Note | When firstly identified, INPP4B was proposed as a tumor suppressor especially when PTEN was deficient (Gewinner et al., 2009; Kofuji et al., 2015; Vo and Fruman, 2015); however, some studies proved that it could promote carcinogenesis. |
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Entity | Melanoma |
Note | Chi et al. showed that INPP4B is upregulated in melanoma cell lines and human tissues. Even though INPP4B was shown to negatively regulate PI3K/AKT signaling and thus, it was thought to be tumor suppressor, INPP4B was demonstrated to be an oncogenic driver through activation of serum glucocorticoid-regulated kinase 3 (SGK3) and independently of AKT. INPP4B downregulation inhibited cell proliferation and tumor growth in xenograft while its overexpression caused enhanced cell proliferation and anchorage-independent growth of melanocytes (Chi et al., 2015). On the other hand, INPP4B expression was inversely correlated with tumor progression in melanocytic neoplasms (Perez-Lorenzo et al., 2014). |
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Entity | Colon Cancer |
Note | INPP4B was demonstrated to be oncogenic and upregulated in human colon cancer cells and tissue. Silencing of INPP4B blocked the activation of AKT and SGK3, and inhibited cell proliferation and tumor growth in xenograft. Overexpression of INPP4B resulted in anchorage-independent growth of normal colon epithelial cells. Also, INPP4B was illustrated to dephosphorylate PTEN in colon cancer cells (Guo et al., 2016). |
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Entity | Thyroid Cancer |
Note | Chew et al. showed loss of Innp4b in Pten heterozygous mice leaded to follicular thyroid carcinoma. INPP4B was also demonstrated to inhibit PI3K-C2 Endometrial Cancer α-mediated AKT2 activation in early endosomes in thyroid cancer cells (Chew et al., 2015). INPP4B was downregulated in human thyroid cancer cell lines and samples (Chew et al., 2015; Kofuji et al., 2015). |
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Entity | Endometrial Cancer |
Note | INPP4B was demonstrated to be downregulated in samples from patients with endometrial cancer (Kofuji et al., 2015). |
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Entity | Prostate Cancer |
Note | Hodgson et al. showed that activation of androgen receptor induced the expression of INPP4B via activation of corepressor, NCOR1, which regulates agonist-bound androgen receptor activity, and decreased the activation of AKT in prostate cancer cell lines. Also, INPP4B expression was shown to be down-regulated in samples from androgen-dependent prostate cancer (Hodgson et al., 2011). Same group also showed that de novo expression of INPP4B suppressed the invasion in vitro and in vivo in human prostate carcinoma cells due to that INPP4B regulated a wide range of genes associated with cell adhesion, extracellular matrix and cytoskeleton. It also inhibited metastases thanks to downregulating metastases-related BIRC5, phosphorylated PKC, expression of PKC in androgen-dependent and -independent manner and PTGS2 (COX-2). Moreover, de novo expressed INPP4B inhibited proinflammatory cytokine CXCL8 (IL-8) and induced PAK6 owing to downregulating PKC (Hodgson et al., 2014). In another study, overexpression of INPP4B in prostate cancer cell line, PC3, inhibited cell proliferation and decreased the levels of phosphorylated AKT (p-AKT), bringing about G1 arrest. Combination of INPP4B overexpression with PARP inhibitor, which arrested the cells in G2/M with an increase in p-AKT level, decreased the p-AKT levels and further inhibited the cell proliferation, suggesting that those combinations could be helpful for treatment of prostate cancer (Ding et al., 2014). INPP4B was also demonstrated to associate with the resistance to chemotherapeutics in prostate cancer. In docetaxel-resistant prostate cancer cell lines, INPP4B was shown to be downregulated. Overexpression of INPP4B resensitized the resistant cell lines towards docetaxel via inhibiting PI3K/AKT activation and expression of the mesenchymal markers fibronectin, N-cadherin, and vimentin, and upregulating the expression level of the epithelial maker E-cadherin (Chen et al., 2016). |
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Entity | Breast Cancer |
Note | INPP4B was shown to be expressed in non-proliferative estrogen receptor (ER)-positive cells in normal breast tissue and ER-positive breast cancer cell lines. Nevertheless, ER-negative breast cancer cell lines did not express INPP4B. As a generalization, INPP4B expression was not seen in phosphatase and tensin homolog (PTEN)-null tumors. Down-regulation of INPP4B in ER-positive breast cancer cell lines increased AKT activation, cell proliferation and xenograft tumor growth while overexpression of INPP4B in ER-negative cell lines decreased the activated AKT and anchorage-independent growth (Fedele et al., 2010). Similarly, in triple negative breast cancer cell line, MDA-MB-231, stably overexpression of INPP4B inhibited cell proliferation and arrested the cell cycle at G1 phase through decreasing the level of phosphorylated AKT. By the combinational therapy approach, INPP4B expression was shown to increase the efficacy of poly-(adenosine diphosphate ribose) polymerase (PARP) inhibitor, AG014699 which is a DNA-damaging agent, arresting cell cycle at G2/M transition but could activate PI3K/AKT pathway (Sun et al., 2014). In a review article, Bertucci and Mitchell reported that INPP4B expression was lost in 84% of basal-like breast cancer; INPP4B loss of heterozygosity (LOH) occurs in 55% of triple negative and basal-like cancers, and 60% of BRCA1 mutant tumors as previously shown by Gewinner et al. (Gewinner et al., 2009; Bertucci and Mitchell, 2013). Similarly, INPP4B LOH was observed in 18.1% of Japanese breast cancer patients. Moreover, INPP4B LOH was significantly correlated with estrogen receptor (ER) and progesterone receptor (PR) negativity, higher nuclear grade, PTEN LOH and poorer prognosis (Tokunaga et al., 2016). In a case study where breast cancer samples from 43 patients were used, INPP4B expression was absent or low for 18% of cases. Low expression INPP4B was associated with larger tumor size and higher nuclear grade (Sueta et al., 2014). In another study, INPP4B was shown to prevent AKT activation but trigger the activation of SGK3, which was overexpressed and hyperactivated in breast cancer and caused to proliferation, invasive migration and tumorigenesis in breast cancer in vitro and in vivo models, via production of PI(3)P (Gasser et al., 2014). |
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Entity | Acute Myeloid Leukemia (AML) |
Note | Dzneladze et al. showed that high levels of INPP4B in AML patients had poor response to induction therapy, shorter event-free survival and shorter overall survival. In cell culture, overexpression of INPP4B increased the colony formation potential, resulted in resistance to daunorubicin and ionizing radiation and supported phosphatase-dependent and AKT-independent proliferation. Hence, the researchers proposed INPP4B as an independent prognostic marker in AML (Dzneladze et al., 2015). Similarly, INPP4B was shown to be overexpressed in samples from patients with AML in another study. Overexpression of INPP4B in patients with AML resulted in reduced response to chemotherapy, early relapse and poor overall survival as figured out by Dzneladze et al. Moreover, overexpression of an inert variant of INPP4B, which did not display phosphatase activity, did not affect the resistance phenotype in vitro. However, silencing of INPP4B sensitized the AML cell lines towards chemotherapeutics, pointing a phosphoinositide phosphatase function-independent involvement of INPP4B in drug resistance in AML (Rijal et al., 2015). |
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Entity | Laryngeal Cancer |
Note | In laryngeal cancer cell line, HEp-2, INPP4B expression was triggered by hypoxia and irradiation. Also, INPP4B overexpression enhanced aerobic glycolysis. It was demonstrated that one of the glycolysis-regulatory gene, hexokinase-2 (HK2) was regulated by INPP4B via AKT-mTOR pathway in this cell line. Silencing of both INPP4B and HK2 sensitized the radioresistant cells toward radiation and chemotherapeutic agents (Min et al., 2013). Moreover, INPP4B was demonstrated to be a marker of radioresistance in HEp-2 cells. INPP4B was shown to be overexpressed in radioresistant HEp-2 cells and that radiation or anticancer drug treatment induced INPP4B expression which was blocked by inhibition of extracellular signal-regulated kinase (ERK). INPP4B overexpression increased the resistance towards radiation and anticancer drugs and depletion of INPP4B re-sensitized the cells (Kim et al., 2012). |
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Entity | Nasopharyngeal Carcinoma (NPC) |
Note | NPC is a viral-associated neoplasm where Epstein-Bar virus latent proteins affect multiple signaling cascades. Yuen et al. showed that INPP4B was downregulated in NPC cell lines compared to normal nasopharyngeal epithelial cell lines. The downregulation was demonstrated to become as a result of hypermethylation of the 5'CpG island of INPP4B (Yuen et al., 2014). |
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Entity | Lung Cancer |
Note | In a case study where samples were obtained from 180 patients with non-small cell lung cancer subtypes, squamous cell carcinoma (SSC) or adenocarcinoma (ADCA), the ratio of INPP4B copy number was determined as 15% ≤1 copies, 62% 2 copies, and 23% ≥3 copies. Also, 47% displayed loss of loss of INPP4B expression which showed a strong correlation with SCC compared to ADCA (Stjernstrom et al., 2014). In another study, MIR937 which targeted INPP4B by directly binding to 3 UTR of INPP4B was upregulated in lung cancer cell line. Overexpression of miR-937 promoted anchorage-dependent and -independent growth while downregulation prevented these effects. Overexpression of miR-937 was shown to knockdown INPP4B which was proposed as the reason for increased growth rate in lung cancer cell lines (Zhang et al., 2016). |
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Entity | Bladder Cancer |
Note | Hsu et al. developed ESR1 (estrogen receptor-α, ERα)--knockout mice to see the effect of ERα in bladder carcinogenesis. They showed that ERα reduced the carcinogen-induced malignant transformation ability. Moreover, ESR1 was demonstrated to control AKT activity via controlling the expression of INPP4B (Hsu et al., 2014). |
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Entity | Ovarian Cancer; Ovarian Teratomas (OTs) in particular |
Note | Teratoma is a class of tumors that are composed of ecto-, meso- and endodermal tissues which are all foreign to the site of the origin. OTs are pathogenically activated non-ovulated germ cells-derived ovary tumors that exhibit disorganized pattern of cellular differentiation. Carriers of Rous sarcoma virus (RSV) Tgkd transgene are susceptible to teratomas. Tgkd transgene was demonstrated to be inserted into intergenic region of Inpp4b and Il15. This insertion was shown to affect Inpp4b expression and dysregulation of Akt pathway, promoting progression of ovarian teratomas (Balakrishnan and Chaillet, 2013). In ovarian cancer cells, INPP4B was illustrated to form a complex with BRCA1 and ATR which are the members of DNA repair mechanism. Loss of INPP4B, which was seen in 40% of patients with ovarian cancer studied, disrupted in BRCA1, ATM and ATR protein stabilities, resulting in DNA defects and sensitized the cells towards inhibitors of PARP, a nuclear enzyme sensing DNA single strand breaks and required for base excision repair (Ip et al., 2014). |
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Entity | Hepatocellular Carcinoma |
Note | In hepatocellular carcinoma cell lines, MIR765 which directly targeted INPP4B was shown to be upregulated. Upregulation of miR-765 and in turn downregulation of INPP4B increased upregulation of p-AKT, CCND1 (Cyclin D1), and downregulation of p- FOXO3, p21 expression; thus it increased cellular proliferation and tumorigenicity. Downregulation of miR-765 rescued the phenotype in these cell lines via upregulation of INPP4B (Xie et al., 2016). |
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Entity | Osteoporosis |
Disease | Osteoporosis is a genetic disease where bone mass is reduced because of dysregulation of osteoclast differentiation and maturation. Ferron et al. proposed Inpp4bα as a regulator of osteoclastogenesis. Inpp4bα was detected to be expressed from early osteoclast differentiation to activation. Moreover, phosphotase-inactivate Inpp4bα triggered the osteoclast activation. Inpp4bα was shown to control intracellular calcium level modulating NFATC1, which is a preosteoclast promoting transcription factor regulating osteoclast maturation, nuclear translocation and activation. Inpp4b-deficient mice displayed increased osteoclast differentiation rate, bringing about decreased bone mass and osteoporosis, and human INPP4B was proposed as a susceptibility locus for osteoporosis. Overall, Inpp4bα was regarded as a negative regulator of osteoclast differentiation (Ferron et al., 2011; Vacher, 2013). |
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Entity | Multiple Sclerosis (MS) |
Disease | MS is a neurodegenerative and neuroinflammatory disease causing impairment of nerve conduction. In a genomic study, INPP4B was shown to regulate nerve conduction velocity. Moreover, an INPP4B polymorphism (rs13102150) was associated with MS cohorts (Lemcke et al., 2014). |
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INPP4B: the new kid on the PI3K block |
Agoulnik IU, Hodgson MC, Bowden WA, Ittmann MM |
Oncotarget 2011 Apr;2(4):321-8 |
PMID 21487159 |
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Role of the inositol polyphosphate-4-phosphatase type II Inpp4b in the generation of ovarian teratomas |
Balakrishnan A, Chaillet JR |
Dev Biol 2013 Jan 1;373(1):118-29 |
PMID 23078915 |
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Phosphoinositide 3-kinase and INPP4B in human breast cancer |
Bertucci MC, Mitchell CA |
Ann N Y Acad Sci 2013 Mar;1280:1-5 |
PMID 23551093 |
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Inositol lipid phosphatases in membrane trafficking and human disease |
Billcliff PG, Lowe M |
Biochem J 2014 Jul 15;461(2):159-75 |
PMID 24966051 |
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INPP4B reverses docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer |
Chen H, Li H, Chen Q |
Biochem Biophys Res Commun 2016 Aug 26;477(3):467-72 |
PMID 27318090 |
|
Endosome and INPP4B |
Chew CL, Chen M, Pandolfi PP |
Oncotarget 2016 Jan 5;7(1):5-6 |
PMID 26700619 |
|
INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas |
Chi MN, Guo ST, Wilmott JS, Guo XY, Yan XG, Wang CY, Liu XY, Jin L, Tseng HY, Liu T, Croft A, Hondermarck H, Scolyer RA, Jiang CC, Zhang XD |
Oncotarget 2015 Nov 24;6(37):39891-907 |
PMID 26573229 |
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Inactivating Frameshift Mutation of INPP4B Encoding a PI3K Pathway Phosphatase in Gastric and Colorectal Cancers |
Choi EJ, Kim MS, Yoo NJ, Lee SH |
Pathol Oncol Res 2016 Jul;22(3):653-4 |
PMID 27068714 |
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Functional identification of a novel transcript variant of INPP4B in human colon and breast cancer cells |
Croft A, Guo ST, Sherwin S, Farrelly M, Yan XG, Zhang XD, Jiang CC |
Biochem Biophys Res Commun 2017 Mar 25;485(1):47-53 |
PMID 28189677 |
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Effects of INPP4B gene transfection combined with PARP inhibitor on castration therapy-resistant prostate cancer cell line, PC3 |
Ding H, Sun Y, Hou Y, Li L |
Urol Oncol 2014 Jul;32(5):720-6 |
PMID 24837011 |
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INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia |
Dzneladze I, He R, Woolley JF, Son MH, Sharobim MH, Greenberg SA, Gabra M, Langlois C, Rashid A, Hakem A, Ibrahimova N, Arruda A, Löwenberg B, Valk PJ, Minden MD, Salmena L |
Leukemia 2015 Jul;29(7):1485-95 |
PMID 25736236 |
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Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers |
Fedele CG, Ooms LM, Ho M, Vieusseux J, O'Toole SA, Millar EK, Lopez-Knowles E, Sriratana A, Gurung R, Baglietto L, Giles GG, Bailey CG, Rasko JE, Shields BJ, Price JT, Majerus PW, Sutherland RL, Tiganis T, McLean CA, Mitchell CA |
Proc Natl Acad Sci U S A 2010 Dec 21;107(51):22231-6 |
PMID 21127264 |
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Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans |
Ferron M, Boudiffa M, Arsenault M, Rached M, Pata M, Giroux S, Elfassihi L, Kisseleva M, Majerus PW, Rousseau F, Vacher J |
Cell Metab 2011 Oct 5;14(4):466-77 |
PMID 21982707 |
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Characterization of the murine Inpp4b gene and identification of a novel isoform |
Ferron M, Vacher J |
Gene 2006 Jul 5;376(1):152-61 |
PMID 16631325 |
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Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling |
Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PP, Cantley LC |
Cancer Cell 2009 Aug 4;16(2):115-25 |
PMID 19647222 |
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INPP4B is an oncogenic regulator in human colon cancer |
Guo ST, Chi MN, Yang RH, Guo XY, Zan LK, Wang CY, Xi YF, Jin L, Croft A, Tseng HY, Yan XG, Farrelly M, Wang FH, Lai F, Wang JF, Li YP, Ackland S, Scott R, Agoulnik IU, Hondermarck H, Thorne RF, Liu T, Zhang XD, Jiang CC |
Oncogene 2016 Jun 9;35(23):3049-61 |
PMID 26411369 |
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Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer |
Hodgson MC, Shao LJ, Frolov A, Li R, Peterson LE, Ayala G, Ittmann MM, Weigel NL, Agoulnik IU |
Cancer Res 2011 Jan 15;71(2):572-82 |
PMID 21224358 |
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Estrogen receptor alpha prevents bladder cancer via INPP4B inhibited akt pathway in vitro and in vivo |
Hsu I, Yeh CR, Slavin S, Miyamoto H, Netto GJ, Tsai YC, Muyan M, Wu XR, Messing EM, Guancial EA, Yeh S |
Oncotarget 2014 Sep 15;5(17):7917-35 |
PMID 25277204 |
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Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment |
Ip LR, Poulogiannis G, Viciano FC, Sasaki J, Kofuji S, Spanswick VJ, Hochhauser D, Hartley JA, Sasaki T, Gewinner CA |
Oncotarget 2015 Apr 30;6(12):10548-62 |
PMID 25868852 |
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Identification of inositol polyphosphate 4-phosphatase type II as a novel tumor resistance biomarker in human laryngeal cancer HEp-2 cells |
Kim JS, Yun HS, Um HD, Park JK, Lee KH, Kang CM, Lee SJ, Hwang SG |
Cancer Biol Ther 2012 Nov;13(13):1307-18 |
PMID 22895072 |
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INPP4B Is a PtdIns(3,4,5)P3 Phosphatase That Can Act as a Tumor Suppressor |
Kofuji S, Kimura H, Nakanishi H, Nanjo H, Takasuga S, Liu H, Eguchi S, Nakamura R, Itoh R, Ueno N, Asanuma K, Huang M, Koizumi A, Habuchi T, Yamazaki M, Suzuki A, Sasaki J, Sasaki T |
Cancer Discov 2015 Jul;5(7):730-9 |
PMID 25883023 |
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Nerve conduction velocity is regulated by the inositol polyphosphate-4-phosphatase II gene |
Lemcke S, Müller S, Möller S, Schillert A, Ziegler A, Cepok-Kauffeld S, Comabella M, Montalban X, Rülicke T, Nandakumar KS, Hemmer B, Holmdahl R, Pahnke J, Ibrahim SM |
Am J Pathol 2014 Sep;184(9):2420-9 |
PMID 25129256 |
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In Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K-AKT Signaling at Endosomes |
Li Chew C, Lunardi A, Gulluni F, Ruan DT, Chen M, Salmena L, Nishino M, Papa A, Ng C, Fung J, Clohessy JG, Sasaki J, Sasaki T, Bronson RT, Hirsch E, Pandolfi PP |
Cancer Discov 2015 Jul;5(7):740-51 |
PMID 25883022 |
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Determinants of the tumor suppressor INPP4B protein and lipid phosphatase activities |
Lopez SM, Hodgson MC, Packianathan C, Bingol-Ozakpinar O, Uras F, Rosen BP, Agoulnik IU |
Biochem Biophys Res Commun 2013 Oct 18;440(2):277-82 |
PMID 24070612 |
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INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells |
Min JW, Kim KI, Kim HA, Kim EK, Noh WC, Jeon HB, Cho DH, Oh JS, Park IC, Hwang SG, Kim JS |
Biochem Biophys Res Commun 2013 Oct 11;440(1):137-42 |
PMID 24051093 |
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A tumor suppressor function for the lipid phosphatase INPP4B in melanocytic neoplasms |
Perez-Lorenzo R, Gill KZ, Shen CH, Zhao FX, Zheng B, Schulze HJ, Silvers DN, Brunner G, Horst BA |
J Invest Dermatol 2014 May;134(5):1359-68 |
PMID 24288008 |
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Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML |
Rijal S, Fleming S, Cummings N, Rynkiewicz NK, Ooms LM, Nguyen NY, Teh TC, Avery S, McManus JF, Papenfuss AT, McLean C, Guthridge MA, Mitchell CA, Wei AH |
Blood 2015 Apr 30;125(18):2815-24 |
PMID 25736313 |
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Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung |
Stjernström A, Karlsson C, Fernandez OJ, Söderkvist P, Karlsson MG, Thunell LK |
Cancer Med 2014 Apr;3(2):337-48 |
PMID 24500884 |
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An integrative analysis of PIK3CA mutation, PTEN, and INPP4B expression in terms of trastuzumab efficacy in HER2-positive breast cancer |
Sueta A, Yamamoto Y, Yamamoto-Ibusuki M, Hayashi M, Takeshita T, Yamamoto S, Iwase H |
PLoS One 2014 Dec 26;9(12):e116054 |
PMID 25542038 |
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INPP4B overexpression enhances the antitumor efficacy of PARP inhibitor AG014699 in MDA-MB-231 triple-negative breast cancer cells |
Sun Y, Ding H, Liu X, Li X, Li L |
Tumour Biol 2014 May;35(5):4469-77 |
PMID 24420152 |
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Biological and clinical significance of loss of heterozygosity at the INPP4B gene locus in Japanese breast cancer |
Tokunaga E, Yamashita N, Kitao H, Tanaka K, Taketani K, Inoue Y, Saeki H, Oki E, Oda Y, Maehara Y |
Breast 2016 Feb;25:62-8 |
PMID 26577950 |
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Inpp4b is a novel negative modulator of osteoclast differentiation and a prognostic locus for human osteoporosis |
Vacher J |
Ann N Y Acad Sci 2013 Mar;1280:52-4 |
PMID 23551105 |
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INPP4B Is a Tumor Suppressor in the Context of PTEN Deficiency |
Vo TT, Fruman DA |
Cancer Discov 2015 Jul;5(7):697-700 |
PMID 26152921 |
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Mir-765 promotes cell proliferation by downregulating INPP4B expression in human hepatocellular carcinoma |
Xie BH, He X, Hua RX, Zhang B, Tan GS, Xiong SQ, Liu LS, Chen W, Yang JY, Wang XN, Li HP |
Cancer Biomark 2016;16(3):405-13 |
PMID 27062697 |
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Epigenetic inactivation of inositol polyphosphate 4-phosphatase B (INPP4B), a regulator of PI3K/AKT signaling pathway in EBV-associated nasopharyngeal carcinoma |
Yuen JW, Chung GT, Lun SW, Cheung CC, To KF, Lo KW |
PLoS One 2014 Aug 15;9(8):e105163 |
PMID 25126743 |
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miR-937 contributes to the lung cancer cell proliferation by targeting INPP4B |
Zhang L, Zeng D, Chen Y, Li N, Lv Y, Li Y, Xu X, Xu G |
Life Sci 2016 Jun 15;155:110-5 |
PMID 27179609 |
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