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Aim: To investigate the long non‐coding RNA DLG1 Antisense RNA 1 (lncRNA DLG1‐AS1) mechanism in cervical cancer cells with gemcitabine (GEM) resistance. Methods: Quantitative real‐time polymerase chain reaction (qRT‐PCR) was used to detect DLG1‐AS1, miR‐16‐5p, and hepatoma‐derived growth factor (HDGF) expression in cervical cancer cells. The effects of DLG1‐AS1 knockdown on cell viability, proliferation, and apoptosis were investigated in GEM‐resistant cervical cancer cells. The binding of DLG1‐AS1 with miR‐16‐5p and of miR‐16‐5p with HDGF was confirmed through dual‐luciferase reporter assays. HDGF expression was detected through Western blotting. A xenograft model was established using stably transfected GEM‐resistant cervical cancer cells to detect the role of DLG1‐AS1 in tumorigenesis in vivo. Results: DLG1‐AS1 expression was significantly elevated in HeLa/GEM and SiHa/GEM cells. DLG1‐AS1 silencing significantly reduced the viability and proliferation of GEM‐resistant cervical cancer cells. DLG1‐AS1 also promoted GEM sensitivity in cervical cancer cells by inhibiting miR‐16‐5p. Moreover, the tumor volume in nude mice in the DLG1‐AS1 knockdown group decreased after GEM treatment. In addition, DLG1‐AS1 targeted miR‐16‐5p, and miR‐16‐5p targeted HDGF. The miR‐16‐5p inhibitor reversed the DLG1‐AS1 knockdown effect in GEM‐resistant cervical cancer cells. Conclusion: Knockdown of DLG1‐AS1 promoted GEM sensitivity in cervical cancer cells by regulating miR‐16‐5p/HDGF. [ABSTRACT FROM AUTHOR]

Hepatoma‐derived growth factor (HDGF) was previously shown to be associated with increased mortality in a small study of idiopathic and connective tissue disease‐associated pulmonary arterial hypertension (PAH). In this study, we measured serum HDGF levels in a large multicenter cohort (total 2017 adult PAH‐Biobank enrollees), we analyzed the associations between HDGF levels and various clinical measures using linear or logistic regression models. Higher HDGF levels were found to be significantly associated with worse pulmonary hemodynamics, prostacyclin treatment; among PAH subtypes, higher HDGF levels were most associated with portopulmonary hypertension (beta = 0.469, p < 0.0001). Both Kaplan–Meier curve and Cox proportional hazard regression demonstrated that higher HDGF levels are associated with a higher risk of mortality (COX hazard ratio 1.31, p < 0.0001). Further, in the Sugen hypoxia (SuHx) rat model, the highest HDGF levels were post‐pulmonary circulation, and HDGF levels significantly increased with the development of PAH. In pulmonary arteries, immunohistochemistry staining showed that HDGF was highly expressed in pulmonary smooth muscle cells in both PAH patients and SuHx rats. In conclusion, we found that higher serum HDGF was linked with increased mortality, and associated with disease severity in a large multi‐center adult PAH cohort (n = 2017). In the SuHX PAH models, circulating HDGF levels are pulmonary in origin and increase with PAH progression. HDGF may be actively involved in vascular remodeling in PAH. [ABSTRACT FROM AUTHOR]

Although identified as a growth factor, the mechanism by which hepatoma‐derived growth factor (HDGF) promotes cancer development remains unclear. We found that nuclear but not cytoplasmic HDGF is closely associated with prognosis of hepatocellular carcinoma (HCC). RNA‐sequencing analysis further demonstrated that the nuclear role of HDGF involved regulation of transcription of lipid metabolism genes. HDGF‐induced expression of lipogenic genes was mainly associated with activation of sterol regulatory element binding protein (SREBP) transcription factor. Coexpression of SREBP‐1 and nuclear HDGF predicts poor prognosis for HCC. In addition, by changing the first amino acid of the PWWP domain from proline to alanine, the type of PWWP domain changed from P‐ to A‐type, resulting in inability to induce SREBP‐1‐mediated gene transcription. The type of PWWP domain affects the recruitment of the C‐terminal binding protein‐1 transcriptional repressor on the promoter of the lipogenic gene. Our data indicate that HDGF acts as a coactivator of SREBP1‐mediated transcription of lipogenic genes. The PWWP domain is crucial for HDGF to promote lipogenesis. Moreover, transcriptional regulation of nuclear HDGF plays important roles in the development of HCC. [ABSTRACT FROM AUTHOR]

Highlights: [•] miR-16 is down-regulated in NSCLC cells and tissues. [•] miR-16 inhibits NSCLC cell growth in vitro. [•] miR-16 suppresses NSCLC cell migration and invasion. [•] HDGF is a direct target of miR-16. [•] miR-16 inhibits NSCLC cell growth and motility by targeting HDGF. [ABSTRACT FROM AUTHOR]

Hepatoma Derived Growth Factor (HDGF) is an endogenous nuclear-targeted mitogen that is linked with human disease. HDGF is a member of the weakly conserved PWWP domain family. This 70-amino acid motif, originally identified from the WHSC1 gene, has been found in more than 60 eukaryotic proteins. In addition to the PWWP domain, many proteins in this class contain known chromatin remodeling domains, suggesting a role for HDGF in chromatin remodeling. We have determined the NMR structure of the HDGF PWWP domain to high resolution using a combination of NOEs, J-couplings, and dipolar couplings. Comparison of this structure to a previously determined structure of the HDGF PWWP domain shows a significant difference in the C-terminal region. Comparison to structures of other PWWP domains shows a high degree of similarity to the PWWP domain structures from Dnmt3b and mHRP. The results of selected and amplified binding assay and NMR titrations with DNA suggest that the HDGF PWWP domain may function as a nonspecific DNA-binding domain. Based on the NMR titrations, we propose a model of the interaction of the PWWP domain with DNA. [ABSTRACT FROM AUTHOR]

Among the many PWWP-containing proteins, the largest group of homologous proteins is related to hepatoma-derived growth factor (HDGF). Within a well-conserved region at the extreme N-terminus, HDGF and five HDGF-related proteins (HRPs) always have a PWWP domain, which is a module found in many chromatin-associated proteins. In this study, we determined the solution structure of the PWWP domain of HDGF-related protein-3 (HRP-3) by NMR spectroscopy. The structure consists of a five-stranded β-barrel with a PWWP-specific long loop connecting β2 and β3 (PR-loop), followed by a helical region including two α-helices. Its structure was found to have a characteristic solvent-exposed hydrophobic cavity, which is composed of an abundance of aromatic residues in the β1/β2 loop (β-β arch) and the β3/β4 loop. A similar ligand binding cavity occurs at the corresponding position in the Tudor, chromo, and MBT domains, which have structural and probable evolutionary relationships with PWWP domains. These findings suggest that the PWWP domains of the HDGF family bind to some component of chromatin via the cavity. [ABSTRACT FROM AUTHOR]