4q31.21; Start: 142,023,160 bp End: 142,847,432 bp; 824.273 bases; Orientation: Minus strand

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.

Melanoma

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).

Colon Cancer

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).

Thyroid Cancer

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).

Endometrial Cancer

INPP4B was demonstrated to be downregulated in samples from patients with endometrial cancer (Kofuji et al., 2015).

Prostate Cancer

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).

Breast Cancer

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).

Acute Myeloid Leukemia (AML)

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).

Laryngeal Cancer

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).

Nasopharyngeal Carcinoma (NPC)

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 5CpG island of INPP4B (Yuen et al., 2014).

Lung Cancer

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).

Bladder Cancer

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).

Ovarian Cancer; Ovarian Teratomas (OTs) in particular

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).

Hepatocellular Carcinoma

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).

Osteoporosis

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).

Multiple Sclerosis (MS)

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).