Isocitrate Dehydrogenase 2 Suppresses the Invasion of Hepatocellular Carcinoma Cells via Matrix Metalloproteinase 9

Tian, Guoyan; Zang, Shufei; Wang, Lei; Luo, Yan; Shi, Junping; Lou, Guo-qiang

doi:10.1159/000438593

Cited by 23 publications

(18 citation statements)

References 36 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with our results, Chen et al found that re-expression of PRSS8 up-regulated E-cadherin expression in human transitional cell carcinomas KU-7 cells [8]. Another protein, MMP9, can degrade extracellular matrix components and thus, promote the invasion of tumour cells [17,18], and was also reduced in parallel with the upregulation of PRSS8. This suggests that PRSS8 may inhibit the metastasis and invasion of HCC through a switch from N-cadherin to E-cadherin expression, and the downregulation of MMP9.…”

Section: Discussionsupporting

confidence: 92%

PRSS8 is Downregulated and Suppresses Tumour Growth and Metastases in Hepatocellular Carcinoma

Zhang

Jia²,

Shi³

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: Protease serine 8 (PRSS8), a trypsin-like serine peptidase, has been shown to function as a tumour suppressor in various malignancies. The present study aimed to investigate the expression pattern, prognostic value and the biological role of PRSS8 in human hepatocellular carcinoma (HCC). Methods: PRSS8 expression in 106 HCC surgical specimens was examined by Real-time polymerase chain reaction (PCR) and immunohistochemistry, and its clinical significance was analysed. The role of PRSS8 in cell proliferation, apoptosis and invasion were examined in vitro and in vivo. Results: PRSS8 mRNA and protein expression were decreased in most HCC tumours from that in matched adjacent non-tumour tissues. Low intratumoral PRSS8 expression was significantly correlated with poor overall survival (OS) in patients with HCC (P = 0.001). PRSS8 expression was an independent prognostic factor for OS (hazard ratio [HR] = 1.704, P = 0.009). Furthermore, restoring PRSS8 expression in high metastatic HCCLM3 cells significantly inhibited cell proliferation and invasion. In contrast, silencing PRSS8 expression in non-metastatic HepG2 cells significantly enhanced cell growth and invasion. Moreover, our in vivo data revealed that attenuated PRSS8 expression in HepG2 cells greatly promoted tumour growth, while overexpression of PRSS8 remarkably inhibited tumour growth in an HCCLM3 xenograft model. Enhanced cell growth and invasion ability mediated by the loss of PRSS8 expression was associated with downregulation of PTEN, Bax and E-cadherin and an upregulation in Bcl-2, MMP9 and N-cadherin. Conclusions: Our data demonstrate that PRSS8 may serve as a tumour suppressor in HCC progression, and represent a valuable prognostic marker and potential therapeutic target for HCC.

show abstract

Section: Discussionsupporting

confidence: 92%

PRSS8 is Downregulated and Suppresses Tumour Growth and Metastases in Hepatocellular Carcinoma

Zhang

Jia²,

Shi³

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…It is thought that the effect of IDH2 expression on neoplastic progression and drug resistance differs with respect to the site of origin and histological type. [50][51][52][53][54][55] Our study suggests the hypothesis that inhibition of wild-type IDH2 may have therapeutic potentials, regardless of IDH2 expression levels. Concordantly, we excluded that the IDH2 mutational status or its aberrant expression was associated to PI responsiveness in MM cells.…”

Section: Discussionmentioning

confidence: 61%

IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies

Bergaggio¹,

Riganti

Garaffo³

et al. 2019

Blood

View full text Add to dashboard Cite

Proteasome inhibitors (PI) are extensively used for the therapy of multiple myeloma (MM) and mantle cell lymphoma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. Here, to identify targets that synergize with PI, we carried out a functional screening in MM cell lines using a short hairpin RNA library against cancer driver genes. Isocitrate dehydrogenase 2 (IDH2) was identified as a top candidate, showing a synthetic lethal activity with the PI carfilzomib (CFZ). Combinations of US Food and Drug Administration–approved PI with a pharmacological IDH2 inhibitor (AGI-6780) triggered synergistic cytotoxicity in MM, mantle cell lymphoma, and Burkitt lymphoma cell lines. CFZ/AGI-6780 treatment increased death of primary CD138+ cells from MM patients and exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone marrow–derived stromal cells. Mechanistically, the CFZ/AGI-6780 combination significantly decreased tricarboxylic acid cycle activity and adenosine triphosphate levels as a consequence of enhanced IDH2 enzymatic inhibition. Specifically, CFZ treatment reduced the expression of nicotinamide phosphoribosyltransferase (NAMPT), thus limiting IDH2 activation through the NAD+-dependent deacetylase SIRT3. Consistently, combination of CFZ with either NAMPT or SIRT3 inhibitors impaired IDH2 activity and increased MM cell death. Finally, inducible IDH2 knockdown enhanced the therapeutic efficacy of CFZ in a subcutaneous xenograft model of MM, resulting in inhibition of tumor progression and extended survival. Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PI, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PI to other malignancies.

show abstract

“…With regard to the six verified downregulated proteins, IDH2 is a mitochondrial NADP-dependent isocitrate dehydrogenase that functions variably in different types of cancer. It has been reported that IDH2 inhibited the invasion of hepatocellular carcinoma cells via the regulation of MMP9, and therefore acted as a tumor suppressor (47). By contrast, in another study the overexpression of IDH2 promoted cell growth in colon cancer (48).…”

Section: Discussionmentioning

confidence: 89%

Quantitative proteomic analysis of the miR‑148a‑associated mechanisms of metastasis in non‑small cell lung cancer

Chu

Lin

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression and protein synthesis. Our previous study demonstrated that miR-148a suppressed the metastasis of non-small cell lung cancer (NSCLC) and. However, the modulatory mechanism of this effect remains unclear. In the present study, quantitative proteomic technology was used to study the protein expression profile of SPC-A-1 cells subsequent to the downregulation of miR-148a expression, in order to elucidate the molecular mechanism of the suppression of NSCLC metastasis by miR-148a. The differentially expressed proteins identified were analyzed using bioinformatics tools, including the Database for Annotation, Visualization and Integrated Discovery and the Search Tool for the Retrieval of Interacting Genes/proteins. In two experiments, 4,048 and 4,083 proteins were identified, and 4,014 and 4,039 proteins were quantified, respectively. In total, 44 proteins were upregulated and 40 proteins were downregulated. This was verified at the protein and mRNA levels by western blotting and reverse transcription-quantitative polymerase chain reaction, respectively. Bioinformatics analysis was used to identify potential interactions and signaling networks for the differentially expressed proteins. This may have provided an appropriate perspective for the comprehensive analysis of the modulatory mechanism underlying the metastasis-suppressive effects of miR-148a in NSCLC. In conclusion, quantitative proteomic technology revealed that miR-148a may regulate a panel of tumor-associated proteins to suppress metastasis in NSCLC.

show abstract

Isocitrate Dehydrogenase 2 Suppresses the Invasion of Hepatocellular Carcinoma Cells via Matrix Metalloproteinase 9

Cited by 23 publications

References 36 publications

PRSS8 is Downregulated and Suppresses Tumour Growth and Metastases in Hepatocellular Carcinoma

PRSS8 is Downregulated and Suppresses Tumour Growth and Metastases in Hepatocellular Carcinoma

IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies

Quantitative proteomic analysis of the miR‑148a‑associated mechanisms of metastasis in non‑small cell lung cancer

Contact Info

Product

Resources

About