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SAG-UPS attenuates proapoptotic SARM and Noxa to confer survival advantage to early hepatocellular carcinoma

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ABSTRACT

Hepatocellular carcinoma (HCC) is a deadly cancer because of its commonly late diagnosis and limited treatment options. SAG (sensitive to apoptosis gene)-dependent UPS (ubiquitin–proteasome system) is a key switch between immune-mediated apoptosis and overactivation-mediated protumorigenesis, prompting us to hypothesize that SAG-UPS modulates chronic inflammation-induced tumorigenesis. Here, we investigated the molecular mechanism by which SAG-UPS regulates death/survival of liver cancer cells. By retrospective studies, we found reciprocal expressions of anti-/proapoptotic factors: SAG/SARM and SAG/Noxa in human primary HCC tissues – the antiapoptotic SAG was significantly upregulated whereas the proapoptotic SARM and Noxa were markedly downregulated, suggesting their involvement in hepatocarcinogenesis. Upregulated SAG-UPS effectively manipulates the levels of high-molecular-weight ubiquitinated SARM and Noxa in carcinoma tissues compared with corresponding normal tissues. SAG-overexpressing HCC cell lines display reduced SARM and Noxa (but not Bcl-2, Bax and Bcl-xL), suggesting that SARM and Noxa are specific substrates of SAG-dependent ubiquitination. SARM overexpression activated caspase-3 and caspase-9, reducing cell viability. SAG knockdown significantly elevated apoptosis with increased cytosolic cytochrome c, confirming SAG-mediated antiapoptosis in HCC. SAG overexpression stimulated protumorigenic cytokines, IL-1β, IL-6 and TNF, but not antitumorigenic IL-12p40 and anti-inflammatory IL-10. This is consistent with higher proinflammatory cytokines (IL-1β, IL-6 and TNF) in hepatoma compared with healthy tissues. Altogether, early stage-upregulated SAG-UPS exacerbates hepatocarcinogenesis progression, through: (1) ubiquitination-mediated degradation of proapoptotic SARM and Noxa; and (2) production of protumorigenic cytokines that induce a protumorigenic microenvironment, conferring survival advantage to HCC cells. Thus, we propose SAG-UPS to be an early diagnostic marker for HCC, and a potential target for therapeutics development.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of SAG-dependent UPS linking chronic inflammation and liver cancer. Left and right sections represent healthy condition and hepatocarcinogenesis, respectively. Chronic infection by hepatitis viruses (HBV and HCV) is a major risk factor for the initiation and development of HCC. During infection, upregulated SAG-UPS via intracrine signaling attenuates proapoptotic Noxa and SARM by ubiquitination, leading to imbalanced anti-/proapoptotic factors. On the other hand, activation of SAG promotes protumorigenic IL-1β, TNF and IL-6 via paracrine signaling, thus exacerbating the tumor microenvironment. In summary, we hypothesize that SAG-dependent UPS is a key player in inflammation-associated carcinogenesis by manipulating the balance between pro-/antitumorigenic cytokines.
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fig6: Schematic representation of SAG-dependent UPS linking chronic inflammation and liver cancer. Left and right sections represent healthy condition and hepatocarcinogenesis, respectively. Chronic infection by hepatitis viruses (HBV and HCV) is a major risk factor for the initiation and development of HCC. During infection, upregulated SAG-UPS via intracrine signaling attenuates proapoptotic Noxa and SARM by ubiquitination, leading to imbalanced anti-/proapoptotic factors. On the other hand, activation of SAG promotes protumorigenic IL-1β, TNF and IL-6 via paracrine signaling, thus exacerbating the tumor microenvironment. In summary, we hypothesize that SAG-dependent UPS is a key player in inflammation-associated carcinogenesis by manipulating the balance between pro-/antitumorigenic cytokines.

Mentions: Chronic inflammation is now accepted as critical in fibrosis, cirrhosis and hepatocarcinogenesis.10 Although hepatic inflammation caused by long-term infection with hepatitis virus is implicated, the key components linking inflammation and liver cancer are only beginning to be unmasked. Chronic inflammation is characterized by continuously expressed cytokines and recruitment of immune cells to the liver. In consideration of our earlier study in macrophages,11 we postulate that overactivated SAG-UPS triggered by a protumorigenic microenvironment could be a key orchestrator of inflammation-associated carcinogenesis (Figure 6). SAG-UPS, in response to chronic infection via both intracrine and paracrine effects, may contribute to a vicious circle of chronic inflammation and carcinogenesis. Being a crucial member at the crossroad between inflammation and cancer, SAG appears to be an important modulator of proinflammatory/protumorigenic molecules (IL-1β, IL-6 and TNF). The tumor-associated macrophage-released cytokines favor a tumor microenvironment that initiates and stimulates the development of HCC, providing survival advantage to the cancer cells in HCC patients.26 In future, a better understanding of the molecular events underlying the relationship between cancer cells and their surrounding microenvironment would enable more realistic strategies for the development of therapeutic targets. In addition, although 9/11 of HCCs are HBV positive, we found that the two hepatoma cases with ‘unknown’ etiology also showed the involvement of SAG-UPS in progressive malignant transformation of liver cancer, hence suggesting the ubiquitous nature of SAG-UPS in cancer progression. This would need further confirmation in future through testing other forms of cancer.


SAG-UPS attenuates proapoptotic SARM and Noxa to confer survival advantage to early hepatocellular carcinoma
Schematic representation of SAG-dependent UPS linking chronic inflammation and liver cancer. Left and right sections represent healthy condition and hepatocarcinogenesis, respectively. Chronic infection by hepatitis viruses (HBV and HCV) is a major risk factor for the initiation and development of HCC. During infection, upregulated SAG-UPS via intracrine signaling attenuates proapoptotic Noxa and SARM by ubiquitination, leading to imbalanced anti-/proapoptotic factors. On the other hand, activation of SAG promotes protumorigenic IL-1β, TNF and IL-6 via paracrine signaling, thus exacerbating the tumor microenvironment. In summary, we hypothesize that SAG-dependent UPS is a key player in inflammation-associated carcinogenesis by manipulating the balance between pro-/antitumorigenic cytokines.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979479&req=5

fig6: Schematic representation of SAG-dependent UPS linking chronic inflammation and liver cancer. Left and right sections represent healthy condition and hepatocarcinogenesis, respectively. Chronic infection by hepatitis viruses (HBV and HCV) is a major risk factor for the initiation and development of HCC. During infection, upregulated SAG-UPS via intracrine signaling attenuates proapoptotic Noxa and SARM by ubiquitination, leading to imbalanced anti-/proapoptotic factors. On the other hand, activation of SAG promotes protumorigenic IL-1β, TNF and IL-6 via paracrine signaling, thus exacerbating the tumor microenvironment. In summary, we hypothesize that SAG-dependent UPS is a key player in inflammation-associated carcinogenesis by manipulating the balance between pro-/antitumorigenic cytokines.
Mentions: Chronic inflammation is now accepted as critical in fibrosis, cirrhosis and hepatocarcinogenesis.10 Although hepatic inflammation caused by long-term infection with hepatitis virus is implicated, the key components linking inflammation and liver cancer are only beginning to be unmasked. Chronic inflammation is characterized by continuously expressed cytokines and recruitment of immune cells to the liver. In consideration of our earlier study in macrophages,11 we postulate that overactivated SAG-UPS triggered by a protumorigenic microenvironment could be a key orchestrator of inflammation-associated carcinogenesis (Figure 6). SAG-UPS, in response to chronic infection via both intracrine and paracrine effects, may contribute to a vicious circle of chronic inflammation and carcinogenesis. Being a crucial member at the crossroad between inflammation and cancer, SAG appears to be an important modulator of proinflammatory/protumorigenic molecules (IL-1β, IL-6 and TNF). The tumor-associated macrophage-released cytokines favor a tumor microenvironment that initiates and stimulates the development of HCC, providing survival advantage to the cancer cells in HCC patients.26 In future, a better understanding of the molecular events underlying the relationship between cancer cells and their surrounding microenvironment would enable more realistic strategies for the development of therapeutic targets. In addition, although 9/11 of HCCs are HBV positive, we found that the two hepatoma cases with ‘unknown’ etiology also showed the involvement of SAG-UPS in progressive malignant transformation of liver cancer, hence suggesting the ubiquitous nature of SAG-UPS in cancer progression. This would need further confirmation in future through testing other forms of cancer.

View Article: PubMed Central - PubMed

ABSTRACT

Hepatocellular carcinoma (HCC) is a deadly cancer because of its commonly late diagnosis and limited treatment options. SAG (sensitive to apoptosis gene)-dependent UPS (ubiquitin–proteasome system) is a key switch between immune-mediated apoptosis and overactivation-mediated protumorigenesis, prompting us to hypothesize that SAG-UPS modulates chronic inflammation-induced tumorigenesis. Here, we investigated the molecular mechanism by which SAG-UPS regulates death/survival of liver cancer cells. By retrospective studies, we found reciprocal expressions of anti-/proapoptotic factors: SAG/SARM and SAG/Noxa in human primary HCC tissues – the antiapoptotic SAG was significantly upregulated whereas the proapoptotic SARM and Noxa were markedly downregulated, suggesting their involvement in hepatocarcinogenesis. Upregulated SAG-UPS effectively manipulates the levels of high-molecular-weight ubiquitinated SARM and Noxa in carcinoma tissues compared with corresponding normal tissues. SAG-overexpressing HCC cell lines display reduced SARM and Noxa (but not Bcl-2, Bax and Bcl-xL), suggesting that SARM and Noxa are specific substrates of SAG-dependent ubiquitination. SARM overexpression activated caspase-3 and caspase-9, reducing cell viability. SAG knockdown significantly elevated apoptosis with increased cytosolic cytochrome c, confirming SAG-mediated antiapoptosis in HCC. SAG overexpression stimulated protumorigenic cytokines, IL-1β, IL-6 and TNF, but not antitumorigenic IL-12p40 and anti-inflammatory IL-10. This is consistent with higher proinflammatory cytokines (IL-1β, IL-6 and TNF) in hepatoma compared with healthy tissues. Altogether, early stage-upregulated SAG-UPS exacerbates hepatocarcinogenesis progression, through: (1) ubiquitination-mediated degradation of proapoptotic SARM and Noxa; and (2) production of protumorigenic cytokines that induce a protumorigenic microenvironment, conferring survival advantage to HCC cells. Thus, we propose SAG-UPS to be an early diagnostic marker for HCC, and a potential target for therapeutics development.

No MeSH data available.


Related in: MedlinePlus