Secretion of hepatoma-derived growth factor is regulated by N-terminal processing

Thakar, Ketan; Kröcher, Tim; Savant, Soniya; Gollnast, Doron; Kelm, Sørge; Dietz, Frank

doi:10.1515/bc.2010.147

Cited by 16 publications

(19 citation statements)

References 41 publications

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“…It is also involved in lung remodeling by stimulating bronchial and alveolar epithelial cell growth (18). HDGF requires nuclear translocation for mitogenic activity (19,20), but it also functions in a poorly understood paracrine manner when secreted into culture media (21,22). As pulmonary vascular remodeling is one of the signature events in PAH pathogenesis (23), HDGF could be involved in these dynamic changes in the pulmonary microvasculature.…”

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confidence: 99%

Hepatoma-derived Growth Factor Predicts Disease Severity and Survival in Pulmonary Arterial Hypertension

Yang¹,

Nies²,

et al. 2016

Am J Respir Crit Care Med

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ORCID IDs: 0000-0001-9273-4578 (J.Y.); 0000-0001-5453-425X (M.K.N.). AbstractRationale: 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.

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confidence: 99%

Hepatoma-derived Growth Factor Predicts Disease Severity and Survival in Pulmonary Arterial Hypertension

Yang¹,

Nies²,

et al. 2016

Am J Respir Crit Care Med

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“…The data shown in Fig. 5 confirm that both the HRP‐2 isoform c and the isoform a Δhelix mutant interact selectively with the lower molecular form of HDGF wt , as well as with the Δ15NHDGF mutant or the S165A mutant which is truncated at the N‐terminus [24]. By contrast, with HRP‐2 isoform a and isoform b almost no detectable HDGF wt was coprecipitated, although these HRP‐2 isoforms interact with both HDGF mutants (S165A and Δ15N).…”

Section: Resultsmentioning

confidence: 73%

“…In a recent study [24], we demonstrated that mutation of a serine at position 165 of HDGF results in its proteolytic cleavage at the N‐terminus, leading to a faster electrophoretic running behaviour, similar to the lower molecular mass band coprecipitating with HRP‐2 isoform c .…”

Section: Resultsmentioning

confidence: 90%

“…By contrast, with HRP‐2 isoform a and isoform b almost no detectable HDGF wt was coprecipitated, although these HRP‐2 isoforms interact with both HDGF mutants (S165A and Δ15N). It appears that only HRP‐2 isoform c and HRP‐2 isoform a Δhelix coprecipitate truncated HDGF, namely the S165A and Δ15N mutants, efficiently enough to enrich the small amounts of a lower molecular mass form present in HDGF wt , which indeed may represent the N‐terminally processed form of HDGF wt possibly due to being not phosphorylated at position S165 [24].…”

Section: Resultsmentioning

confidence: 99%

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Interaction of HRP‐2 isoforms with HDGF. Chromatin binding of a specific heteromer

et al. 2012

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Hepatoma-derived growth-factor-related protein 2 (HRP-2) belongs to a family with five additional members: hepatoma-derived growth factor (HDGF); lens epithelium-derived growth factor; and the HDGF-related proteins -1, -3 and -4. Very little is known regarding the function of HRP-2 in particular. This study shows for the first time heteromer formation of different members of the HRP family; HDGF and HRP-2. In addition, we discovered a previously unknown splice variant of HRP-2 mRNA encoding for a protein with a 53-amino acid deletion in its hath region. This HRP-2 isoform c interacts preferentially with a processed form of HDGF probably because of the loss of an a helix of HRP-2. Furthermore, in contrast to other isoforms of HRP-2, isoform c binds to chromatin similar to its most closely related family member lens epithelium-derived growth factor with potential consequences regarding its function in HIV integration. Interestingly, only the new HRP-2 isoform c and a processed form of HDGF are displaced from condensed mitotic metaphase chromatin. In conclusion, these observations provide a new perspective for understanding the biological functions of HDGF and related proteins.

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“…HDGF lacks a classical signal peptide and the secretion mechanism of HDGF is still not well known. Thakar et al (2010) have demonstrated that the secretion of HDGF is regulated by its N-terminal processing. Autophagy, also called secretory autophagy, was demonstrated to be essential in some kinds of unconventional secretion (Ponpuak et al 2015).…”

Section: Discussionmentioning

confidence: 99%

High Serum HDGF Levels Are Predictive of Bone Metastasis and Unfavorable Prognosis in Non-Small Cell Lung Cancer

Zhang

Liu

Chen

et al. 2017

Tohoku J. Exp. Med.

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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.

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Secretion of hepatoma-derived growth factor is regulated by N-terminal processing

Cited by 16 publications

References 41 publications

Hepatoma-derived Growth Factor Predicts Disease Severity and Survival in Pulmonary Arterial Hypertension

Hepatoma-derived Growth Factor Predicts Disease Severity and Survival in Pulmonary Arterial Hypertension

Interaction of HRP‐2 isoforms with HDGF. Chromatin binding of a specific heteromer

High Serum HDGF Levels Are Predictive of Bone Metastasis and Unfavorable Prognosis in Non-Small Cell Lung Cancer

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