Differential sensitivity of hepatocellular carcinoma cells to suppression of hepatocystin transcription under hypoxic conditions View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2016-09-17

AUTHORS

Jeong-Ju Yoo, Dong Hyeon Lee, Yuri Cho, Eun Ju Cho, Jeong-Hoon Lee, Su Jong Yu, Yoon Jun Kim, Chung Yong Kim, Jung-Hwan Yoon

ABSTRACT

Mutations in the gene encoding hepatocystin/80 K-H (PRKCSH) cause autosomal dominant polycystic liver disease. Hepatocystin deficiency impairs glucosidase II activity, which is critical for processing and folding glycoproteins in the endoplasmic reticulum (ER). Hypoxia is known as a strong stimulus for generating survival signals in hepatocellular carcinoma (HCC) cells. However, hypoxia may induce cell apoptosis under conditions of severe ER stress. Thus, we hypothesized that suppression of hepatocystin transcription induces HCC cell death under hypoxic conditions due to excessive ER stress. A new human HCC cell line, SNU-3058, was established following primary culture of tumor cells harvested from a Korean patient with rapidly growing hypovascular HCC. In cell culture, human HCC cells (Huh-7, SNU-761, and SNU-3058) were treated with control siRNA or hepatocystin siRNA with or without doxorubicin under hypoxic conditions. Cell viability, ER stress, unfolded protein response (UPR), and apoptosis were assessed using the MTS assay, immunoblot assay, and RT-PCR. Suppression of hepatocystin transcription attenuated proliferation in Huh-7 and SNU-761 cells, while proliferation was amplified in SNU-3058 cells. Similar results were observed following treatment with doxorubicin. Hepatocystin siRNA transfection increased cell death in Huh-7 and decreased cell death in SNU-3058. In SNU-3058, hepatocystin siRNA amplified GRP78, known as a pro-survival and cyto-protective signal, and attenuated the pro-apoptotic signal CHOP. These findings suggest that suppression of hepatocystin transcription induce the UPR, which alleviates damage associated with ER stress in SNU-3058. UPR had a limited role in protecting SNU-761 cells, resulting in cell death through apoptosis. In addition, blocking of pro-survival UPR signal by bacitracin or GRP78 knockdown, attenuated hepatocystin siRNA-induced proliferation in SNU-3058 cells under hypoxia. In this study, we demonstrated that different sensitivities to hepatocystin siRNA among human HCC cell lines are dependent on appropriate UPRs to hypoxia-induced ER stress following hepatocystin siRNA transfection. Because UPR is the main evasive mechanism for apoptosis induced by suppression of hepatocystin, targeting hepatocystin via UPR suppression could be a strategy for treating HCC. More... »

PAGES

581-590

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10863-016-9677-5

DOI

http://dx.doi.org/10.1007/s10863-016-9677-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1021288656

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27640193


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62 cell death
63 cell lines
64 cell viability
65 cells
66 conditions
67 control siRNA
68 culture
69 cyto-protective signal
70 damage
71 death
72 deficiency impairs glucosidase II activity
73 different sensitivities
74 differential sensitivity
75 disease
76 dominant polycystic liver disease
77 doxorubicin
78 endoplasmic reticulum
79 evasive mechanisms
80 excessive ER stress
81 findings
82 genes
83 glucosidase II activity
84 glycoprotein
85 hepatocellular carcinoma cells
86 hepatocystin
87 hepatocystin siRNA
88 hepatocystin transcription
89 hepatocystin transcription induces HCC cell death
90 hepatocystin/80
91 human HCC cell lines
92 human HCC cells
93 hypovascular HCC
94 hypoxia
95 hypoxic conditions
96 impairs glucosidase II activity
97 induces HCC cell death
98 knockdown
99 limited role
100 lines
101 liver disease
102 main evasive mechanism
103 mechanism
104 mutations
105 new human HCC cell line
106 patients
107 polycystic liver disease
108 primary cultures
109 pro-apoptotic signal CHOP
110 pro-survival UPR signal
111 processing
112 proliferation
113 protein response
114 response
115 results
116 reticulum
117 role
118 sensitivity
119 severe ER stress
120 siRNA
121 siRNA transfection
122 signal CHOP
123 signals
124 similar results
125 stimuli
126 strategies
127 stress
128 strong stimulus
129 study
130 suppression
131 suppression of hepatocystin
132 survival signals
133 transcription
134 transcription induces HCC cell death
135 transfection
136 treatment
137 tumor cells
138 unfolded protein response
139 viability
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