Upregulation of miR‑95-3p inhibits growth of osteosarcoma by targeting HDGF

Osteosarcoma is the most common bone malignancy and miR-95-3p plays an important role in multiple cancers. The purpose of this study was to explore the effect and potential mechanism of miR-95-3p on the growth of osteosarcoma. In vitro, the osteosarcoma cell lines, SAOS-2 and U2OS cells, were transfected with miR-95-agomir to assess the role of miR-95-3p in proliferation and apoptosis of osteosarcoma cells. We determined that overexpression of miR-95-3p significantly attenuated cell proliferation but enhanced apoptosis in SAOS-2 and U2OS cells. We also found that overexpression of miR-95-3p in osteosarcoma cells downregulated the expression of hepatoma-derived growth factor (HDGF). Next, knockdown of HDGF by siRNA targeting HDGF clearly inhibited cell proliferation and induced apoptosis in U2OS cells. In vivo, a tumor formation assay in BALB/c nude mice was conducted by injecting the pre-miR-95 or control vector lentivirus-infected U2OS cells to determine the effect of miR-95-3p on the growth of osteosarcoma. Results showed miR-95-3p overexpression inhibited the osteosarcoma growth and downregulated the HDGF expression in xenografted tumor. For mechanism study, we co-transfected HDGF/pcDNA3.1 plasmid and miR-95-agomir to U2OS cells, and we demonstrated that overexpression of HDGF could attenuate the effects of miR-95-3p on U2OS cell proliferation, apoptosis and migration. These findings indicated that miR-95-3p might act as a potential tumor suppressor in osteosarcoma by targeting HDGF. Thus, miR-95-3p may become a potential therapeutic in treatment of osteosarcoma.     

肝癌衍生生长因子在胃腺癌中表达的研究

目的研究在胃腺癌中肝癌衍生生长因子(HDGF)的表达情况和临床意义。方法利用免疫组织化学检测手段观察18例正常胃上皮组织,25例胃高/中分化及21例低/未分化腺癌组织中HDGF的表达。在不同分化级别的胃腺癌标本中应用卡方检验比较HDGF的表达,并分析HDGF表达与临床病理特征的相关性。结果 HDGF表达率在正常胃上皮组织中为17%,而胃腺癌中上调为69%,差异有统计学意义(χ~2=14.61,P0.05);HDGF表达与胃腺癌组织的分化程度(χ~2=4.76,P0.05)、浸润深度(χ~2=5.97,P0.05)和淋巴结侵袭(χ~2=8.81,P0.05)有关。结论 HDGF相比正常胃组织在胃腺癌中明显上调,并且和其临床病理因素正相关,提示HDGF于发病进程的潜在促进作用。     

MiR-610 inhibits cell proliferation and invasion in colorectal cancer by repressing hepatoma-derived growth factor

MicroRNAs (miRNAs) act as key regulators of gene expression and their dysregulation is linked to carcinogenesis and tumor progression. MiR-610 has been implicated as an anti-tumor miRNA in multiple types of cancers. However, its biological role and the underlying mechanism in colorectal cancer (CRC) have not been well explored. In this study, we report that miR-610 expression is decreased in CRC samples while ectopic expression of miR-610 suppresses cell proliferation, migration and invasion, and influences the expression of epithelial-mesenchymal transition (EMT)-associated proteins by up-regulating E-cadherin expression and down-regulating vimentin expression. Using a luciferase reporter assay, we reveal that miR-610 directly targets hepatoma-derived growth factor (HDGF) by binding to its 3’UTR. A negative correlation was also observed between miR-610 and HDGF expression in CRC tissues. Further studies show that inhibition of HDGF recapitulates the anti-tumor function of miR-610, whereas re-expression of HDGF partially abrogates the inhibitory effects of miR-610. Collectively, our findings indicate that miR-610 exerts its function by directly targeting HDGF. The miR-610/HDGF axis is a novel therapeutic target for CRC.     

Hepatoma-derived growth factor-related protein-3: a new neurotrophic and neurite outgrowth-promoting factor for cortical neurons

Hepatoma-derived growth factor-related proteins (HRPs) make up a family of six members. Hepatoma-derived growth factor-related protein-3 (HRP-3) is the only family member whose expression is almost restricted to nervous tissue. Here we show that soluble HRP-3 acts as a novel neurotrophic factor for cultured primary cortical neurons. Antibody-mediated neutralization of HRP-3 function results in neuronal degeneration. In contrast, HRP-3 as the only addition to a culture medium not supporting neuronal survival rescues neurons to an extent comparable to the addition of FCS. Besides this neuroprotective capability, the protein exerts a neurite outgrowth-promoting effect when it is presented as a coated substrate but not as a soluble factor. This study points to an important role of HRP-3 during the development of the nervous system.     

肝癌衍生生长因子与肿瘤关系的研究进展

肝癌衍生生长因子（HDGF）是最初从人肝癌细胞系HuH-7培养的细胞液中分离提纯到的一种新的生长因子,在人体内分布广泛,它参与细胞的增殖及分化、组织器官生长、发育,损伤后组织的修复等。研究发现HDGF在乳腺癌、胰腺癌、非小细胞肺癌、肝癌、胃癌、胶质细胞瘤等肿瘤组织中表达增高。HDGF与肿瘤的发生、发展、侵袭、转移有关。HDGF可能成为肿瘤的分子标志物,有望成为肿瘤治疗的潜在靶点。本文就HDGF目前的研究动态及其临床意义加以综述。     

肝癌衍生生长因子在胃腺癌组织中的表达及意义

目的探讨肝癌衍生生长因子（HDGF）在胃腺癌发生、发展及转移中的作用。方法运用免疫组织化学S-P方法检测32例正常胃上皮组织、60例胃腺癌组织中HDGF的表达,同时检测血管内皮生长因子（VEGF）在胃腺癌组织中的表达。采用X2检验比较HGDF在两种组织中的表达,分析HDGF表达与胃腺癌临床病理学因素和VEGF的关系。结果胃腺癌组织中HDGF的阳性表达率为68．3％,正常胃上皮组织中HDGF的阳性表达率为25．0％,两者差异有统计学意义（X2=15．752,P〈0．01）;HDGF表达与胃腺癌组织的浸润程度（X2=6．459,P=0．011）和淋巴结转移有关（X2=5．844,P=0．016）;HDGF与VEGF表达呈正相关。结论HDGF在胃腺癌组织中的表达显著高于在正常胃上皮组织中的表达,与胃腺癌浸润程度和淋巴结转移密切相关,与VEGF表达呈正相关。提示HDGF在胃腺癌的发生、发展及转移中具有重要作用。     

Hepatoma-derived growth factor (HDGF) is dispensable for normal mouse development

Hepatoma-derived growth factor (HDGF) is suggested to be involved in organ development and exhibits proliferative, angiogenic, and neurotrophic activity. The in vivo functions are, however, so far unknown. In this study, we generated HDGF-deficient mice, in which parts of the HDGF gene were replaced by a gene encoding green fluorescent protein (eGFP). HDGF-/- mice are viable with no apparent morphological abnormalities. Cultured HDGF-deficient dermal fibroblasts show unaltered proliferation rates and cell-cycle distributions. In contrast to previous studies, our data demonstrate that signal pathways involved in the response to extracellular HDGF do not depend on the presence of intracellular HDGF. Contrary to the reported role of HDGF as a modulator of apoptosis, similar apoptotic rates were found between wild-type and HDGF-deficient fibroblasts following tumor necrosis factor alpha (TNFalpha) -induced apoptosis or cellular stress. The lack of obvious biochemical and morphological phenotypes in HDGF-deficient mice demonstrates that in vivo HDGF is dispensable for normal development in mice.     

Hepatoma-derived growth factor is a novel prognostic factor for gastrointestinal stromal tumors

Proliferating activity as mitotic count is generally accepted as a major prognostic indicator for gastrointestinal stromal tumors (GISTs). Hepatoma-derived growth factor (HDGF) is a novel growth factor and elevated in several types of cancer. Our study was designed to elucidate the expression and prognostic role of HDGF in GISTs. A total 178 surgically resected CD117-positive GISTs specimens were collected for immunohistochemical analysis using antibodies against HDGF. The immunoreactivities were scored as labeling index (LI) and correlated with clinicopathologic parameters of GIST patients. The HDGF immunoreactivities were detected in both nucleus and cytoplasm of GISTs tissues. Besides, the nuclear and cytoplasmic HDGF was parallely upregulated in GISTs (p < 0.001). The nuclear HDGF LI were positively correlated with that of PCNA (p < 0.001) and Ki-67 (p < 0.001), tumor mitosis (p < 0.001), tumor sizes (p = 0.007) and NIH risk categories (p < 0.001). In addition, the cytoplasmic HDGF LI were also positively correlated with that of PCNA (p = 0.031) and Ki-67 (p = 0.038), tumor sizes (p = 0.003) and tumor mitosis (p = 0.015). Patients with higher HDGF levels had earlier tumor recurrence and unfavorable outcome (p < 0.05). In addition to standard prognostic factors (NIH risk categories), the nuclear HDGF LI is an independent prognostic factor for disease free and overall survivals of GIST patients after operation. We conclude that HDGF is a novel prognostic factor for GIST patients.     

人脑胶质瘤中肝癌衍生生长因子及细胞周期素D1的表达及意义

目的探讨肝癌衍生生长因子（hepatoma—derived growth factor,HDGF）与细胞周期素D1（cyclin D1）在人脑胶质瘤中的表达及意义。方法采用免疫组织化学法检测9例脑外伤内减压切除的正常脑组织和55例不同级别脑胶质瘤组织中HDGF和cyclin D1的表达强度。结果在55例胶质瘤组织中,HDGF及eyclin D1的表达阳性率分别为74．5％（41／55）和63．6％（35／55）,显著高于正常对照脑组织中的表达水平（3／9和2／9,P=0．008和P=0．024）。胶质瘤组织恶性程度越高,HDGF及cyclin D1表达越强（P=0．006和P〈0．001）。胶质瘤组织中HDGF与cyclin D1的表达水平呈正相关性（r=0．728,P〈0．001）。结论HDGF与cyclin D1蛋白在脑胶质瘤的发生发展中起重要作用。