<p>INPP4B inhibits cell proliferation, invasion and chemoresistance in human hepatocellular carcinoma</p>

Abstract

Background: Inositol polyphosphate 4-phosphatase type II (INPP4B) has been identified as a negative regulator of phosphatidyl inositol 3-kinase (PI3K)/Akt signaling in human several cancers. However, the expression, clinical significance and biological function of INPP4B in human hepatocellular carcinoma (HCC) clinical tissues and cell lines are little known. Materials and methods: We evaluated the expression of INPP4B in 86 cases of paired human HCC samples by immunohistochemistry, and the clinical significance of INPP4B expression was analyzed. The expression of INPP4B in five HCC cell lines was detected through using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses. The role of INPP4B gene on HCC cell proliferation, apoptosis, migration, invasion as well as epithelial-to-mesenchymal transition (EMT) and chemoresistance was examined via INPP4B mammalian expression vector and small interfering RNA (siRNA) transfection in vitro. Western blot analysis was used to explore the downstream molecules modulated by INPP4B. Results: Immunohistochemistry analysis revealed that INPP4B was significantly downregulated in HCC tissues compared with the corresponding normal tissues. The rate of INPP4B-positive staining was markedly lower in metastatic samples than in those of non-metastatic samples. Univariate analysis showed that INPP4B expression was indicated to have a marked association with histological grades, tumor size and tumor metastasis. Moreover, INPP4B overexpression suppressed cell proliferation, migration, invasion and EMT, but induced cell apoptosis and chemosensitivity in human HCC cell lines. In contrast, INPP4B knockdown had the opposite effects on the biological behaviors of HCC cells. Furthermore, INPP4B was found to inhibit the activation of PI3K/Akt signaling in HCC cells. Conclusion: Our findings suggest that INPP4B is a tumor suppressing gene in human HCC, and might act as a novel therapeutic target for HCC patients.

INPP4B protects from metabolic syndrome and associated disorders

“…5b, c ). In the human liver, INPP4B was detected in the cytoplasm and cell membrane of normal hepatocytes and its protein levels decreased in primary and, especially, metastatic hepatocellular carcinoma 37 , which undergo significant metabolic reprogramming. Similar to the mouse liver, hepatic INPP4B expression in patients with NAFLD was significantly reduced compared to healthy controls (GSE126848) 38 and there was a highly significant correlation between steatosis score and INPP4B mRNA levels (Fig.…”

“…5a, b and Supplementary Data 2 ). Lipid metabolism and peroxisome biogenesis are known targets of the PPAR family of transcription factors 37 , 39 , 40 . PPARG is a transcriptional regulator of fatty acid uptake and storage, while PPARA activity stimulates fatty acid oxidation 41 .…”

Expression and Functional Identification of INPP4B in Gallbladder Cancer Patients and Gallbladder Cancer Cells

“…Previous studies suggested that INPP4B is involved in the apoptosis of tumor cells [15,30]. The apoptosis levels of different lentivirus infection GBC-SD and SGC-996 cells were analysed by ow cytometry.…”

“…Recently, Inositol polyphosphate-4-phosphatase type II (INPP4B), as a phosphoinositide phosphatase, has been proved to be a negative regulator of the PI3K-Akt signaling and plays a role of tumor suppressor gene (TSG) [9][10][11][12]. Low expression of INPP4B in several type of cancers is associated with poor clinical outcomes [13][14][15]. Knockdown of INPP4B could enhance breast cancer, melanoma and prostate cancer cell lines proliferation and migration, suggesting its TSG role in these cancer cells [11,15,16].…”

“…Low expression of INPP4B in several type of cancers is associated with poor clinical outcomes [13][14][15]. Knockdown of INPP4B could enhance breast cancer, melanoma and prostate cancer cell lines proliferation and migration, suggesting its TSG role in these cancer cells [11,15,16]. However, recently, some studies have reported that INPP4B is highly expressed in colon cancer, acute myeloid leukemia and melanoma, which plays a role of oncogene and has a positive correlation with poor clinical outcomes [17][18][19].…”