Complement C1q stimulates the progression of hepatocellular tumor through the activation of discoidin domain receptor 1

Lee, Ji‐Hyun; Poudel, Barun; Ki, Hyeon-Hui; Nepali, Sarmila; Lee, Young-Mi; Shin, Jeon Soo; Kim, Dae‐Ki

doi:10.1038/s41598-018-23240-6

Cited by 31 publications

(33 citation statements)

References 46 publications

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“…Additionally, widespread complement activation with deposition of iC3b, C3d, C4d, and C5b‐9 around steatotic hepatocytes is associated with increased numbers of invading neutrophils, proinflammatory cytokine expression, and disease severity . C1q has been associated with HCC development through activation of the collagen receptor discoidin domain receptor 1 . Thus, NASH and related HCC could be decreased by inhibition of a constantly activated complement system, for instance, by targeting the alternative pathway …”

Section: Liver Injurymentioning

confidence: 99%

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The Role of Complement in Liver Injury, Regeneration, and Transplantation

et al. 2019

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The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal part of liver homeostasis, immune responses, and crosstalk with other effector systems in both innate and adaptive immunity. The liver produces the majority of the complement proteins and is the home of important immune cells such as Kupffer cells. Liver immune responses are delicately tuned between tolerance to many antigens flowing in from the alimentary tract, a tolerance that likely makes the liver less prone to rejection than other solid organ transplants, and reaction to local injury, systemic inflammation, and regeneration. Notably, complement is a double‐edged sword as activation is detrimental by inducing inflammatory tissue damage in, for example, ischemia–reperfusion injury and transplant rejection yet is beneficial for liver tissue regeneration. Therapeutic complement inhibition is rapidly developing for routine clinical treatment of several diseases. In the liver, targeted inhibition of damaged tissue may be a rational and promising approach to avoid further tissue destruction and simultaneously preserve beneficial effects of complement in areas of proliferation. Here, we argue that complement is a key system to manipulate in the liver in several clinical settings, including liver injury and regeneration after major surgery and preservation of the organ during transplantation.

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Section: Liver Injurymentioning

confidence: 99%

“…(27) C1q has been associated with HCC development through activation of the collagen receptor discoidin domain receptor 1. (28) Thus, NASH and related HCC could be decreased by inhibition of a constantly activated complement system, for instance, by targeting the alternative pathway. (29)…”

Section: Emerging Challenges In Liver Injury: Nashmentioning

confidence: 99%

The Role of Complement in Liver Injury, Regeneration, and Transplantation

et al. 2019

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“…The antibody was generated by immunization of C1q −/− C57BL/6 mice with purified mouse C1q. The antibody has been previously shown to recognize C1q with a high degree of specificity in a myriad of different tissues and cell types by immunoblotting, immunohistochemistry, and immunofluorescence procedures [27][28][29][30]. The C1q antibody detects a band migrating at~26 kDa in immunoblots.…”

Section: Histology and Immunoreagentsmentioning

confidence: 99%

Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex

Datta

Leslie

Morozov

et al. 2020

J Neuroinflammation

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Background: Cognitive impairment in schizophrenia, aging, and Alzheimer's disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q. Methods: Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC. Results: C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM. Conclusions: These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.

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“…( 33 ) C1Q binds DDR1 directly, and activation of this signaling pathway might be involved in the progression of HCC. ( 34 ) CAT has an important function in the development and progression of HCC. ( 35 ) CETP is a significant determinant of lipoprotein function, and regulates plasma high‐density lipoprotein (HDL) levels.…”

Section: Discussionmentioning

confidence: 99%

Proteome Multimarker Panel With Multiple Reaction Monitoring–Mass Spectrometry for Early Detection of Hepatocellular Carcinoma

Yeo

Kim²,

Kim

et al. 2020

Hepatol Commun

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There is an urgent need for new biomarkers that address the shortcomings of current screening methods which fail to detect a large proportion of cases with hepatocellular carcinoma (HCC) at early stage. To develop a robust, multiple‐biomarker panel based on multiple reaction monitoring–mass spectrometry with high performance in detecting early‐stage HCC within at‐risk populations. In the discovery set, 150 samples were analyzed to identify candidate biomarkers. The resulting list of candidates was tested in the training set (713 samples) to establish a multimarker panel, which was evaluated in the validation set (305 samples). We identified 385 serum HCC biomarker candidates in the discovery set and developed a multimarker panel consisting of 28 peptides that best differentiated HCC from controls. The area under the receiver operating characteristic curve of multimarker panel was significantly higher than alpha‐fetoprotein (AFP) in the training (0.976 vs. 0.804; P < 0.001) and validation (0.898 vs. 0.778; P < 0.001) sets. In the validation set, this multimarker panel, compared with AFP, showed significantly greater sensitivity (81.1% vs. 26.8%; P < 0.001) and lower specificity (84.8% vs. 98.8%; P < 0.001) in detecting HCC cases. Combining AFP with the multimarker panel did not significantly improve the area under the receiver operating characteristic curve compared with the panel alone in the training (0.981 vs. 0.976; P = 0.37) and validation set (0.906 vs. 0.898; P = 0.75). Conclusion: The multiple reaction monitoring–mass spectrometry multimarker panel consisting of 28 peptides discriminates HCC cases from at‐risk controls with high performance and may have potential for clinical application in HCC surveillance.

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Complement C1q stimulates the progression of hepatocellular tumor through the activation of discoidin domain receptor 1

Cited by 31 publications

References 46 publications

The Role of Complement in Liver Injury, Regeneration, and Transplantation

The Role of Complement in Liver Injury, Regeneration, and Transplantation

Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex

Proteome Multimarker Panel With Multiple Reaction Monitoring–Mass Spectrometry for Early Detection of Hepatocellular Carcinoma

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