transferase (TUTase) to selectively block let-7 microRNA biogenesis in undifferentiated cells. Zcchc11 (TUTase4/TUT4) was previously identified as an enzyme responsible for LIN28-mediated prelet-7 uridylation and control of let-7 expression. Here we investigate the protein and RNA determinants for this interaction. Biochemical dissection and reconstitution assays reveal the TUTase domains necessary and sufficient for LIN28-enhanced prelet-7 uridylation. A single C2H2-type zinc finger domain of Zcchc11 was found to be responsible for the functional interaction with LIN28. We identify Zcchc6 (TUTase7) as an alternative TUTase that functions with LIN28 in vitro, and accordingly, we find Zcchc11 and Zcchc6 redundantly control let-7 biogenesis in embryonic stem cells. Our study indicates that LIN28 uses two different TUTases to control let-7 expression and has important implications for stem cell biology as well as cancer.
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LIN28a and LIN28b inhibit let 7 microrna biogenesis by distinct mechanisms
Cell, 2011Co-Authors: Elena Piskounova, John P Hagan, Christos Polytarchou, James E Thornton, Robert J Lapierre, Charalabos Pothoulakis, Dimitrios Iliopoulos, Richard I GregoryAbstract:Summary LIN28A and LIN28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. LIN28A recruits a TUTase (Zcchc11/TUT4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike LIN28A, LIN28B represses let-7 processing through a Zcchc11-independent mechanism. LIN28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts are restricted to LIN28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either LIN28A or LIN28B. LIN28A is expressed in HER2-overexpressing breast tumors, whereas LIN28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which LIN28A and LIN28B function and have implications for the development of new strategies for cancer therapy.
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LIN28 recruits the tutase zcchc11 to inhibit let 7 maturation in mouse embryonic stem cells
Nature Structural & Molecular Biology, 2009Co-Authors: John P Hagan, Elena Piskounova, Richard I GregoryAbstract:LIN28 and LIN28B, two developmentally regulated RNA-binding proteins and likely proto-oncogenes, selectively inhibit the maturation of let-7 family microRNAs (miRNAs) in embryonic stem cells and certain cancer cell lines. Moreover, let-7 precursors (pre-let-7) were previously found to be terminally uridylated in a LIN28-dependent fashion. Here we identify Zcchc11 (zinc finger, CCHC domain containing 11) as the 3' terminal uridylyl transferase (TUTase) responsible for LIN28-mediated pre-let-7 uridylation and subsequent blockade of let-7 processing in mouse embryonic stem cells. We demonstrate that Zcchc11 activity is UTP-dependent, selective for let-7 and recruited by LIN28. Furthermore, knockdown of either Zcchc11 or LIN28, or overexpression of a catalytically inactive TUTase, relieves the selective inhibition of let-7 processing and leads to the accumulation of mature let-7 miRNAs and repression of let-7 target reporter genes. Our results establish a role for Zcchc11-catalyzed pre-let-7 uridylation in the control of miRNA biogenesis.
John P Hagan - One of the best experts on this subject based on the ideXlab platform.
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the LIN28 let 7 pathway in cancer
Frontiers in Genetics, 2017Co-Authors: Julien Balzeau, Miriam R Menezes, Siyu Cao, John P HaganAbstract:Among all tumor suppressor microRNAs, reduced let-7 expression occurs most frequently in cancer and typically correlates with poor prognosis. Activation of either LIN28A or LIN28B, two highly related RNA binding proteins (RBPs) and proto-oncogenes, is responsible for the global post-transcriptional downregulation of the let-7 microRNA family observed in many cancers. Specifically, LIN28A binds the terminal loop of precursor let-7 and recruits the Terminal Uridylyl Transferase (TUTase) ZCCHC11 that polyuridylates pre-let-7, thereby blocking microRNA biogenesis and tumor suppressor function. For LIN28B, the precise mechanism responsible for let-7 inhibition remains controversial. Functionally, the decrease in let-7 microRNAs leads to overexpression of their oncogenic targets such as MYC, RAS, HMGA2, BLIMP1, among others. Furthermore, mouse models demonstrate that ectopic LIN28 expression is sufficient to drive and/or accelerate tumorigenesis via a let-7 dependent mechanism. In this review, the LIN28/let-7 pathway is discussed, emphasizing its role in tumorigenesis, cancer stem cell biology, metabolomics, metastasis, and resistance to ionizing radiation and several chemotherapies. Also, emerging evidence will be presented suggesting that molecular targeting of this pathway may provide therapeutic benefit in cancer.
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fetal deficiency of LIN28 programs life long aberrations in growth and glucose metabolism
Stem Cells, 2013Co-Authors: Gen Shinoda, Hao Zhu, Samar P. Shah, Ng Shyhchang, Yvanka T De Soysa, Marc T Seligson, Nora Abosido, Akiko Yabuuchi, John P HaganAbstract:LIN28A/B are RNA binding proteins implicated by genetic association studies in human growth and glucose metabolism. Mice with ectopic over-expression of LIN28a have shown related phenotypes. Here, we describe the first comprehensive analysis of the physiologic consequences of LIN28a and LIN28b deficiency in knockout (KO) mice. LIN28a/b-deficiency led to dwarfism starting at different ages, and compound gene deletions showed a cumulative dosage effect on organismal growth. Conditional gene deletion at specific developmental stages revealed that fetal but neither neonatal nor adult deficiency resulted in growth defects and aberrations in glucose metabolism. Tissue-specific KO mice implicated skeletal muscle-deficiency in the abnormal programming of adult growth and metabolism. The effects of LIN28b KO could be rescued by Tsc1 haplo-insufficiency in skeletal muscles. Our data implicate fetal expression of LIN28a/b in the regulation of life-long effects on metabolism and growth, and demonstrate that fetal LIN28b acts at least in part via mTORC1 signaling.
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LIN28a and LIN28b inhibit let 7 microrna biogenesis by distinct mechanisms
Cell, 2011Co-Authors: Elena Piskounova, John P Hagan, Christos Polytarchou, James E Thornton, Robert J Lapierre, Charalabos Pothoulakis, Dimitrios Iliopoulos, Richard I GregoryAbstract:Summary LIN28A and LIN28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. LIN28A recruits a TUTase (Zcchc11/TUT4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike LIN28A, LIN28B represses let-7 processing through a Zcchc11-independent mechanism. LIN28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts are restricted to LIN28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either LIN28A or LIN28B. LIN28A is expressed in HER2-overexpressing breast tumors, whereas LIN28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which LIN28A and LIN28B function and have implications for the development of new strategies for cancer therapy.
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LIN28 recruits the tutase zcchc11 to inhibit let 7 maturation in mouse embryonic stem cells
Nature Structural & Molecular Biology, 2009Co-Authors: John P Hagan, Elena Piskounova, Richard I GregoryAbstract:LIN28 and LIN28B, two developmentally regulated RNA-binding proteins and likely proto-oncogenes, selectively inhibit the maturation of let-7 family microRNAs (miRNAs) in embryonic stem cells and certain cancer cell lines. Moreover, let-7 precursors (pre-let-7) were previously found to be terminally uridylated in a LIN28-dependent fashion. Here we identify Zcchc11 (zinc finger, CCHC domain containing 11) as the 3' terminal uridylyl transferase (TUTase) responsible for LIN28-mediated pre-let-7 uridylation and subsequent blockade of let-7 processing in mouse embryonic stem cells. We demonstrate that Zcchc11 activity is UTP-dependent, selective for let-7 and recruited by LIN28. Furthermore, knockdown of either Zcchc11 or LIN28, or overexpression of a catalytically inactive TUTase, relieves the selective inhibition of let-7 processing and leads to the accumulation of mature let-7 miRNAs and repression of let-7 target reporter genes. Our results establish a role for Zcchc11-catalyzed pre-let-7 uridylation in the control of miRNA biogenesis.
Yingqun Huang - One of the best experts on this subject based on the ideXlab platform.
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LIN28 regulates HER2 and promotes malignancy through multiple mechanisms
Cell cycle (Georgetown Tex.), 2012Co-Authors: Chen Feng, Veronique Neumeister, Jennifer Bordeaux, Nita J. Maihle, David L. Rimm, Yingqun HuangAbstract:The RNA binding protein LIN28 and its paralog LIN28B are associated with advanced human malignancies. Blocking the biogenesis of let-7 miRNA, a tumor suppressor, by LIN28/LIN28B has been thought to underlie their roles in cancer. Here we report that the mRNA for the human epidermal growth factor receptor 2 (HER2), a HER-family receptor tyrosine kinase known to play a critical role in cell proliferation and survival and also a major therapeutic target in breast cancer, is among several targets of LIN28 regulation. We show that LIN28 stimulates HER2 expression at the posttranscriptional level, and that enforced LIN28 expression promotes cancer cell growth via multiple mechanisms. Consistent with its pleiotropic role in regulating gene expression, LIN28 overexpression in primary breast tumors is a powerful predictor of poor prognosis, representing the first report on the impact of LIN28 expression on clinical outcome in human cancer. While revealing another layer of regulation of HER2 expression in addition ...
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Determinants of mRNA recognition and translation regulation by LIN28
Nucleic acids research, 2011Co-Authors: Xinxiang Lei, Chong Qiao, Martin A. Newman, Scott M. Hammond, Yingqun HuangAbstract:LIN28 is critical for stem cell maintenance and is also associated with advanced human malignancies. Our recent genome-wide studies mark LIN28 as a master post-transcriptional regulator of a subset of messenger RNAs important for cell growth and metabolism. However, the molecular basis underpinning the selective mRNA target regulation is unclear. Here, we provide evidence that LIN28 recognizes a unique motif in multiple target mRNAs, characterized by a small but critical ‘A’ bulge flanked by two G:C base pairs embedded in a complex secondary structure. This motif mediates LIN28-dependent stimulation of translation. As LIN28 is also known to inhibit the biogenesis of a cohort of miRNAs including let-7, we propose that LIN28 binding to different RNA types (precursor miRNAs versus mRNAs) may facilitate recruitment of different co-factors, leading to distinct regulatory outcomes. Our findings uncover a putative yet unexpected motif that may constitute a mechanistic base for the multitude of functions regulated by LIN28 in both stem cells and cancer cells.
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genome wide studies reveal that LIN28 enhances the translation of genes important for growth and survival of human embryonic stem cells
Stem Cells, 2011Co-Authors: Shuping Peng, Xinxiang Lei, Lingling Chen, Li Yang, Haifan Lin, Gordon G Carmichael, Yingqun HuangAbstract:LIN28 inhibits the expression of let-7 microRNAs but also exhibits let-7-independent functions. Using immunoprecipitation and deep sequencing, we show here that LIN28 preferentially associates with a small subset of cellular mRNAs. Of particular interest are those for ribosomal proteins and metabolic enzymes, the expression levels of which are known to be coupled to cell growth and survival. Polysome profiling and reporter analyses suggest that LIN28 stimulates the translation of many or most of these targets. Moreover, LIN28-responsive elements were found within the coding regions of all target genes tested. Finally, a mutant LIN28 that still binds RNA but fails to interact with RNA helicase A (RHA), acts as a dominant-negative inhibitor of LIN28-dependent stimulation of translation. We suggest that LIN28, working in concert with RHA, enhances the translation of genes important for the growth and survival of human embryonic stem cells. STEM CELLS 2011;496–504
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Evidence that LIN28 stimulates translation by recruiting RNA helicase A to polysomes.
Nucleic acids research, 2011Co-Authors: Jianyu Jin, Chen Feng, Wei Jing, Xinxiang Lei, Shuping Peng, Kathleen Boris-lawrie, Yingqun HuangAbstract:The stem cell protein LIN28 functions to inhibit the biogenesis of a group of miRNAs but also stimulates the expression of a subset of mRNAs at the post-transcriptional level, the underlying mechanism of which is not yet understood. Here we report the characterization of the molecular interplay between LIN28 and RNA helicase A (RHA) known to play an important role in remodeling ribonucleoprotein particles during translation. We show that reducing LIN28 expression results in decreased RHA association with polysomes while increasing LIN28 expression leads to elevated RHA association. Further, the carboxyl terminus of LIN28 is necessary for interaction with both the amino and carboxyl termini of RHA. Importantly, a carboxyl terminal deletion mutant of LIN28 that retains RNA-binding activity fails to interact with RHA and exhibits dominant-negative effects on LIN28-dependent stimulation of translation. Taken together, these results lead us to suggest that LIN28 may stimulate translation by actively recruiting RHA to polysomes.
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LIN28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells
Nucleic acids research, 2009Co-Authors: Caihong Qiu, Shuping Peng, Jianquan Wang, Yingqun HuangAbstract:LIN28 acts as a repressor of microRNA processing and as a post-transcriptional regulatory factor for a subset of mRNAs. Here we report that in human embryonic stem cells LIN28 facilitates the expression of the pivotal pluripotency factor Oct4 at the post-transcriptional level. We provide evidence that LIN28 binds Oct4 mRNA directly through high affinity sites within its coding region and that an interaction between LIN28 and RNA helicase A (RHA) may play a part in the observed regulation. We further demonstrate that decreasing RHA levels impairs LIN28-dependent stimulation of translation in a reporter system. Taken together with previous studies showing that RHA is required for efficient translation of a specific class of mRNAs, these findings suggest a novel mechanism by which LIN28 may affect target mRNA expression and represent the first evidence of post-transcriptional regulation of Oct4 expression by LIN28 in human embryonic stem cells.
Elena Piskounova - One of the best experts on this subject based on the ideXlab platform.
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LIN28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7).
RNA (New York N.Y.), 2012Co-Authors: James E Thornton, Elena Piskounova, Hao-ming Chang, Richard I GregoryAbstract:The pluripotency factor LIN28 recruits a 39 terminal uridylyl transferase (TUTase) to selectively block let-7 microRNA biogenesis in undifferentiated cells. Zcchc11 (TUTase4/TUT4) was previously identified as an enzyme responsible for LIN28-mediated prelet-7 uridylation and control of let-7 expression. Here we investigate the protein and RNA determinants for this interaction. Biochemical dissection and reconstitution assays reveal the TUTase domains necessary and sufficient for LIN28-enhanced prelet-7 uridylation. A single C2H2-type zinc finger domain of Zcchc11 was found to be responsible for the functional interaction with LIN28. We identify Zcchc6 (TUTase7) as an alternative TUTase that functions with LIN28 in vitro, and accordingly, we find Zcchc11 and Zcchc6 redundantly control let-7 biogenesis in embryonic stem cells. Our study indicates that LIN28 uses two different TUTases to control let-7 expression and has important implications for stem cell biology as well as cancer.
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LIN28a and LIN28b inhibit let 7 microrna biogenesis by distinct mechanisms
Cell, 2011Co-Authors: Elena Piskounova, John P Hagan, Christos Polytarchou, James E Thornton, Robert J Lapierre, Charalabos Pothoulakis, Dimitrios Iliopoulos, Richard I GregoryAbstract:Summary LIN28A and LIN28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. LIN28A recruits a TUTase (Zcchc11/TUT4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike LIN28A, LIN28B represses let-7 processing through a Zcchc11-independent mechanism. LIN28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts are restricted to LIN28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either LIN28A or LIN28B. LIN28A is expressed in HER2-overexpressing breast tumors, whereas LIN28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which LIN28A and LIN28B function and have implications for the development of new strategies for cancer therapy.
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LIN28 recruits the tutase zcchc11 to inhibit let 7 maturation in mouse embryonic stem cells
Nature Structural & Molecular Biology, 2009Co-Authors: John P Hagan, Elena Piskounova, Richard I GregoryAbstract:LIN28 and LIN28B, two developmentally regulated RNA-binding proteins and likely proto-oncogenes, selectively inhibit the maturation of let-7 family microRNAs (miRNAs) in embryonic stem cells and certain cancer cell lines. Moreover, let-7 precursors (pre-let-7) were previously found to be terminally uridylated in a LIN28-dependent fashion. Here we identify Zcchc11 (zinc finger, CCHC domain containing 11) as the 3' terminal uridylyl transferase (TUTase) responsible for LIN28-mediated pre-let-7 uridylation and subsequent blockade of let-7 processing in mouse embryonic stem cells. We demonstrate that Zcchc11 activity is UTP-dependent, selective for let-7 and recruited by LIN28. Furthermore, knockdown of either Zcchc11 or LIN28, or overexpression of a catalytically inactive TUTase, relieves the selective inhibition of let-7 processing and leads to the accumulation of mature let-7 miRNAs and repression of let-7 target reporter genes. Our results establish a role for Zcchc11-catalyzed pre-let-7 uridylation in the control of miRNA biogenesis.
Dengfeng Cao - One of the best experts on this subject based on the ideXlab platform.
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RNA-binding protein LIN28 is a sensitive marker of ovarian primitive germ cell tumours
Histopathology, 2011Co-Authors: Debin Xue, Yan Peng, Robert W. Allan, Fenghua Wang, Dengfeng CaoAbstract:Xue D, Peng Y, Wang F, Allan R W & Cao D (2011) Histopathology59, 452–459 RNA-binding protein LIN28 is a sensitive marker of ovarian primitive germ cell tumours Aims: LIN28 is an RNA-binding protein that has been detected in testicular germ cell tumours (GCTs), but its status in ovarian GCTs is unknown. The aim was to determine the immunohistochemical profile of LIN28 in ovarian GCTs. Methods and results: Immunohistochemistry of LIN28 was performed in 110 primary and 11 metastatic ovarian GCTs. The percentage of tumour cells stained was scored as 0, 1+ (1–30% cells), 2+ (31–60%), 3+ (61–90%), and 4+ (>90%). To determine its specificity, we stained LIN28 in 119 non-GCTs, including 37 clear cell carcinomas. Strong 4+ LIN28 staining was seen in 4/4 (100%) gonadoblastomas, 7/7 (100%) embryonal carcinomas (ECs), and 41/41 (100%) yolk sac tumours (YSTs). Among 39 dysgerminomas, 4+ staining was seen in 37 and 3+ staining in two (strong in 37; mixed weak and strong in two). Twelve of 14 immature teratomas showed variable LIN28 staining (1+ to 4+) in the immature neuroepithelium (weak to strong staining), whereas mature teratomas, carcinoids, struma ovarii and strumal carcinoids were negative. Only 5/117 non-GCTs (1/37 clear cell carcinomas) showed weak to moderate 1–2+ staining. Conclusions: LIN28 is a sensitive marker for gonadoblastomas, dysgerminomas, ECs, and YSTs. LIN28 can be used to distinguish them from non-GCTs.
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RNA-binding protein LIN28 is a marker for testicular germ cell tumors.
Human pathology, 2011Co-Authors: Dengfeng Cao, Robert W. Allan, Liang Cheng, Yan Peng, Charles C. Guo, Neha Dahiya, Shirin AkhiAbstract:LIN28 is an RNA-binding protein involved in maintaining the pluripotency of embryonic stem cells. Using formalin-fixed, paraffin-embedded tissue blocks, we performed immunohistochemical staining of LIN28 in 103 primary and 81 metastatic testicular germ cell tumors (54 intratubular germ cell neoplasias, unclassified type; 49 primary and 20 metastatic classic seminomas; 35 primary and 24 metastatic embryonal carcinomas; 35 primary and 15 metastatic yolk sac tumors; 23 primary and 12 metastatic teratomas; 6 primary and 10 metastatic choriocarcinomas; and 5 spermatocytic seminomas). The percentage of tumor cell stained was scored as 0 (0%), 1+ (≤30%), 2+ (31%-60%), 3+ (61%-90%), and 4+ (>90%). We stained LIN28 in 327 non-germ cell tumors to determine its specificity. We also compared LIN28 with SALL4 (Sal-like 4) and OCT4 (octamer-binding transcription factor 4) in all germ cell tumors. The staining was cytoplasmic for LIN28 and nuclear for SALL4 and OCT4. Strong 4+ LIN28 staining was seen in all 54 intratubular germ cell neoplasias, 59 embryonal carcinomas, and 50 yolk sac tumors. Positive LIN28 staining was seen in all 69 classic seminomas (1+ in 3, 3+ in 3, and 4+ in 63) (63, strong). Variable staining of LIN28 was seen in 10 of 35 teratomas (1+ to 3+, weak to strong intensity), 12 of 16 choriocarcinomas (1+ to 4+, weak to strong intensity), and 1 of 5 spermatocytic seminomas (2+, weak). Only 10 of 327 non-germ cell tumors showed 1+ weak LIN28 staining. Therefore, LIN28 is a highly sensitive marker for testicular intratubular germ cell neoplasias, classic seminomas, embryonal carcinomas, and yolk sac tumors with relatively high specificity. LIN28 can be used as a diagnostic marker for these tumors and has demonstrated a similar level of diagnostic utility as SALL4 (except for a few classic seminomas), although it does not show an advantage over SALL4. The major advantage of LIN28 over OCT4 is in diagnosing yolk sac tumors (yolk sac tumors negative for OCT4).
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rna binding protein LIN28 is a marker for primary extragonadal germ cell tumors an immunohistochemical study of 131 cases
Modern Pathology, 2011Co-Authors: Dengfeng Cao, Robert W. Allan, Yan Peng, Fenghua Wang, Aijun Liu, Kaiyong Mei, Shuangping Guo, Ty W Abel, Zhaoli Lane, Maria M RodriguezAbstract:LIN28 has been shown to have an important role in primordial germ cell development and malignant transformation of germ cells in mouse. In this study, we examined the immunohistochemical profile of LIN28 in 131 primary human extragonadal germ cell tumors (central nervous system (CNS) 76, mediastinum 17, sacrococcygeal region 30, pelvis 3, vagina 2, liver 1, omentum 1, and retroperitoneum 1), including the following tumors and/or components: 57 seminomas/germinomas, 10 embryonal carcinomas, 74 yolk sac tumors, 6 choriocarcinomas, 15 mature, and 13 immature teratomas. We compared LIN28 with SALL4 to assess its diagnostic value. To determine its specificity, we examined LIN28 in 406 extragonadal-non-germ cell tumors (103 carcinomas, 91 sarcomas, 9 melanomas, 12 mesotheliomas, 83 lymphomas, 9 plasmacytomas, 82 CNS tumors, and 17 thymic epithelial tumors). The staining was semi-quantitatively scored as 0 (no cell stained), 1+ (0–30%), 2+ (31–60%), 3+ (61–90%), and 4+ (>90%). LIN28 staining was seen in all seminomas/germinomas (3+ in 1 and 4+ in 56), embryonal carcinomas (4+ in all 10), and yolk sac tumors (3+ in 3 and 4+ in 71). Variable LIN28 staining was seen in 5 of 6 choriocarcinomas (1+ to 4+), 8 of 13 immature teratomas (1+ to 2+ in immature elements), and in 1 of 15 mature teratomas (1+). Only 11 of 406 non-germ cell tumors showed 1+ LIN28 staining. Therefore, LIN28 is a sensitive (100% sensitivity) marker for primary extragonadal seminomas/germinomas, embryonal carcinomas, and yolk sac tumors with high specificity. Compared with SALL4, LIN28 demonstrated a similar level of diagnostic sensitivity for seminomas/germinomas and embryonal carcinomas. For primary extragonadal yolk sac tumors, although SALL4 stained all tumors (1+ in 1, 2+ in 2, 3+ in 10, and 4+ in 61), LIN28 stained more tumor cells (mean 95 vs 90%, P=0.03) and was therefore more sensitive. For primary extragonadal yolk sac tumors, combining LIN28 and SALL4 can achieve a higher diagnostic sensitivity than either alone.