• Title/Summary/Keyword: Insulin-like Growth Factor Binding Protein

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Synergism Induced by Combination of Farnesyl Transferase Inhibitor SCH66336 and Insulin like-Growth Factor Binding Protein-3 in apoptosis of Non-Small Cell Lung Cancer Cell lines (비소세포성 폐암 세포주에서 Farnesyl Transferase Inhibitor SCH66336과 인슐린양 성장 인자 결합 단백-3의 병용처리에 의한 세포고사 상승 작용)

  • Kim, Young;Kim, Se Kyu;Kim, Hyung Jung;Chang, Joon;Ahn, Chul Min;Kim, Sung Kyu;Chang, Yoon Soo
    • Tuberculosis and Respiratory Diseases
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    • v.58 no.2
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    • pp.120-128
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    • 2005
  • Background : Insulin-like growth factor binding protein (IGFBP)-3 regulates non-small cell lung cancer(NSCLC) cell proliferation in vitro and in vivo by inhibiting IGF-mediated signaling pathways. To have better strategies for the treatment of lung cancer, we analyzed the combining effects of adenovirus expressing IGFBP-3 (Ad5CMV-BP3) and SCH66336, a farnesyl transferase inhibitor (FTI) designed to block Ras-mediated proliferative signaling pathways. Methods : To measure the combining effects of Ad5CMV-BP3 and SCH66336 on the proliferation of NSCLC cells, human NSCLC cell lines (H1299, H596, A549, H460, and H358), SCH66336, recombinant adenovirus expressing IGFBP-3 (Ad5CMV-BP3) and athymic nude mice were used in these experiments. Results : The combination of Ad5CMV-BP3 and SCH66336 produced a synergistic enhancement in antiproliferative effects over a range of clinically achievable concentrations in a variety of NSCLC cell lines. Furthermore, we observed a significant reduction in growth of NSCLC xenograft induced in athymic nude mice. Conclusion : In conclusion, this study demonstrated for the first time that the FTI SCH66336 synergizes with IGFBP-3 and enhances its apoptotic activity in NSCLC cells in vitro and in vivo. The combined treatment of Ad5CMV-BP3 and SCH66336 raises the possibility of using this regimen in clinic for the treatment of NSCLC.

The relationship between adiponectin, leptin, insulin, insulin-like growth factor and IGF binding protein-3 in cord blood and neonatal anthropometric parameters (제대혈에서 아디포넥틴, 렙틴, 인슐린, IGF-I, IGFBP-3와 신생아의 신체계측과의 상관관계)

  • Cho, Hai Jung;Kim, Ji Young;Kim, Me Jin;Hwang, Il Tae;Lee, Hae Ran
    • Clinical and Experimental Pediatrics
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    • v.51 no.7
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    • pp.722-728
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    • 2008
  • Purpose : This study was designed to examine the effects of adiponectin, leptin, insulin, insulin-like growth factor (IGF)-I and IGF binding protein (BP)-3 levels in cord blood on weight, length, and adiposity at birth in healthy term infants. In addition, we evaluated the mechanism to change the hormone levels in appropriate for gestational age (AGA) during the first month. Methods : We collected cord blood from 200 term neonates (109 males, 91 females) with no perinatal problems, and measured the hormone levels and anthropometric parameters including weight, length, and skin-fold thickness. Term neonates were divided into 3 groups as follows: birth weight appropriate for gestational age (AGA) (n=132), birth weight less for gestational age (SGA) (n=29), and birth weight more for gestational age (LGA) (n=39). Venous blood samples of 15 fullterm healthy neonates were obtained at 3, 7, and 30 d after birth. Results : The adiponectin, insulin, and IGF-I levels were significantly lower in the SGA group than in the AGA and LGA groups. The leptin levels were significantly higher in the LGA group than in the AGA and SGA groups. Cord blood adiponectin, leptin, insulin, IGF-I, and IGFBP-3 levels correlated significantly and positively with birth weight and the sum of the skin-fold thickness. A significant positive correlation was observed between adiponectin, leptin, and IGF-I levels and birth weight. Adiponectin level correlated significantly with that leptin level (r=0.191, P=0.038), but not with insulin, IGF-I and IGFBP-3 levels. IGF-I levels were higher in females than in males. At 7 d after birth, the leptin level decreased along with physiologic weight loss, and then increased. IGF-I, also decreased at 3 d, significantly increased 1 month later. Conclusion : We suggest that adiponectin, leptin, insulin, IGF-I, and IGFBP-3 play an important role in regulating fetal growth. Adiponectin may be involved in regulating fetal growth through mechanisms different from those mediated by insulin or IGF-I. High levels of IGF-I in female neonates indicates a gender difference which serves as evidence for in utero sexual dimorphism. It is likely that IGF-I has a more important role than that of hormones in postnatal growth.

Induction of Apoptosis by IGFBP3 Overexpression in Hepatocellular Carcinoma Cells

  • Han, Jian-Jun;Xue, De-Wen;Han, Qiu-Rong;Liang, Xiao-Hong;Xie, Li;Li, Sheng;Wu, Hui-Yong;Song, Bao
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.23
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    • pp.10085-10089
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    • 2015
  • Background: The insulin-like growth factor (IGF) system comprises a group of proteins that play key roles in regulating cell growth, differentiation, and apoptosis in a variety of cellular systems. The aim of this study was to investigate the role of insulin-like growth factor binding protein 3 (IGFBP3) in hepatocellular carcinoma. Materials and Methods: Expression of IGF2, IGFBP3, and PTEN was analyzed by qRT-PCR. Lentivirus vectors were used to overexpress IGFBP3 in hepatocellular carcinoma cell (HCC) lines. The effect of IGFBP3 on proliferation was investigated by MTT and colony formation assays. Results: Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells. Conclusions: Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells.

Interaction between IGFBP-5 and TNFR1

  • Kim, Eun-Jung;Jeong, Mi-Suk;Hwang, Jae-Ryoung;Lee, Je-Ho;Jang, Se-Bok
    • Bulletin of the Korean Chemical Society
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    • v.31 no.7
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    • pp.2019-2024
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    • 2010
  • Insulin-like growth factor binding protein 5 (IGFBP-5) plays an important role in controlling cell survival, differentiation and apoptosis. Apoptosis can be induced by an extrinsic pathway involving the ligand-mediated activation of death receptors such as tumor necrosis factor receptor 1 (TNFR1). To determine whether IGFBP-5 and TNFR1 interact as members of the same apoptosis pathway, recombinant IGFBP-5 and TNFR1 were isolated. The expression and purification of the full-length TNFR1 and truncated IGFBP-5 proteins were successfully performed in E. coli. The binding of both IGFBP-5 and TNFR1 proteins was detected by surface plasmon resonance spectroscopy (BIAcore), fluorescence measurement, electron microscopy, and size-exclusion column (SEC) chromatography. IGFBP-5 indeed binds to TNFR1 with an apparent $K_D$ of 9 nM. After measuring the fluorescence emission spectra of purified IGFBP-5 and TNFR1, it was found that the tight interaction of these proteins is accompanied by significant conformational changes of one or both. These results indicate that IGFBP-5 acts potently as a novel ligand for TNFR1.

Roles of the Insulin-like Growth Factor System in the Reproductive Function;Uterine Connection (Insulin-like Growth Factor Systems의 생식기능에서의 역할;자궁편)

  • Lee, Chul-Young
    • Clinical and Experimental Reproductive Medicine
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    • v.23 no.3
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    • pp.247-268
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    • 1996
  • It has been known for a long time that gonadotropins and steroid hormones play a pivotal role in a series of reproductive biological phenomena including the maturation of ovarian follicles and oocytes, ovulation and implantation, maintenance of pregnancy and fetal growth & development, parturition and mammary development and lactation. Recent investigations, however, have elucidated that in addition to these classic hormones, multiple growth factors also are involved in these phenomena. Most growth factors in reproductive organs mediate the actions of gonadotropins and steroid hormones or synergize with them in an autocrine/paracrine manner. The insulin-like growth factor(IGF) system, which is one of the most actively investigated areas lately in the reproductive organs, has been found to have important roles in a wide gamut of reproductive phenomena. In the present communication, published literature pertaining to the intrauterine IGF system will be reviewed preceded by general information of the IGF system. The IGF family comprises of IGF-I & IGF-II ligands, two types of IGF receptors and six classes of IGF-binding proteins(IGFBPs) that are known to date. IGF-I and IGF-II peptides, which are structurally homologous to proinsulin, possess the insulin-like activity including the stimulatory effect of glucose and amino acid transport. Besides, IGFs as mitogens stimulate cell division, and also play a role in cellular differentiation and functions in a variety of cell lines. IGFs are expressed mainly in the liver and messenchymal cells, and act on almost all types of tissues in an autocrine/paracrine as well as endocrine mode. There are two types of IGF receptors. Type I IGF receptors, which are tyrosine kinase receptors having high-affinity for IGF-I and IGF-II, mediate almost all the IGF actions that are described above. Type II IGF receptors or IGF-II/mannose-6-phosphate receptors have two distinct binding sites; the IGF-II binding site exhibits a high affinity only for IGF-II. The principal role of the type II IGF receptor is to destroy IGF-II by targeting the ligand to the lysosome. IGFs in biological fluids are mostly bound to IGFBP. IGFBPs, in general, are IGF storage/carrier proteins or modulators of IGF actions; however, as for distinct roles for individual IGFBPs, only limited information is available. IGFBPs inhibit IGF actions under most in vitro situations, seemingly because affinities of IGFBPs for IGFs are greater than those of IGF receptors. How IGF is released from IGFBP to reach IGF receptors is not known; however, various IGFBP protease activities that are present in blood and interstitial fluids are believed to play an important role in the process of IGF release from the IGFBP. According to latest reports, there is evidence that under certain in vitro circumstances, IGFBP-1, -3, -5 have their own biological activities independent of the IGF. This may add another dimension of complexity of the already complicated IGF system. Messenger ribonucleic acids and proteins of the IGF family members are expressed in the uterine tissue and conceptus of the primates, rodents and farm animals to play important roles in growth and development of the uterus and fetus. Expression of the uterine IGF system is regulated by gonadal hormones and local regulatory substances with temporal and spatial specificities. Locally expressed IGFs and IGFBPs act on the uterine tissue in an autocrine/paracrine manner, or are secreted into the uterine lumen to participate in conceptus growth and development. Conceptus also expresses the IGF system beginning from the peri-implantation period. When an IGF family member is expressed in the conceptus, however, is determined by the presence or absence of maternally inherited mRNAs, genetic programming of the conceptus itself and an interaction with the maternal tissue. The site of IGF action also follows temporal (physiological status) and spatial specificities. These facts that expression of the IGF system is temporally and spatially regulated support indirectly a hypothesis that IGFs play a role in conceptus growth and development. Uterine and conceptus-derived IGFs stimulate cell division and differentiation, glucose and amino acid transport, general protein synthesis and the biosynthesis of mammotropic hormones including placental lactogen and prolactin, and also play a role in steroidogenesis. The suggested role for IGFs in conceptus growth and development has been proven by the result of IGF-I, IGF-II or IGF receptor gene disruption(targeting) of murine embryos by the homologous recombination technique. Mice carrying a null mutation for IGF-I and/or IGF-II or type I IGF receptor undergo delayed prenatal and postnatal growth and development with 30-60% normal weights at birth. Moreover, mice lacking the type I IGF receptor or IGF-I plus IGF-II die soon after birth. Intrauterine IGFBPs generally are believed to sequester IGF ligands within the uterus or to play a role of negative regulators of IGF actions by inhibiting IGF binding to cognate receptors. However, when it is taken into account that IGFBP-1 is expressed and secreted in primate uteri in amounts assessedly far exceeding those of local IGFs and that IGFBP-1 is one of the major secretory proteins of the primate decidua, the possibility that this IGFBP may have its own biological activity independent of IGF cannot be excluded. Evidently, elucidating the exact role of each IGFBP is an essential step into understanding the whole IGF system. As such, further research in this area is awaited with a lot of anticipation and attention.

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Determination of optimal dietary valine concentrations for improved growth performance and innate immunity of juvenile Pacific white shrimp Penaeus vannamei

  • Daehyun Ko;Chorong Lee;Kyeong-Jun Lee
    • Fisheries and Aquatic Sciences
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    • v.27 no.3
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    • pp.171-179
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    • 2024
  • A study was conducted to evaluate dietary valine (Val) requirement for Pacific white shrimp (Penaeus vannamei). Five isonitrogenous (353 g/kg) and isocaloric (4.08 kcal/g) semi-purified diets containing graded levels of Val (2.7, 5.1, 8.7, 12.1 or 16.0 g/kg) were formulated. Quadruplicate groups of 12 shrimp (average body weight: 0.46 ± 0.00 g) were fed one of the experimental diets (2%-5% of total body weight) for 8 weeks. Maximum weight gain was observed in 8.7 g/kg Val group. However, the growth performance was reduced when Val concentration in diets were higher than 12.1 g/kg. Feed conversion ratio was significantly increased with 2.7 and 16.0 g/kg Val inclusion. Shrimp fed the diets containing 2.7 g/kg Val showed significantly lower protein efficiency ratio, whole-body crude protein and Val concentrations. Dietary inclusion of Val significantly improved the relative expression of insulin-like growth factor binding protein and immune-related genes (prophenoloxidase, lysozyme and crustin) in the hepatopancreas and 8.7 g/kg Val group showed highest expression among all the groups. The dietary requirement of Val for maximum growth of juvenile P. vannamei, estimated using polynomial regression analysis on growth, was 9.54 g/kg of Val (27.2 g/kg based on protein level) and maximum growth occurred at 9.27 g/kg of Val (26.2 g/kg based on protein level) based on broken-line regression analysis.

Differential Gene Expression in Estradiol-3-Benzoate-Treated Liver and Chemically- Induced Hepatocellular Carcinoma

  • KIM , SEYL;KANG, JIN-SEOK;JANG, DONG-DEUK;LEE, KOOK-KYUNG;KIM, SOON-AE;HAN, BEOM-SEOK;PARK, YOUNG-IN
    • Journal of Microbiology and Biotechnology
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    • v.14 no.6
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    • pp.1286-1294
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    • 2004
  • In a previous study by the current authors, hepatocellular carcinoma (HCC) was determined to be epidemiologically sex-dependent, and the incidence and multiplicity of HCC found to decrease in estradiol-3 benzoate (EB)-treated F344 rats. Therefore, to ascertain the anticancer mechanism of EB, a commercially available cDNA microarray, with a total of 14,815 cDNA rat gene clones, was used to determine the differentially expressed genes in nontreated livers, EB-treated livers, and diethynitrosolamine (DEN)-induced HCC. In the sequenced experiment, a total of 85 genes were differentially expressed at either two or more times the rate of the normal expression, where 33 genes were downregulated by EB, and 52 genes upregulated. Candidate genes were selected according to significant changes observed in the mRNA expression in the EB-treated livers compared with the nontreated livers, then these genes were filtered according to their different expression patterns in the DEN-induced tumors compared to the estrogen-treated livers. To confirm the microarray data, a real-time PCR analysis was performed for ten selected genes: the H-ras revertant protein 107 (H­rev107), insulin-like growth factor binding protein (lOFBP), parathyroid hormone receptor (PI'HR), SH3 domain binding protein (SH3BP), metallothionein, src-suppressed C-kinase substrate (SSeCK) gene, phosphodiesterase I, CD44, epithelial membrane protein 3 (EMP3), and estrogen receptor a (ERa). The SSeCK and phosphodiesterase I genes were both upregulated in the DEN-induced hepatocarcinomas, yet their possible carcinogenic functions remain unknown. Meanwhile, the other genes were downregulated, including the genes related to growth regulation (IOFBP, H-revI07, ER$\alpha$), adipogenesis inhibition (PTHR), and tumor suppression (metallothionein).

Prostate Cancer Risk in Relation to a Single Nucleotide Polymorphism in the Insulin-like Growth Factor-binding Protein-3 (IGFBP3) Gene: a Meta-analysis

  • Mao, Ye-Qing;Xu, Xin;Lin, Yi-Wei;Chen, Hong;Hu, Zheng-Hui;Xu, Xiang-Lai;Zhu, Yi;Wu, Jian;Zheng, Xiang-Yi;Qin, Jie;Xie, Li-Ping
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.12
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    • pp.6299-6303
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    • 2012
  • Insulin-like growth factor-binding protein-3 (IGFBP3) has been identified as a putative tumor suppressor with multifunctional roles in the IGF axis. Recently, there have been a growing body of studies investigating the relation between the IGFBP3 A-202C polymorphism, circulating IGFBP3 and prostate cancer risk, but their outcomes varied leading to controversy. Hence, it is necessary to perform a meta-analysis covering all eligible studies to shed a light on the association of IGFBP3 A-202C and cancer risk. Finally, we included a total of 11 relevant articles between 2003 and 2010 covering 14 case-control studies including 9,238 cases and 8,741 controls for our analysis. Our results showed that A-202C was a marginal risk factor of prostate cancer (allele contrast: OR=1.08, 95% CI :1.01-1.16; dominant model: OR=1.11, 95% CI :1.01-1.22; heterozygote codominant model: OR=1.11, 95% CI :1.03-1.18; homozygote contrast: OR=1.19, 95% CI :1.03-1.37). Stratification analysis revealed that sample size and control source were two major heterogeneous meta-factors especially in the recessive model (source: Population-based control group :p=0.30,I2=16.7%, Hospital-based control group: p=0.20, I2=30.3%; sample size: Small: p=0.22,I2= 32.8%, Medium: p=0.09,I2=48%, Large p=0.60,I2=0.0%); However, contrary to previous findings, no significance was found in racial subgroups. No significant publication bias was found in our analysis. Considering the robustness of the results and the discrepancy among some studies, there might be some unsolved confounding factors, and further more critical large studies are needed for confirmation.

Human umbilical cord blood mesenchymal stem cells engineered to overexpress growth factors accelerate outcomes in hair growth

  • Bak, Dong Ho;Choi, Mi Ji;Kim, Soon Re;Lee, Byung Chul;Kim, Jae Min;Jeon, Eun Su;Oh, Wonil;Lim, Ee Seok;Park, Byung Cheol;Kim, Moo Joong;Na, Jungtae;Kim, Beom Joon
    • The Korean Journal of Physiology and Pharmacology
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    • v.22 no.5
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    • pp.555-566
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    • 2018
  • Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) are used in tissue repair and regeneration; however, the mechanisms involved are not well understood. We investigated the hair growth-promoting effects of hUCB-MSCs treatment to determine whether hUCB-MSCs enhance the promotion of hair growth. Furthermore, we attempted to identify the factors responsible for hair growth. The effects of hUCB-MSCs on hair growth were investigated in vivo, and hUCB-MSCs advanced anagen onset and hair follicle neogeneration. We found that hUCB-MSCs co-culture increased the viability and up-regulated hair induction-related proteins of human dermal papilla cells (hDPCs) in vitro. A growth factor antibody array revealed that secretory factors from hUCB-MSCs are related to hair growth. Insulin-like growth factor binding protein-1 (IGFBP-1) and vascular endothelial growth factor (VEGF) were increased in co-culture medium. Finally, we found that IGFBP-1, through the co-localization of an IGF-1 and IGFBP-1, had positive effects on cell viability; VEGF secretion; expression of alkaline phosphatase (ALP), CD133, and ${\beta}-catenin$; and formation of hDPCs 3D spheroids. Taken together, these data suggest that hUCB-MSCs promote hair growth via a paracrine mechanism.

Alterations of mRNA and lncRNA profiles associated with the extracellular matrix and spermatogenesis in goats

  • Chen, Haolin;Miao Xiaomeng;Xu, Jinge;Pu, Ling;Li, Liang;Han, Yong;Mao, Fengxian;Ma, Youji
    • Animal Bioscience
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    • v.35 no.4
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    • pp.544-555
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    • 2022
  • Objective: Spermatozoa are produced within the seminiferous tubules after sexual maturity. The expression levels of mRNAs and lncRNAs in testicular tissues are different at each stage of testicular development and are closely related to formation of the extracellular matrix (ECM) and spermatogenesis. Therefore, we set out to study the expression of lncRNAs and mRNAs during the different developmental stages of the goat testis. Methods: We constructed 12 RNA libraries using testicular tissues from goats aged 3, 6, and 12 months, and studied the functions of mRNAs and lncRNAs using the gene ontogeny (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases. Relationships between differentially expressed genes (DEGs) were analyzed by lncRNA-mRNA co-expression network and protein-protein interaction network (PPI). Finally, the protein expression levels of matrix metalloproteinase 2 (MMP2), insulin-like growth factor 2 (IGF2), and insulin-like growth factor-binding protein 6 (IGFBP6) were detected by western blotting. Results: We found 23, 8, and 135 differentially expressed lncRNAs and 161, 12, and 665 differentially expressed mRNAs that were identified between 3 vs 6, 6 vs 12, and 3 vs 12 months, respectively. GO, KEGG, and PPI analyses showed that the differential genes were mainly related to the ECM. Moreover, MMP2 was a hub gene and co-expressed with the lncRNA TCONS-0002139 and TCONS-00093342. The results of quantitative reverse-transcription polymerase chain reaction verification were consistent with those of RNA-seq sequencing. The expression trends of MMP2, IGF2, and IGFBP6 protein were the same as that of mRNA, which all decreased with age. IGF2 and MMP2 were significantly different in the 3 vs 6-month-old group (p<0.05). Conclusion: These results improve our understanding of the molecular mechanisms involved in sexual maturation of the goat testis.