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Although the functions of long noncoding RNA (lncRNA) called FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) have been well studied in multiple human cancer types, its expression status and detailed roles in cervical cancer remain unknown and merit investigation. This study was aimed at assessing FOXD2-AS1 expression in cervical cancer and at determining its effects on the aggressive behavior of cervical cancer in vitro and in vivo. Expression of FOXD2-AS1 in cervical cancer tissues and cell lines was determined via reverse-transcription quantitative PCR. The effects of FOXD2-AS1 on cervical cancer cells were examined by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-Htetrazolium bromide (MTT) assay, flow-cytometric analysis, migration and invasion assays, and an in vivo tumorigenicity assay. FOXD2-AS1 was found to be significantly upregulated in cervical cancer tissues and cell lines. High FOXD2-AS1 expression was notably linked with the Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and depth of cervical invasion in patients with cervical cancer. Kaplan-Meier survival analysis revealed significantly shorter overall survival of patients when the tumor expression of FOXD2-AS1 was higher in comparison with those in patients with lower FOXD2-AS1 expression. In vitro functional assays revealed that downregulation of FOXD2-AS1 led to suppression of proliferation, migration, and invasiveness as well as to the induction of apoptosis of cervical cancer cells. In addition, FOXD2-AS1 silencing hindered tumor growth in vivo. Mechanism investigation revealed that FOXD2-AS1 functioned as a molecular sponge of microRNA-760 (miR-760). Furthermore, hepatoma-derived growth factor (HDGF) was validated as a direct target gene of miR-760 in cervical cancer cells. Moreover, an miR-760 knockdown reversed the effects of FOXD2-AS1 silencing on cervical cancer cells. FOXD2-AS1 possesses significant oncogenic activity in cervical cancer progression; this activity is mediated by sponging of miR-760 with consequent upregulation of HDGF. The FOXD2-AS1-miR-760-HDGF axis might harbor promising targets for novel treatment strategies of cervical cancer. [ABSTRACT FROM AUTHOR]

Background/Aim: We identified a new growth factor, hepatoma-derived growth factor (HDGF), which is a presumed growth-stimulating factor of hepatocellular carcinoma (HCC). Recently, we identified two microRNAs (miR-6072 and miR-3137) induced by HDGF, which were also found to be associated with the prognosis of HCC patients. This study aimed to identify the target genes of these HDGF-related microRNAs. Materials and Methods: A public database was searched for candidate target genes of HDGF-related microRNAs. Using the microarray system, the genes whose expression changed in response to HDGF administration were determined. Finally, a public cancer genomics database was searched for genes that were induced by HDGF and associated with the prognosis of HCC. Results: A total of 1,132 genes were identified as common target genes of the 2 HDGF-related microRNAs. Among these genes, a microarray system showed that the expression of 6 genes was increased (≥1.5-fold) or decreased (≤0.67- fold) after HDGF administration. Using a cancer genomics database, two of the six genes were found to be related to the prognosis of HCC. A high expression of alkylglycerone phosphate synthase (AGPS) was significantly associated with a poor survival (p=0.0025, 0.0063 and 0.0081 for the 1-, 3- and 5-year survival, respectively). A high expression of the shroom family member 4 (SHROOM4) gene was found to be significantly associated with a better survival (p=0.003, 0.0006 and 0.0006 for the 1-, 3- and 5-year survival, respectively). Conclusion: This study identified potential target genes of HDGF-related microRNAs that were associated with the prognosis of HCC. [ABSTRACT FROM AUTHOR]

We prepared three-dimensional (3-D) organoids of human stomach cancers and examined the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori (H. pylori). In addition, the effects of hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFα) on the growth and invasion activity of H. pylori-infected gastric cancer organoids were examined. Cytotoxin-associated gene A (CagA)-green fluorescence protein (GFP)-labeled H. pylori was used to trace the infection in gastric organoids. The cytotoxicity of Cag encoded toxins from different species of H. pylori did not affect the proliferation of each H. pylori-infected cancer organoid. To clarify the role of HDGF and TNFα secreted from H. pylori-infected cancer organoids, we prepared recombinant HDGF and TNFα and measured the cytotoxicity and invasion of gastric cancer organoids. HDGF controlled the growth of each organoid in a species-specific manner of H. pylori, but TNFα decreased the cell viability in H. pylori-infected cancer organoids. Furthermore, HDGF controlled the invasion activity of H. pylori-infected cancer organoid in a species-dependent manner. However, TNFα decreased the invasion activities of most organoids. We found different signaling of cytotoxicity and invasion of human gastric organoids in response to HDGF and TNFα during infection by H. pylori. Recombinant HDGF and TNFα inhibited the development and invasion of H. pylori-infected gastric cancer differently. Thus, we propose that HDGF and TNFα are independent signals for development of H. pylori-infected gastric cancer. The signaling of growth factors in 3-D organoid culture systems is different from those in two-dimensional cancer cells. [ABSTRACT FROM AUTHOR]

We prepared three-dimensional (3-D) organoids of human stomach cancers and examined the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori (H. pylori). In addition, the effects of hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFα) on the growth and invasion activity of H. pylori-infected gastric cancer organoids were examined. Cytotoxin-associated gene A (CagA)-green fluorescence protein (GFP)-labeled H. pylori was used to trace the infection in gastric organoids. The cytotoxicity of Cag encoded toxins from different species of H. pylori did not affect the proliferation of each H. pylori-infected cancer organoid. To clarify the role of HDGF and TNFα secreted from H. pylori-infected cancer organoids, we prepared recombinant HDGF and TNFα and measured the cytotoxicity and invasion of gastric cancer organoids. HDGF controlled the growth of each organoid in a species-specific manner of H. pylori, but TNFα decreased the cell viability in H. pylori-infected cancer organoids. Furthermore, HDGF controlled the invasion activity of H. pylori-infected cancer organoid in a species-dependent manner. However, TNFα decreased the invasion activities of most organoids. We found different signaling of cytotoxicity and invasion of human gastric organoids in response to HDGF and TNFα during infection by H. pylori. Recombinant HDGF and TNFα inhibited the development and invasion of H. pylori-infected gastric cancer differently. Thus, we propose that HDGF and TNFα are independent signals for development of H. pylori-infected gastric cancer. The signaling of growth factors in 3-D organoid culture systems is different from those in two-dimensional cancer cells.

Jie Situ,1,* Hao Zhang,1,* Zi Jin,2 Ke Li,1 Yunhua Mao,1 Wentao Huang1 1Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Hepatological Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wentao HuangDepartment of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510000, People’s Republic of ChinaEmail lucken_hwt@163.comPurpose: MicroRNA-939 (miR-939) has crucial roles in several types of human cancer. However, the expression profile and precise functions of miR-939 in prostate cancer (PCa) are still unclear. This study aimed to determine miR-939 expression in PCa and explore its roles in PCa tumorigenesis.Methods: miR-939 expression was determined in PCa tissues and cell lines using reverse transcription–quantitative polymerase chain reaction. Cell Counting Kit-8, colony formation, and flow cytometric assays were used to determine the role of miR-939 in PCa cell proliferation and apoptosis in vitro, whereas a tumor xenograft model was generated to evaluate the effect of miR-939 on tumor growth in vivo. Transwell assays were performed to investigate whether miR-939 affects the migration and invasiveness of PCa cells.Results: miR-939 was found to be downregulated in PCa tissues and cell lines, and this downregulation was significantly correlated with tumor stage and lymphatic metastasis. Patients with PCa exhibiting low miR-939 expression had shorter overall survival than those exhibiting high miR-939 expression. Exogenous miR-939 expression suppressed PCa cell proliferation, colony formation, migration, and invasion in vitro; enhanced apoptosis in vitro; and decreased tumor growth in vivo. Investigation of the underlying molecular mechanisms revealed hepatoma-derived growth factor (HDGF) as a direct target gene of miR-939 in PCa. HDGF was found to be significantly upregulated in PCa tissues, and its expression was inversely correlated with miR-939 expression. HDGF silencing and miR-939 upregulation showed similar effects in PCa. Restored HDGF expression counteracted the tumor-suppressive activity of miR-939 overexpression in PCa cells. Furthermore, ectopic miR-939 expression inhibited the WNT/β-catenin pathway activation in PCa both in vitro and in vivo by downregulating HDGF.Conclusion: miR-939 functions as a tumor suppressor during PCa tumorigenesis by directly targeting HDGF and deactivating the WNT/β-catenin pathway, suggesting the miR-939/HDGF/WNT/β-catenin pathway as an effective target for PCa therapy.Keywords: microRNA-939, prostate cancer, hepatoma-derived growth factor, WNT/β-catenin signaling

Ruofeng Yin,1 Junzhi Liu,2 Dongxu Zhao,1 Fei Wang1 1Department of Orthopedics, China-Japan Union Hospital Jilin University, Changchun, Jilin 130033, People’s Republic of China; 2Department of Quality Control, China-Japan Union Hospital Jilin University, Changchun, Jilin 130033, People’s Republic of ChinaCorrespondence: Fei WangDepartment of Orthopedics, China-Japan Union Hospital Jilin University, No. 126, Xiantai Road, Changchun, Jilin 130033, People’s Republic of ChinaEmail wangfei_king@163.comPurpose: ASB16 antisense RNA 1 (ASB16-AS1) is a cancer-associated long non-coding RNA that contributes to tumorigenesis and tumor development. Nevertheless, to the best of our knowledge, whether and how ASB16-AS1 is implicated in osteosarcoma (OS) malignancy remains unclear and therefore warrants exploration. Our current study focused on making in-depth investigation of ASB16-AS1 in OS. In the present study, the expression pattern of ASB16-AS1 in OS tissues and cell lines was analyzed. In addition, we examined the clinical value of ASB16-AS1 for OS patients. Furthermore, we explored the impacts of ASB16-AS1 on the malignant phenotype of OS cells in vitro and in vivo as well as the underlying mechanism.Methods: ASB16-AS1, microRNA-760 (miR-760) and hepatoma-derived growth factor (HDGF) expressions were measured using reverse transcription-quantitative PCR. Cell proliferation and apoptosis were evaluated using CCK-8 and flow cytometry analyses, respectively, and cell migration and invasion were determined via cell migration and invasion assays.Results: ASB16-AS1 expression was significantly elevated in OS tissues and cell lines, and increased ASB16-AS1 expression was related to patients’ tumor size, TNM stage, and distant metastasis. The overall survival rate of OS patients presenting high ASB16-AS1 expression was shorter than that of patients presenting low ASB16-AS1 expression. Reduced ASB16-AS1 expression inhibited OS cell proliferation, migration, and invasion; promoted cell apoptosis; and impaired tumor growth in vivo. Mechanistically, ASB16-AS1 served as a sponge for miR-760 and positively modulated the expression of its target HDGF. Finally, inhibiting miR-760 and restoring HDGF expression abolished the impacts of ASB16-AS1 knockdown on the malignant characteristics of OS cells.Conclusion: ASB16-AS1 is a novel oncogenic lncRNA in OS cells. ASB16-AS1 increased HDGF expression by sponging miR-760, thereby conferring cancer-promoting roles in OS. ASB16-AS1 is a potential early diagnostic and therapeutic target in OS.Keywords: osteosarcoma therapy, ASB16-AS1, hepatoma-derived growth factor, microRNA-760

Nucleosome assembly protein 1-like 1 (NAP1L1) is significantly involved in the development of various cancers. However, its role in the molecular mechanism of nasopharyngeal carcinoma (NPC) remains undetermined. In this study, we detected the upregulated expression of NAP1L1 mRNA and protein levels by quantitative polymerase chain reaction and Western blot analysis in NPC cell lines. Results of the immunohistochemistry analysis of NPC tissue biopsies showed that upregulated NAP1L1 protein expression promoted NPC progression and negatively correlated with poor prognosis in NPC patients. Suppression of NAP1L1 expression by small interfering RNA (siRNA) or small hairpin RNA (shRNA) methods significantly decreased cell proliferation in vivo and in vitro. Mechanism analysis revealed that the regulation of cell growth was enriched by Gene Set Enrichment Analysis based on RNA sequencing data. Cell cycle-induced genes CCND1 and E2F1 were downregulated in NAP1L1 knockdown NPC cells. Reduced NAP1L1 suppressed the recruitment of hepatoma-derived growth factor (HDGF) and decreased its expression. Knockdown of HDGF reduced the expression of c-JUN, a key oncogenic transcription factor that can induce the expression of cyclin D1 (CCND1), reducing cell cycle progression and suppressing cell growth in NPC. Transfecting HDGF or c-JUN could reverse the growth-suppressive effects in NAP1L1-downregulated NPC cells. The data obtained in this study suggest that NAP1L1 acts as a potential oncogene by activating HDGF/c-JUN/CCND1 signaling in NPC.

Glioma is the most common primary malignant tumor of the central nervous system and has a poor prognosis. Therefore, exploring the key molecular targets is a new opportunity for basic research and clinical treatment of glioma. Previous studies found that circRNA-hsa_circ_0073237 was upregulated in gliomas. Our further analyses of the biological function and molecular mechanism of hsa_circ_0073237 showed that hsa_circ_0073237 was also upregulated in glioma cell lines and could combine with miR-345 to inhibit its expression. miR-345 was downregulated in glioma tissues and cells, and targeted to regulate the expression of hepatoma-derived growth factor (HDGF), while HDGF expression was enhanced in glioma. Hsa_circ_0073237 promoted the expression of HDGF in glioma cells by adsorbing miR-345. Hsa_circ_0073237 siRNA, miR-345, and HDGF siRNA effectively inhibited cell viability and invasion and promoted cell apoptosis. When expression of hsa_circ_0073237 and miR-345 was inhibited simultaneously, cell viability, apoptosis, and invasion did not change significantly; however, after transfection with HDGF overexpression vector, the effects of hsa_circ_0073237 siRNA and miR-345 on glioma cell viability, apoptosis, and invasion were obviously reversed. Further construction of glioma xenograft models in nude mice confirmed that the introduction of miR-345 in vivo effectively inhibited tumor growth, significantly reduced tumor diameter and weight, and obviously decreased the expression of HDGF. Therefore, hsa_circ_0073237 can regulate the biological functions of glioma cells through miR-345/HDGF, thereby affecting the progression of tumors, indicating that the hsa_circ_0073237/miR-345/HDGF pathway may be a key target for the treatment of glioma. [ABSTRACT FROM AUTHOR]

Introduction: Information regarding the expression and roles of LIPE antisense RNA 1 (LIPE-AS1) in prostate cancer (PCa) progression is currently limited. We experimentally determined LIPE-AS1 expression in PCa tissues and cell lines. The specific functions of LIPE-AS1 in the oncogenicity of PCa were explored by evaluating a series of cellular functions. Moreover, the molecular mechanisms underlying the oncogenic roles of LIPE-AS1 in PCa were investigated. Methods: The expression level of LIPE-AS1 was determined via quantitative reverse transcription polymerase chain reaction. Functional experiments, including the Cell Counting Kit-8 assay, Transwell migration and invasion assays, and tumor xenograft experiments, were used to determine the effects of LIPE-AS1 on PCa cells. The putative miRNA-binding LIPE-AS1 was predicted via bioinformatics analysis and further verified using the luciferase reporter and RNA immunoprecipitation assays. Results: LIPE-AS1 was expressed at high levels in PCa cells; this result is consistent with that of The Cancer Genome Atlas database. Patients with PCa manifesting high LIPE-AS1 expression had shorter overall survival than those manifesting low LIPE-AS1 expression. Downregulated LIPE-AS1 inhibited PCa cell proliferation, migration, and invasion in vitro and impaired tumor growth in vivo. With respect to its mechanism, LIPE-AS1 functioned as a competing endogenous RNA for microRNA-654-3p (miR-654-3p) in PCa cells, and hepatoma-derived growth factor (HDGF) was the direct target of miR-654-3p. HDGF was positively regulated by LIPE-AS1 in PCa cells via the absorption of miR-654-3p. Rescue experiments confirmed that miR-654-3p downregulation or HDGF overexpression counteracts the inhibitory effects of LIPE-AS1 depletion on PCa cell proliferation, migration, and invasion. Conclusion: LIPE-AS1 promotes PCa malignancy by targeting the miR-654-3p/HDGF axis. Determining the LIPE-AS1/miR-654-3p/HDGF pathway may increase our understanding of PCa pathogenesis and contribute toward a wider applied scope. [ABSTRACT FROM AUTHOR]

Situ J, Zhang H, Jin Z, Li K, Mao Y, Huang W. Onco Targets Ther. 2020;13:4257–4270. The Editor and Publisher of OncoTargets and Therapy wish to retract the published article. Concerns were raised over alleged image duplication in Figure 8A with similar images from unrelated articles, specifically: Figure 8A appears to have been duplicated with a similar image in Figure 6A from Chen et al, 2019 (https://doi.org/10.3892/ijmm.2019.4429). The authors did not respond to our queries and the Editor determined the findings of the study were no longer valid and advised for the article to be retracted. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Yin R, Liu J, Zhao D, Wang F. Onco Targets Ther. 2020;13:2261–2274. The Editor and Publisher of OncoTargets and Therapy wish to retract the published article. Concerns were raised regarding the alleged duplication of images in Figures 2C, 4B and 6B with similar images from unrelated articles, specifically: Figure 2C, panel U2OS si-ASB16-AS1 appears to have been duplicated with a similar image in Figure 6C, panel Huh7 si-GAS6-AS+NC inhibitor from Ai et al, 2020 (https://doi.org/10.1080/15384101.2020.1729323). Figure 4B, panels HOS agomir-NC; agomir-760 appear to have been duplicated with similar images in Figure 6C, panel Sw1990 miR-769 mimics+pcDNA3.1-ETS1 and 5C, panel Panc-1 si-ETS1, respectively from Cheng et al, 2020 (https://doi.org/10.2147/OTT.S218876). Figure 6B, panel U2OS si-NC appears to have been duplicated with similar images in Figures 5C, panel H522 NC siRNA from Kang et al, 2019 (https://doi.org/10.2147/OTT.S204004) and 3D, panel si-HAND2-AS1 from Yu et al, 2020 (https://doi.org/10.2147/OTT.S233256), respectively. The authors responded to our queries but were unable to provide an explanation for the alleged image duplication and could not provide the original raw data or ethics approval documents for their study and have therefore agreed to retract the article. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Hepatitis is an important health problem worldwide. Novel molecular targets are in demand for detection and management of hepatitis. Hepatoma‐derived growth factor (HDGF) has been delineated to participate in hepatic fibrosis and liver carcinogenesis. However, the relationship between hepatitis and HDGF remains unclear. This study aimed to elucidate the role of HDGF during hepatitis using concanavalin A (ConA)‐induced hepatitis model. In cultured hepatocytes, ConA treatment‐elicited HDGF upregulation at transcriptional level and promoted HDGF secretion while reducing intracellular HDGF protein level and cellular viability. Similarly, mice receiving ConA administration exhibited reduced hepatic HDGF expression and elevated circulating HDGF level, which was positively correlated with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. By using HDGF knockout (KO) mice, it was found the ConA‐evoked cell death was prominently alleviated in KO compared with control. Besides, it was delineated HDGF ablation conferred protection by suppressing the ConA‐induced neutrophils recruitment in livers. Above all, the ConA‐mediated activation of tumor necrosis factor‐α (TNF‐α)/interleukin‐1β (IL‐1β)/interleukin‐6 (IL‐6)/cyclooxygenase‐2 (COX‐2) inflammatory signaling was significantly abrogated in KO mice. Treatment with recombinant HDGF (rHDGF) dose‐dependently stimulated the expression of TNF‐α/IL‐1β/IL‐6/COX‐2 in hepatocytes, further supporting the pro‐inflammatory function of HDGF. Finally, application of HDGF antibody not only attenuated the ConA‐mediated inflammatory cascade in hepatocytes, but also ameliorated the ConA‐induced hepatic necrosis and AST elevation in mice. In summary, HDGF participates in ConA‐induced hepatitis via neutrophils recruitment and may constitute a therapeutic target for acute hepatitis. [ABSTRACT FROM AUTHOR]

Introduction: Hepatic malignancy is one of the most common malignant neoplasms around the globe, and hepatocellular carcinoma (HCC) is the most common type. In this study, the roles and mechanisms of MiRNA-610 in the chemo resistance of HCC will be discussed.Material and Methods: The expression of MiRNA-610 and hepatoma-derived growth factor (HDGF) in HCC tissues and cell line was detected by quantitative real-time PCR. The proliferation and chemo resistance were analysed by MTT assay. Flow cytometry was used to examine the apoptosis rate. Luciferase reporter assay was used to verify the correlation between MiRNA-610 and HDGF. HDGF protein expression was detected by Western blot.Results: Our study confirmed the low-expression of MiRNA-610 in HCC tissues and cell line. Its low expression was related to high T stages and poor differentiation of HCC, and was a prognostic factor for HCC. MiRNA-610 upregulation inhibited cell proliferation and induced apoptosis of HepG2 cells. MiRNA-610 enhancement decreased the half maximal inhibitory concentration for cisplatin (DDP) and depressed the DDP resistance in HepG2 cells. The specific correlation between MiRNA-610 and HDGF was tested by luciferase reporter assay and western blot. The transfection with HDGF expression vector up-regulated the expression of HDGF protein silenced by MiRNA-610 enhancement. HDGF overexpression was found to reverse partly the regulatory roles of MiRNA-610 on malignancy and DDP resistance.Conclusions: MiRNA-610 not only played a tumour suppressor role in HCC but also affected chemo resistance to DDP. This role is mainly mediated through targeted silencing of the HDGF gene, which may offer a new potential therapeutic target and improve the clinical therapeutic effect for HCC. [ABSTRACT FROM AUTHOR]

Although the functions of long noncoding RNA (lncRNA) called FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) have been well studied in multiple human cancer types, its expression status and detailed roles in cervical cancer remain unknown and merit investigation. This study was aimed at assessing FOXD2-AS1 expression in cervical cancer and at determining its effects on the aggressive behavior of cervical cancer in vitro and in vivo. Expression of FOXD2-AS1 in cervical cancer tissues and cell lines was determined via reverse-transcription quantitative PCR. The effects of FOXD2-AS1 on cervical cancer cells were examined by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, flow-cytometric analysis, migration and invasion assays, and an in vivo tumorigenicity assay. FOXD2-AS1 was found to be significantly upregulated in cervical cancer tissues and cell lines. High FOXD2-AS1 expression was notably linked with the Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and depth of cervical invasion in patients with cervical cancer. Kaplan–Meier survival analysis revealed significantly shorter overall survival of patients when the tumor expression of FOXD2-AS1 was higher in comparison with those in patients with lower FOXD2-AS1 expression. In vitro functional assays revealed that downregulation of FOXD2-AS1 led to suppression of proliferation, migration, and invasiveness as well as to the induction of apoptosis of cervical cancer cells. In addition, FOXD2-AS1 silencing hindered tumor growth in vivo. Mechanism investigation revealed that FOXD2-AS1 functioned as a molecular sponge of microRNA-760 (miR-760). Furthermore, hepatoma-derived growth factor (HDGF) was validated as a direct target gene of miR-760 in cervical cancer cells. Moreover, an miR-760 knockdown reversed the effects of FOXD2-AS1 silencing on cervical cancer cells. FOXD2-AS1 possesses significant oncogenic activity in cervical cancer progression; this activity is mediated by sponging of miR-760 with consequent upregulation of HDGF. The FOXD2-AS1–miR-760–HDGF axis might harbor promising targets for novel treatment strategies of cervical cancer.

Background/Aim: Hepatoma-derived growth factor (HDGF) is involved in the progression of hepatocellular carcinoma (HCC). The present study assessed the epigenomic changes in hepatoma-derived cells through HDGF stimulation. Materials and Methods: We used two hepatoma-derived cell lines (HepG2 and SK-Hep1) and searched for microRNAs whose expression commonly changed in response to HDGF administration. We further explored a genetic database to investigate the association of the candidate microRNAs with the survival of HCC patients. Results: Despite both HepG2 and SK-Hep1 cells being categorized as hepatoma-derived cells, the microRNA profile differed between these two lines. However, HepG2 and SK-Hep1 cells shared 30 up-regulated and 2 down-regulated microRNAs. Of these, miR-6072 and miR-3137 were significantly associated with a poor prognosis in HCC patients. Conclusion: We identified two candidate microRNAs whose expression increased in response to HDGF stimulation. Both these molecules were associated with a poor prognosis of HCC patients. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNAs) serve key roles in the progress of various types of cancer. The expression of miRNA (miR)-139-5p is downregulated in several types of tumor and has been recognized as a tumor suppressor. However, the role of miR-139-5p in non-small cell lung cancer (NSCLC) has not been investigated in detail. In the present study, it was demonstrated that miR-139-5p was significantly downregulated in NSCLC cells and tissues, and the overexpression of miR-139-5p in vitro induced apoptosis and significantly inhibited the viability and proliferation of A549 and H1299 cells. In addition, upregulation of miR-139-5p significantly inhibited the migration and invasion of A549 and H1299 cells. Hepatoma-derived growth factor (HDGF) was identified as a direct target of miR-139-5p. Rescue experiments demonstrated that the inhibitory function of miR-139-5p on cell viability, migration and invasion was partially mediated by suppressing HDGF expression. Furthermore, miR-139-5p exhibited efficient inhibition of tumor growth in a xenograft tumor mouse model of A549 cells. In summary, the results from the present study suggested that miR-139-5p may serve an important role in NSCLC by targeting HDGF and causing inhibition of cell viability and metastasis, as well as induction of apoptosis. miR-139-5p may also have the potential to serve as a therapeutic target for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Although the functions of long noncoding RNA (lncRNA) called FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) have been well studied in multiple human cancer types, its expression status and detailed roles in cervical cancer remain unknown and merit investigation. This study was aimed at assessing FOXD2-AS1 expression in cervical cancer and at determining its effects on the aggressive behavior of cervical cancer in vitro and in vivo. Expression of FOXD2-AS1 in cervical cancer tissues and cell lines was determined via reverse-transcription quantitative PCR. The effects of FOXD2-AS1 on cervical cancer cells were examined by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, flow-cytometric analysis, migration and invasion assays, and an in vivo tumorigenicity assay. FOXD2-AS1 was found to be significantly upregulated in cervical cancer tissues and cell lines. High FOXD2-AS1 expression was notably linked with the Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and depth of cervical invasion in patients with cervical cancer. Kaplan–Meier survival analysis revealed significantly shorter overall survival of patients when the tumor expression of FOXD2-AS1 was higher in comparison with those in patients with lower FOXD2-AS1 expression. In vitro functional assays revealed that downregulation of FOXD2-AS1 led to suppression of proliferation, migration, and invasiveness as well as to the induction of apoptosis of cervical cancer cells. In addition, FOXD2-AS1 silencing hindered tumor growth in vivo. Mechanism investigation revealed that FOXD2-AS1 functioned as a molecular sponge of microRNA-760 (miR-760). Furthermore, hepatoma-derived growth factor (HDGF) was validated as a direct target gene of miR-760 in cervical cancer cells. Moreover, an miR-760 knockdown reversed the effects of FOXD2-AS1 silencing on cervical cancer cells. FOXD2-AS1 possesses significant oncogenic activity in cervical cancer progression; this activity is mediated by sponging of miR-760 with consequent upregulation of HDGF. The FOXD2-AS1 –miR-760–HDGF axis might harbor promising targets for novel treatment strategies of cervical cancer. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma is the most common histologic subtype of lung cancer. The aim of the present study was to assess the expression of hepatoma-derived growth factor (HDGF) and protein kinase Cα (PRKCA) in lung adenocarcinoma (LADC), and to determine the association between the combined expression of these two proteins and clinicopathological characteristics of patients with LADC. The expression of HDGF and PRKCA mRNA was assessed by GEO database analysis, and HDGF and PRKCA protein levels were examined by immunohistochemistry using a tissue microarray. High HDGF and PRKCA expression was observed in LADC tissue compared to normal samples, and increased HDGF and PRKCA expression was associated with AJCC clinical stage, tumor classification, node classification, and lymph node metastasis. GEO database analysis revealed no significant differences between HDGF mRNA and PRKCA mRNA in LADC tissue. However, high PRKCA protein expression was associated with high HDGF protein expression, and patients with high HDGF and PRKCA expression exhibited poorer overall survival rates than patients with low expression levels of the two proteins. The results of the present study suggest that upregulation of both HDGF and PRKCA may be an unfavourable factor for lung adenocarcinoma progression. [ABSTRACT FROM AUTHOR]

Introduction: Recently, hepatoma-derived growth factor (HDGF) has been considered as a significantly important factor in determining the prognosis and estimating the probability of tumor cell invasions, recurrence, and lymph node metastasis in different cancers, including breast malignancies. Materials and Methods: Immunohistochemistry (IHC) study for HDGF was performed on paraffin-embedded blocks of patients with breast carcinoma in Modarres hospital, Tehran, Iran, since 1387–1390 (74 cases); three separate pathologists read the slides after complete IHC staining. Thereafter, necessary information was recorded from patient files, and eventually, findings were analyzed by SPSS program. Results: Expression of nuclear HDGF has significant statistical correlation with tumor grade according to Nottingham grading scheme; this correlation is also seen with nuclear pleomorphism of tumor cells and mitotic count. No correlation between age and tumor size with expression of HDGF is found. Lymph node metastasis is in inverse ratio to nuclear HDGF staining. Conclusion: Nuclear expression of HDGF in tumor cells is increased concordantly to tumor grade, which implies us to the role of this marker in determining the prognosis and choosing the most suitable treatment plan.

Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The lack of effective glioma therapeutics mandates the development of novel treatment strategies. Hepatoma-derived growth factor (HDGF) has been considered as a potential glioma therapeutic target, and its expression level in gliomas is positively related to the malignant grade. Although there are no effective and specific inhibitors against this target, small interfering RNA targeting HDGF (siHDGF)-mediated RNA interference (RNAi) can inhibit the target protein function by knockdown of HDGF expression. However, the application of siHDGF in glioma research and therapy is hampered by the challenge to safe and effective in vivo systemic delivery of siHDGF to gliomas. To address this question, we develop the peptide H 7 K(R 2) 2 -modified pH-sensitive self-assembled hybrid nanoparticles encapsulating siHDGF (H 7 K(R 2) 2 -PSNPs (siHDGF)). The acidic glioma microenvironment is beneficial to the membrane penetration of H 7 K(R 2) 2 -PSNPs and the encapsulated siHDGF. Following systemic administration, H 7 K(R 2) 2 -PSNPs (siHDGF) can effectively deliver siHDGF into the brain and malignant glioma cells, and therefore can significantly downregulate HDGF expression, inhibit malignant phenotypes of glioma cells, result in reduced tumor volumes and prolonged survival times in nude mice bearing U251 human glioblastoma. Thus, systemic administration of H 7 K(R 2) 2 -PSNPs (siHDGF) offers an effective way for the targeted delivery of siHDGF and may serve as a practical malignant glioma therapy. Unlabelled Image • H 7 K(R 2) 2 -PSNPs were developed to deliver siHDGF for malignant glioma treatment. • Acidic microenvironment attenuates the interaction of PLGA core and polyhistidine. • The pH responsiveness confers the tumor targeting to H 7 K(R 2) 2 -PSNPs. • Intravenously administrated H 7 K(R 2) 2 -PSNPs deliver siHDGF into malignant gliomas. • H 7 K(R 2) 2 -PSNPs (siHDGF) have potent anti-glioma effects in vitro and vivo. [ABSTRACT FROM AUTHOR]

An accumulation of evidence has demonstrated that abnormal microRNA (miRNA or miR) expression is associated with different types of cancer, including endometrial cancer (EC). The dysregulation of miRNAs may serve important roles in the development and progression of EC by regulating multiple aggressive biological behaviors, including cell proliferation, apoptosis, metastasis and angiogenesis. An in-depth understanding of the miRNAs associated with EC initiation and progression may be crucial for identifying successful therapeutic techniques. miR-873 has been demonstrated to be dysregulated in different types of cancer. However, the expression status and regulatory roles of miR-873 are yet to be elucidated in EC. In the present study, reverse transcription-quantitative PCR was carried out to detect miR-873 expression in EC tissues and cell lines. Cell Counting Kit-8 and in vitro invasion assays were utilized to determine the influence of miR-873 on the proliferation and invasion of EC cells. miR-873 expression was revealed to be downregulated in EC tissues and cell lines. Decreased miR-873 expression was significantly associated with International Federation of Gynecology and Obstetrics stage and lymph node metastasis of patients with EC. Functional assays revealed that resumed miR-873 expression suppressed the proliferation and invasion of EC cells. Additionally, hepatoma-derived growth factor (HDGF) was indicated to be a direct target gene of miR-873 in EC cells. HDGF was highly expressed in EC tissues and inversely correlated with miR-873 expression. HDGF silencing also imitated the tumor-suppressor activity of miR-873 overexpression in EC cells. A series of rescue experiments identified that recovered HDGF expression hindered the anti-proliferative and anti-invasive roles of miR-873 upregulation in EC cells. In conclusion, the present study indicated that miR-873 serves an important role as a tumor suppressor in EC development by directly targeting HDGF. The results may provide a novel insight into clinical treatments, which can be used to prevent EC aggression. [ABSTRACT FROM AUTHOR]

Dysregulated microRNA (miRNA) expression is involved in the occurrence and development of colorectal cancer (CRC) through the regulation of various important physiological events. Hence, miRNAs may be used as effective targets for CRC treatment; however, this hypothesis warrants further investigation. miRNA-511 (miR-511) plays vital roles in the progression of different tumor types. However, the expression, exact role, and the mechanisms underlying the regulation of colorectal carcinogenesis and progression by miR-511 remain poorly understood. This study presents that miR-511 expression was decreased in CRC tissues and cell lines compared with that in adjacent nonneoplastic tissues and normal human colon epithelium cell lines, respectively. The enforced expression of miR-511 in CRC cells significantly reduced cell proliferation and invasion. Hepatoma-derived growth factor (HDGF) was mechanically validated as a direct target of miR-511 in CRC. Furthermore, miR-511 was negatively associated with HDGF in CRC tissues. The restored HDGF expression can abrogate the tumor-suppressive roles of miR-511 in CRC cells. More importantly, miR-511 overexpression suppressed the PI3K/AKT signaling pathway in CRC. These results suggest that miR-511 can potentially serve as a therapeutic target for the therapy of patients with CRC. [ABSTRACT FROM AUTHOR]

The development of hepatocellular carcinoma (HCC) is an important complication of viral infection induced by hepatitis virus C, and our major research theme is to identify a new growth factor related to the progression of HCC. HDGF (hepatoma-derived growth factor) is a novel growth factor that belongs to a new gene family. HDGF was initially purified from the conditioned medium of a hepatoma cell line. HDGF promotes cellular proliferation as a DNA binding nuclear factor and a secreted protein acting via a receptor-mediated pathway. HDGF is a unique multi-functional protein that can function as a growth factor, angiogenic factor and anti-apoptotic factor and it participates in the development and progression of various malignant diseases. The expression level of HDGF may be an independent prognostic factor for predicting the disease-free and overall survival in patients with various malignancies, including HCC. Furthermore, the overexpression of HDGF promotes the proliferation of HCC cells, while a reduction in the HDGF expression inhibits the proliferation of HCC cells. This article provides an overview of the characteristics of HDGF and describes the potential role of HDGF as a growth-promoting factor for HCC.

Background/aim: We identified a new growth factor, hepatoma-derived growth factor (HDGF), which is a presumed growth-stimulating factor of hepatocellular carcinoma (HCC). Recently, we identified two microRNAs (miR-6072 and miR-3137) induced by HDGF, which were also found to be associated with the prognosis of HCC patients. This study aimed to identify the target genes of these HDGF-related microRNAs., Materials and Methods: A public database was searched for candidate target genes of HDGF-related microRNAs. Using the microarray system, the genes whose expression changed in response to HDGF administration were determined. Finally, a public cancer genomics database was searched for genes that were induced by HDGF and associated with the prognosis of HCC., Results: A total of 1,132 genes were identified as common target genes of the 2 HDGF-related microRNAs. Among these genes, a microarray system showed that the expression of 6 genes was increased (≥1.5-fold) or decreased (≤0.67-fold) after HDGF administration. Using a cancer genomics database, two of the six genes were found to be related to the prognosis of HCC. A high expression of alkylglycerone phosphate synthase (AGPS) was significantly associated with a poor survival (p=0.0025, 0.0063 and 0.0081 for the 1-, 3- and 5-year survival, respectively). A high expression of the shroom family member 4 (SHROOM4) gene was found to be significantly associated with a better survival (p=0.003, 0.0006 and 0.0006 for the 1-, 3- and 5-year survival, respectively)., Conclusion: This study identified potential target genes of HDGF-related microRNAs that were associated with the prognosis of HCC., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Nasopharyngeal carcinoma (NPC), which arises from the nasopharynx epithelium, is most common in Southeast Asia, particularly in Southern China. To date, a variety of microRNAs have been demonstrated to serve key functions in the progression and development of NPC. microRNA-425 (miR-425) has previously been reported to be frequently abnormally expressed in a number of different types of human cancer, including lung, gastric, cervical, breast and prostate cancer. However, to the best of our knowledge, the expression patterns, functions and underlying mechanisms of miR-425 in NPC remain largely unexplored. In the present study, the expression of miR-425 was revealed to be low in NPC tissues and cell line. Resumption of miR-425 expression suppressed cell viability and invasion in NPC. Hepatoma-derived growth factor (HDGF) was identified as a direct target gene of miR-425 in NPC. HDGF was highly expressed at mRNA and protein levels in NPC tissues. Additionally, HDGF mRNA was negatively correlated with miR-425 expression in NPC tissues. Furthermore, overexpression of HDGF almost completely rescued the tumor-suppressing effects of miR-425 on NPC cell viability and invasion. Taken together, these results demonstrated that miR-425 acted as a tumor suppressor in NPC by targeting HDGF, suggesting that it may be a novel therapeutic target for the treatments of patients with NPC. [ABSTRACT FROM AUTHOR]

Hepatoma‑derived growth factor (HDGF) regulates various cellular processes involved in the onset and development of tumors. To evaluate the role of HDGF in human gliomas, western blotting analysis, immunohistochemistry staining and reverse transcription‑quantitative polymerase chain reaction were performed to detect HDGF protein and mRNA expression levels in glioma and intractable epileptic brain tissue. Various clinicopathological characteristics, including age, gender, World health Organization grade, HDGF expression level, Karnofsky performance Status (KPS) and Ki‑67 index were obtained from medical records. The correlation between HDGF expression and these clinicopathological characteristics was statistically evaluated. Following this, multivariate liner regression was used to evaluate their effect on patient survival time. HDGF expression, at the protein and mRNA levels, was observed to be more upregulated in glioma tissues compared with intractable epileptic brain tissue without tumor. Furthermore, the level of HDGF expression was positively associated with the grade of malignancy [grades Ⅱ~Ⅳ, Ki‑67 index ≥20% or KPS <80 (P<0.05)] and poor prognosis in glioma patients. Notably, the univariate survival analysis identified a negative correlation between HDGF‑expression and survival time (P<0.01) and multivariate liner regression demonstrated that HDGF expression is an independent prognostic factor for gliomas (P=0.01). Overall, HDGF upregulation may be a crucial step in the development and invasion of glioma. Further survival analysis highlighted its prognostic value for this malignancy, implying its potential as a promising therapeutic target for gliomas. [ABSTRACT FROM AUTHOR]

Introduction: Recently, hepatoma-derived growth factor (HDGF) has been considered as a significantly important factor in determining the prognosis and estimating the probability of tumor cell invasions, recurrence, and lymph node metastasis in different cancers, including breast malignancies. Materials and Methods: Immunohistochemistry (IHC) study for HDGF was performed on paraffin-embedded blocks of patients with breast carcinoma in Modarres hospital, Tehran, Iran, since 1387-1390 (74 cases); three separate pathologists read the slides after complete IHC staining. Thereafter, necessary information was recorded from patient files, and eventually, findings were analyzed by SPSS program. Results: Expression of nuclear HDGF has significant statistical correlation with tumor grade according to Nottingham grading scheme; this correlation is also seen with nuclear pleomorphism of tumor cells and mitotic count. No correlation between age and tumor size with expression of HDGF is found. Lymph node metastasis is in inverse ratio to nuclear HDGF staining. Conclusion: Nuclear expression of HDGF in tumor cells is increased concordantly to tumor grade, which implies us to the role of this marker in determining the prognosis and choosing the most suitable treatment plan. [ABSTRACT FROM AUTHOR]

Hepatoma-derived growth factor (HDGF) plays a critical role in tumor cell proliferation, anti-apoptosis, VEGF expression, lymph node metastasis and poor prognosis in human gastric cancer. Gastric cancer, as one of the most prevalent cancers worldwide, is the second leading cause of cancer-related mortality in the world for the prognosis of gastric cancer is generally poor, especially in patients with advanced stage. Helicobacter pylori (H. pylori) infection causes the chronic inflammation of stomach as well as the development of gastric cancer, with a three to six-fold increased risk of gastric cancer. Carcinoma-associated fibroblasts (CAFs) are myofibroblasts in tumor microenvironment, which possess various abilities to promote the progression of cancer by stimulating neoangiogenesis, proliferation, migration, invasion and therapy resistance of tumor cell. Mesenchymal stem cells (MSCs) are reported to promote tumor malignance through differentiation of MSCs toward CAFs. In the present study, we demonstrated that H. pylori infection promotes HDGF expression in human gastric cancer cells. HBMMSCs treated with HDGF assume properties of CAF-like myofibroblastic phenotypes, including expression of myofibroblast markers (α-smooth muscle actin (α-SMA), procollagen α1, tropomyoson I, desmin, fibroblast activation protein (FAP)), and fibroblast markers (prolyl-4-hydroxylase A1 (PHA1) and fibroblast specific protein-1 (FSP-1)/S100A4). HDGF recruits HBMMSCs, and then HBMMSCs further contributes to cell survival and invasive motility in human gastric cancer cells. Treatment of HDGF neutralizing antibody (HDGF-NAb) and serum significantly inhibit HDGF-regulated differentiation and recruitment of HBMMSCs. These findings suggest that HDGF might play a critical role in gastric cancer progress through stimulation of HBMMSCs differentiation to myofibroblast-like cells.

MicroRNAs (miRNAs/miRs) are a class of conserved non‑coding endogenous small regulatory RNAs that regulate target gene expression by binding to the 3'‑untranslated region of target mRNAs in a base‑pairing manner, resulting in repression of transcription or degradation of target mRNAs. It has been demonstrated previously that the abnormal expression of miRNAs is involved in the carcinogenesis and progression of cervical cancer. The aim of the present study was to investigate the expression, biological functions and underlying molecular mechanisms of miR‑195 in cervical cancer. The reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to detect the expression level of miR‑195 in cervical cancer tissues and cell lines. Following transfection, an MTT assay, cell migration and invasion assays, western blot analysis and a dual‑luciferase reporter assay were performed in human cervical cancer cells. In the present study, it was identified that miR‑195 was downregulated in cervical cancer tissues and cell lines. Additionally, upregulation of miR‑195 and knockdown of hepatoma‑derived growth factor (HDGF) inhibited proliferation, migration and invasion of cervical cancer cells. Furthermore, a dual‑luciferase reporter assay identified that HDGF was a direct target gene of miR‑195. RT‑qPCR and western blot analysis demonstrated that miR‑195 mimic inhibited HDGF expression at the mRNA and protein levels, whereas miR‑195 inhibitor enhanced HDGF expression at the mRNA and protein levels. These results indicated that miR‑195 targeted HDGF to inhibit the behavior of tumors in cervical cancer. These results also suggested that miR‑195 was a potential therapeutic biomarker of cervical cancer. [ABSTRACT FROM AUTHOR]

Hepatoma-derived growth factor (HDGF) is a protein with diverse intracellular functions. Moreover, after non-conventional secretion, extracellular HDGF is able to influence different signaling pathways, leading for example to induction of processes like epithelial-mesenchymal transition (EMT) and cell migration. Intriguingly, in recent proteome studies, HDGF was also found secreted by special microvesicles called exosomes. Recently, we demonstrated the existence of two new HDGF isoforms (B and C). These isoforms are involved in different cellular processes than HDGF-A. Along this line, in the present study we discovered that full length HDGF-A clearly is located inside of exosomes, whereas the isoforms HDGF-B and HDGF-C are found exclusively on the outer surface. Furthermore, while HDGF-B and HDGF-C seem to use exosomes mediated pathway exclusively, HDGF-A was found also as unbound protein in the conditioned media. The new finding of an intra- or extra-exosomal localisation of protein splice variants opens a fascinating new perspective concerning functional diversity of HDGF isoforms. Dysregulation of HDGF expression during cancer development and tumor progression is a commonly known fact. With our new findings, unraveling the potential functional impact according to physiological versus pathophysiologically altered levels and compositions of intra- and extra-exosomal HDGF has to be addressed in future studies. [ABSTRACT FROM AUTHOR]

Hepatoma-derived growth factor (HDGF) is a heparin-binding protein possessing mitogenic activity and could be secreted from necrotic cells passively or actively, thereby functioning as a damage-associated molecular pattern (DAMP). The high expression of HDGF in non-small cell lung cancer (NSCLC) tissues is associated with unfavorable prognosis. However, the clinical significance of serum HDGF has not been elucidated in NSCLC yet. In the present study, we compared the serum levels of HDGF in 235 patients with NSCLC (141 adenocarcinoma and 94 squamous cell carcinoma cases) with those in 40 healthy subjects. Moreover, we explored the correlation between serum HDGF levels and clinicopathologic factors or the overall survival rates. We thus found that the serum HDGF levels were significantly higher in NSCLC patients than those in healthy subjects (P < 0.001). Moreover, there was no significant difference in the serum HDGF levels between adenocarcinoma and squamous cell carcinoma. Importantly, the higher serum levels of HDGF were significantly associated with bone metastasis and with lower overall survival rates. Thus, serum HDGF was identified as an independent prognostic factor indicating poor prognosis of NSCLC. Using A549 human lung adenocarcinoma cell line, we demonstrated that an autophagy inhibitor, chloroquine, could inhibit the HDGF secretion, while quercetin, an autophagy inducer derived from a traditional Chinese drug, could facilitate HDGF secretion. In conclusion, high serum levels of HDGF were significantly correlated to bone metastasis and poorer prognosis of NSCLC. We suggest that anti-HDGF therapy is potential to protect NSCLC patients with advanced stages from bone metastasis. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary arterial hypertension (PAH) is a fatal disease, and pulmonary microvascular remodeling is an important contributor to PAH development. Therefore, we hypothesized that a circulating angiogenic factor could predict disease severity and survival.Objectives: We sought to assess the relationship of serum hepatoma-derived growth factor (HDGF) with PAH disease severity and survival.Methods: Using a newly developed enzyme-linked immunosorbent assay, we evaluated circulating HDGF levels in two independent PAH cohorts and two different characterized control cohorts. Clinical and laboratory data were also used to assess the value of HDGF as a PAH prognostic biomarker.Measurements and Main Results: Serum HDGF levels were significantly elevated in two independent PAH cohorts. Importantly, serum HDGF levels were not elevated in a noncardiac chronic disease cohort. Further, patients with elevated HDGF had significantly lower exercise tolerance, worse New York Heart Association functional class, and higher levels of N-terminal pro-brain natriuretic peptide. HDGF was a strong predictor of mortality, with an unadjusted hazard ratio of 4.5 (95% confidence interval, 1.9-10.3; P = 0.003 by log-rank test). In multivariable Cox proportional hazards models, elevated HDGF levels predicted decreased survival after being adjusted for age, PAH subtype, invasive hemodynamics, and N-terminal pro-brain natriuretic peptide.Conclusions: Elevated HDGF was associated with worse functional class, exertional intolerance, and increased mortality in PAH, suggesting HDGF as a potential biomarker for predicting mortality and as having possible diagnostic value for distinguishing PAH from non-PAH. HDGF may add additional value in PAH risk stratification in clinical trials and may represent a potential target for future PAH drug development. [ABSTRACT FROM AUTHOR]

Background and objective Our previous studies revealed that hepatoma-derived growth factor (HDGF) is highly expressed in non-small cell lung cancer (NSCLC) cells, playing important roles in promoting NSCLC cells growth and invasion. The aim of this study is to detect the expression of HDGF in 158 cases of surgically resected NSCLC and evaluate its clinical significance. Methods Immunohistochemical SP method was used to detect the expression of HDGF in 158 NSCLC tissues and 12 normal control lung tissues. Survival analysis was further conducted. Results HDGF was found significantly highly expressed in 158 NSCLC tissues compared with normal control lung tissues (P < 0.001). The 5-year survival rate was 38.2% in HDGF high expression cases, compared with 63.1% in HDGF low expression cases, the difference was statistically significant (P=0.009). Linear correlation analysis discovered a significantly negative correlation between HDGF expression and the survival time (r=-0.183, P=0.022). COX proportion hazard model analysis revealed that pathological stages and HDGF expression were independent prognostic factors for this group of 158 resected NSCLC cases. Conclusion HDGF is highly expressed in human NSCLC tissues, predicting worse prognosis in resected NSCLCs. It might be useful molecular biomarker for predicting the prognosis of resected NSCLCs.

Marsdenia tenacissima (Roxb.) Wight et Arn. is a traditional Chinese herbal medicine, and its water-soluble ingredient Marsdenia tenacissima extract (MTE), was widely used for cancer treatment. The multi-pharmacological efficacies and mechanisms of MTE in directly inhibiting tumor cells have been extensively studied. However, the anti-tumor effects of MTE in the tumor-associated macrophages (TAMs) microenvironment remain unclear. To uncover the role of hepatoma-derived growth factor (HDGF) in the interaction between TAMs and non-small cell lung cancer (NSCLC) cells. To evaluate the anti-tumor effects of MTE on the vicious crosstalk between TAMs and NSCLC by targeting HDGF. HDGF-overexpression PC-9 and H292 NSCLC cell lines were constructed and verified. RNA-sequencing (RNA-seq) was performed in HDGF-overexpression PC-9 cells to probe the differential expression of genes. THP-1-derived macrophages were characterized using specific markers after stimulation with phorbol-12-myristate 13-acetate (PMA) and rhIL-4 or rhHDGF. The role of HDGF both in NSCLC cells and TAMs was determined using approaches like Western blot, qRT-PCR, ELISA, and flow cytometry. The interaction between tumor cells and TAMs were assessed by indirect co-culture H1975, PC-9 cells with M2 type macrophages. The effects of MTE on anti-tumor and macrophage polarization were evaluated in vitro and in vivo. RNA-seq results identified IL-4 as a critical response to HDGF in NSCLC. HDGF induced macrophages polarizing toward M2 type, and promoted NSCLC cells proliferation, migration and invasion in vitro. On the one hand, HDGF dose-dependently promoted IL-4 expression in NSCLC cells. On the other hand, HDGF induced M2 macrophage polarization through the IL-4/JAK1/STAT3 signaling pathway. MTE treatment significantly decreased the expression and secretion of HDGF in NSCLC cells. Meanwhile, MTE treatment led to M2 macrophage repolarization, as evidenced by decreased expression of M2 markers and increased levels of M1 markers. Importantly, MTE treatment significantly suppressed tumor development in C57BL/6 mice bearing Lewis lung cancer (LLC) cells in vivo , accompanied by decreased plasma HDGF levels, reduced M2 macrophages infiltration and increased M1 macrophages proportion in mice tumor tissues. HDGF upregulated IL-4 expression in NSCLC cells, and promoted M2 polarization by the IL-4/JAK1/STAT3 signaling pathway in macrophages. MTE disturbed the interaction between NSCLC and TAMs in vitro , and inhibited tumor growth in vivo , at least in part, by suppressing HDGF. Therefore, our present study revealed a novel anti-tumor mechanism of MTE through inhibiting HDGF expression and enhancing macrophage polarization from M2 to M1 phenotype. [Display omitted] • HDGF increased IL-4 expression in NSCLC cells. • HDGF induced the polarization of M2 macrophages. • Marsdenia tenacissima extract (MTE) inhibited HDGF expression in NSCLC cells. • MTE suppressed M2 macrophage polarization in vitro and in vivo. [ABSTRACT FROM AUTHOR]

To clarify the clinicopathological and biological role of hepatoma-derived growth factor (HDGF) and β-catenin in synovial sarcoma. Our results showed that histological type and HDGF/β-catenin expression were the two important independent prognostic factors for overall survival in synovial sarcoma patients. HDGF knockdown dramatically inhibited cellular proliferation, colony formation, and migration but induced G1 phase arrest and apoptosis in SW982 cells. Recombinant HDGF enhanced synovial sarcoma cell growth and partially retrieved the cell growth suppression in SW982 cells upon HDGF knockdown. HDGF knockdown dramatically suppressed β-catenin and its downstream gene expression in SW982 cells. Intriguingly, β-catenin knockdown dramatically suppressed HDGF expression in SW982 cells. A direct interaction of HDGF and β-catenin was found in SW982 cells. Three HDGF-binding elements in β-catenin promoter were found and specific for transcriptional activation of β-catenin in SW982 cells. In conclusion, our findings first indicate that the interaction of HDGF and β-catenin may play a crucial role in tumorigenesis of synovial sarcoma. [ABSTRACT FROM AUTHOR]

We aimed to elucidate the effects of hepatoma-derived growth factor ( HDGF) on growth and metastasis of hepatocellular carcinoma (HCC) cells. Tissue microarrays with 236 HCC specimens and 18 extrahepatic metastases were utilized to detect the HDGF expression by immunohistochemistry. Meanwhile, HDGF expressions in HCC cell lines with different metastatic potentials were examined using immunofluorescence staining, real-time PCR and western blotting. After HDGF silencing, the growth and metastatic potentials of HCC cells were evaluated by soft agar assay, invasion assay, together with tumorigenicity assay in nude mice. The gelatin zymography was performed by detecting MMP-2 and MMP-9 levels. Additionally, western blotting was conducted to determine the levels of total and phosphorylated ERK1/2, JNK, p38 and Akt. The results showed that HDGF was overexpressed in HCC metastasis tumour, and the expression increased with the differentiation degree of tumours (Grade I 44.0%, Grade II 48.4% and Grade III 65.6%). Consistently, HDGF levels were positively associated with the metastatic capability of HCC cells (MHCC97L < MHCC97H < HCCLM3). The growth and metastasis were suppressed by HDGF-siRNA. Gelatinolytic activities were enhanced in the three metastatic HCC cell lines, but had no significant difference among them. The tumourigenicity and metastatic capability of HCCLM3 cells in nude mice were inhibited after silencing HDGF. Meanwhile, HDGF-siRNA specifically suppressed the total and phosphorylated protein levels of ERK1/2, while not JNK, p38 and Akt. In conclusion, HDGF was overexpressed in HCC patients and cells, and HDGF might be closely correlated with HCC metastasis via regulating ERK signalling pathway. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Hepatoma-derived growth factor (HDGF) is involved in diverse, apparently unrelated processes, such as cell proliferation, apoptosis, DNA-repair, transcriptional control, ribosome biogenesis and cell migration. Most of the interactions of HDGF with diverse molecules has been assigned to the hath region of HDGF. In this study we describe two previously unknown HDGF isoforms, HDGF-B and HDGF-C, generated via alternative splicing with structurally unrelated N-terminal regions of their hath region, which is clearly different from the well described isoform, HDGF-A. In silico modeling revealed striking differences near the PHWP motif, an essential part of the binding site for glycosaminoglycans and DNA/RNA. This observation prompted the hypothesis that these isoforms would have distinct interaction patterns with correspondingly diverse roles on cellular processes. Indeed, we discovered specific associations of HDGF-B and HDGF-C with cytoskeleton elements, such as tubulin and dynein, suggesting previously unknown functions of HDGF in retrograde transport, site directed localization and/or cytoskeleton organization. In contrast, the main isoform HDGF-A does not interact directly with the cytoskeleton, but via RNA with messenger ribonucleoprotein (mRNP) complexes. In summary, the discovery of HDGF splice variants with their discrete binding activities and subcellular distributions opened new avenues for understanding its biological function and importance. [ABSTRACT FROM AUTHOR]

MicroRNA-497 (miR-497) has been reported to be downregulated in certain types of cancer, including breast, gastric, endometrial, colorectal and prostate cancer as well as hepatocellular and nasopharyngeal carcinoma. The present study aimed to investigate the underlying mechanism of the tumor suppressor function of miR-497 in prostate cancer. Following transfection with miR-497, the DU145 and PC-3 prostate cancer cell lines were subjected to Transwell migration and invasion assays, western blot analysis and a luciferase assay. It was revealed that miRNA-497 inhibited the migration and invasion of prostate cancer cells. In addition, is was indicated that miRNA-497 directly targets hepatoma-derived growth factor (HDGF) in prostate cancer cells. These results suggested that restoration of miR-497 and the resulting downregulation of HDFG may represent a promising therapeutic strategy for prostate cancer. [ABSTRACT FROM AUTHOR]

Hepatoma-derived growth factor (HDGF) has been reported to be a potential predictive and prognostic marker for several types of cancer and important in malignant biological behaviors. However, its role in human hilar cholangiocarcinoma remains to be elucidated. Our previous study demonstrated that high expression levels of HDGF in hilar cholangiocarcinoma tissues correlates with tumor progression and patient outcome. The present study aimed to elucidate the detailed functions of the HDGF protein. This was performed by downregulating the protein expression of HDGF in the FRH0201 hilar cholangiocarcinoma cell line by RNA interference (RNAi) in vitro, and revealed that downregulation of the HDGF protein significantly inhibited the malignant biological behavior of the FRH0201 cells. In addition, further investigation revealed that downregulation of the protein expression of HDGF significantly decreased the secretion of vascular endothelial growth factor, which may be the mechanism partially responsible for the inhibition of malignant biological behaviors. These findings demonstrated that HDGF is important in promoting malignant biological behaviors, including proliferation, migration and invasion of hilar cholangiocarcinoma FRH0201 cells. Inhibition of the expression of HDGF downregulated the malignant biological behaviors, suggesting that downregulation of the protein expression of HDGF by RNAi may be a novel therapeutic approach to inhibit the progression of hilar cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Aim: To investigate the expression of hepatoma-derived growth factor (HDGF) in osteosarcoma (OS) and the correlation with clinicopathologic factors, prognosis, and tumor progression. Method: HDGF expression in OS tissues was detected by immunohistochemistry. The correlation between HDGF and clinicopathologic factors was analyzed by chi-square test, and the association between HDGF expression and the overall survival rates was evaluated by univariate analysis using Kaplan-Meier method. HDGF concentration in cell medium or cell lysates was detected by enzyme-linked immunosorbent assay method. The effect of extrinsic and intrinsic HDGF on OS cell proliferation was detected by MTT assay after recombinant HDGF stimulation or HDGF knockdown, respectively. Results: Proportion of HDGF high expression was 18.69% (20/107) in OS. HDGF high expression was significantly associated with larger tumor size (P=0.004). With experiments in vitro, we demonstrated that human recombinant HDGF could activate AKT and MAPK signaling pathway, resulting in OS cell proliferation. By knocking down HDGF expression, we proved that intrinsic HDGF was required in OS proliferation. Conclusion: High HDGF expression was significantly associated with larger OS tumor size and could promote OS cell proliferation, indicating that HDGF could be an effective biomarker and a potential drug target in OS treatment. [ABSTRACT FROM AUTHOR]

Recent evidence suggested that nonirradiated cancer-associated fibroblasts (CAFs) promoted aggressive phenotypes of cancer cells through epithelial–mesenchymal transition (EMT). Hepatoma-derived growth factor (HDGF) is a radiosensitive gene of esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the effect of irradiated fibroblasts on EMT and HDGF expression of ESCC. Our study demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of ESCC cells and the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. Scattering of ESCC cells was also accelerated by the supernatant from irradiated fibroblasts. Exposure of ESCC cells to supernatant from irradiated fibroblasts resulted in decreased E-cadherin, increased vimentin in vitro and β-catenin was demonstrated to localize to the nucleus in tumor cells with irradiated fibroblasts in vivo models. The expression of HDGF and β-catenin were increased in both fibroblasts and ESCC cells of irradiated group in vitro and in vivo models. Interestingly, the tumor cells adjoining the stromal fibroblasts displayed strong nuclear HDGF immunoreactivity, which suggested the occurrence of a paracrine effect of fibroblasts on HDGF expression. These data suggested that irradiated fibroblasts promoted invasion, growth, EMT and HDGF expression of ESCC. [ABSTRACT FROM AUTHOR]

Background and aims It is suggested that regulatory immune cells play a critical role in cancer cell growth by facilitating cancer cells to escape from the immune surveillance. The generation of the immune regulatory cells in cancer has not been fully understood yet. This study aims to investigate the role of the hepatoma-derived growth factor (HDGF) in the generation of regulatory T cells (Treg). Methods CCL-9.1 cells (A mouse hepatoma cell line), were cultured. The expression of HDGF in CCL-9.1 cells was assessed by quantitative RT-PCR and Western blotting. The generation of Foxp3 + T cells was assessed by cell culture and flow cytometry. The immune suppressor function of the Foxp3 + T cells on CD8 + T cell activities was assessed by the carboxyfluorescein succinimidyl ester (CFSE)-dilution assay and enzyme-linked immunosorbent assay. Results The results showed that exposure to PolyIC markedly increased the expression of HDGF in CCL-9.1 cells. Coculture of CCL-9.1 cells and CD4 + CD25 − T cells in the presence of PolyIC generated the Forkhead box protein (Foxp)3 + T cells. The exposure to HDGF increased the expression of Foxp3 and decreased the expression of GATA3 in CD4 + T cells. After activation, the Foxp3 + T cells suppressed the CD8 + T cell proliferation and the release of the cytotoxic cytokines. Conclusions Liver cancer cell-derived HDGF can induce Foxp3 + T cells; the latter has the immune suppressor functions on CD8 + T cell activities. [ABSTRACT FROM AUTHOR]

Hepatoma-derived growth factor (HDGF) is an acidic heparin-binding protein involved in tumor progression and poor prognosis of kinds of cancers. Aimed at investigating the functions of HDGF in intrahepatic cholangiocarcinoma (IHCC), we detected the expression of HDGF by immunohistochemistry in 83 patients. Associations of HDGF with clinicopathologic features, microvascular density (MVD), and overall survival rates were further analyzed by Chi-square method, univariate or multivariate analysis. HDGF functions in IHCC proliferation, invasion, and angiogenesis were detected by MTT, transwell, and tube formation assays, respectively. As a result, we found that HDGF-positive expression rate in IHCC was 51.8 % (43/83) in IHCC. HDGF expression was significantly correlated to MVD ( P = 0.031), lymphatic invasion ( P = 0.030), distant metastasis ( P = 0.002), and TNM stage ( P = 0.037). HDGF was further identified as an independent prognostic factor in IHCC with Kaplan-Meier method ( P = 0.003) and Cox-regression model ( P = 0.008). Moreover, both intracellular and extracellular HDGF were proved to promote the proliferation, invasion, and angiogenesis of IHCC cell lines. In conclusion, HDGF was identified as an independent prognostic biomarker in IHCC. HDGF can promote IHCC cells progression, including proliferation, invasion, and angiogenesis, indicating HDGF could become a new promising and potential drug target of IHCC. [ABSTRACT FROM AUTHOR]

HDGF is an important regulator of a broad range of cancer cell activities and plays important roles in cancer cell transformation, apoptosis, angiogenesis and metastasis. Such a divergent influence of HDGF on cancer cell activities derives from its multiple inter- and sub-cellular localizations where it interacts with a range of different binding partners. Interestingly, high levels of HDGF could be detected in patients' serum of some cancers. This review is focused on the role of HDGF in tumorigenesis and metastasis, and provides insight for application in clinical cancer therapy as well as its clinical implications as a prognostic marker in cancer progression. [ABSTRACT FROM AUTHOR]

Electrostatic interaction is a major driving force in the binding of proteins to highly acidic glycosaminoglycan, such as heparin. Although NMR backbone chemical shifts have generally been used to identify the heparin-binding site on a protein, however, there is no correlation between the binding free energies and the perturbed backbone chemical shifts for individual residues. The binding event occurs at the end of a side chain of basic residue, and does not require causing significant alterations in the backbone environment at a distance of multiple bonds. We used the H 2 CN NMR pulse sequence to detect heparin binding through the side-chain resonances Hε–Cε–Nζ of Lys and Hδ–Cδ–Nε of Arg in the two proteins of hepatoma-derived growth factor (HDGF) and basic fibroblast growth factor (FGF2). H 2 CN titration experiments revealed chemical shift perturbations in the side chains, which were correlated with the free energy changes in various mutants. The residues K19 in HDGF and K125 in FGF2 demonstrated the most significant perturbations, consistent with our previous observation that the two residues are crucial for binding. The result suggests that H 2 CN NMR provides a precise evaluation for the electrostatic interactions. The discrepancy observed between backbone and side chain chemical shifts is correlated to the solvent accessibility of residues that the K19 and K125 backbones are highly buried with the restricted backbone conformation and are not strongly affected by the events at the end of the side chains. [ABSTRACT FROM AUTHOR]

Hepatoma-derived growth factor (HDGF) has been verified to serve as a credible prognostic marker for several types of cancers, but its role in urologic carcinomas remains undetermined. In this study, we analyzed the significance of HDGF, as well as its relative factors such as vascular endothelial growth factor-A (VEGF-A) and Ki-67, in penile squamous cell carcinoma (PSCC). Formalin-fixed paraffin-embedded PSCC samples from 54 patients receiving surgery at Qilu Hospital of Shandong University were included in the retrospective study. The expressions of HDGF, VEGF-A, and Ki-67 were detected by immunohistochemistry of a non-biotin polymerized horseradish peroxidase method. The relationships between the expressions of HDGF and VEGF-A, Ki-67 were assessed. Moreover, their correlations with clinical pathologic characteristics and disease prognosis were, respectively, evaluated. HDGF, VEGF-A, and Ki-67 were positively expressed in 28 (51.9 %), 29 (53.7 %), and 26 (48.1 %) patients, respectively. The expressions of VEGF-A and Ki-67 were closely correlated with PSCC type ( P < 0.05). A statistically significant relationship between the expressions of HDGF and VEGF-A in PSCC was observed ( P = 0.03). Patients with symptom interval of more than 6 months had a significantly poorer survival rate than those with symptom interval less than 6 months (43.3 vs. 70.8 %, P = 0.043). Patients with positive HDGF expression also showed a significantly poorer survival rate than those with negative HDGF expression (39.3 vs. 73.1 %, P = 0.013). Logistic regression demonstrated that the expression level of HDGF was an independent predictor for the prognosis of postoperative patients. The expression of HDGF significantly correlated with VEGF-A, but not Ki-67 expression. Overexpression of HDGF, rather than VEGF-A or Ki-67, was confirmed to be an independent prognosticator of poor outcome for PSCC patients. [ABSTRACT FROM AUTHOR]

We sought to investigate the clinicopathological significance and biological function of hepatoma-derived growth factor ( HDGF) in Ewing's sarcoma. Our results showed that HDGF expression is up-regulated in Ewing's sarcoma. Nuclear HDGF expression is significantly associated with tumour volume ( p < 0.001), metastases at diagnosis ( p < 0.001), low overall survival rate ( p < 0.001) and low disease-free survival rate ( p < 0.001). HDGF knock-down results in significant reduction of Ewing's sarcoma cell growth, proliferation and enhances tumourigenesis, both in vitro and in vivo. Meanwhile, HDGF knock-down causes cell cycle arrest and enhanced sensitization to serum starvation-induced apoptosis. Furthermore, recombinant HDGF promotes proliferation and colony formation of Ewing's sarcoma cells. Ninety-eight candidate HDGF downstream genes were identified in Ewing's sarcoma cells using cDNA microarray analysis. In addition, we found that HDGF knock-down inhibited FLI1 expression in Ewing's sarcoma cells at the mRNA and protein levels. Our findings suggest that HDGF exhibits oncogenic properties and may be a novel prognostic factor in Ewing's sarcoma. Targeting HDGF might be a potential therapeutic strategy for Ewing's sarcoma. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Hepatoma-derived growth factor (HDGF), a heparin-binding growth factor, has a wide range of biological functions, including mitogenic activity and vascular development. Recent studies demonstrated that HDGF also acted as an oncogene with aberrantly increased activity in multiple human cancers; however, little is known about the biological function of HDGF in gallbladder cancer (GBC). In this study, we focused on the clinical significance and biological functions of HDGF in GBC and found that Nuclear HDGF protein overexpression was frequently detected in GBC tissues. Patients with nuclear HDGF-positive tumors had worse overall survival than patients with HDGF-negative tumors. Furthermore, treatment of GBC lines with HDGF-targeting siRNA oligonucleotides (HDGF-siRNA) significantly reduced the proliferation of GBC-SD and SGC-996 cell lines and diminished both anchorage-independent growth on soft agar and cell migration. These data indicate that HDGF acts as a putative oncogene in GBC and could be a novel diagnostic and therapeutic target for GBC. [ABSTRACT FROM AUTHOR]

Background: Hepatoma-derived growth factor (HDGF) is reported to play an important role in tumorigenesis and cancer progression. However, growing evidence indicates its participation in immune system activation. This study analyzed the relationship among serum HDGF levels, disease activity, and laboratory markers in patients with rheumatoid arthritis (RA)., Methods: Blood samples from 165 patients with RA, 42 with osteoarthritis (OA), and 28 healthy controls, were used to evaluate the serum HDGF levels. Correlations of serum HDGF levels with age, 28-joint count disease activity score (DAS28), and laboratory findings were assessed by Pearson correlation and receiver operator characteristic (ROC) curve analyses to obtain HDGF optimal cutoffs according to the disease status. Immunohistochemical staining was performed on the knee synovial tissue samples from patients with RA and OA (n = 10 each) to investigate HDGF joint expression., Results: Serum HDGF levels were significantly correlated with DAS28 erythrocyte sedimentation rate (r = 0.412, p < 0.001) and C-reactive protein values (r = 0.376, p < 0.001). The optimal cutoffs of serum HDGF levels from the ROC analysis were 5.79 and 5.14 for the differentiation of active/inactive disease and remission/non-remission, respectively. The ideal cutoff of serum HDGF levels to differentiate RA and OA was determined as 5.47. Serial serum HDGF level analyses in 21 patients with RA revealed that serum HDGF levels significantly decreased after improvement in disease activity (p = 0.046). HDGF expression was not observed in the synovial tissues of the patients with RA and OA., Conclusion: Serum HDGF level could be a potential laboratory biomarker for the severity of RA., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)