The role of programmed cell death 4 (PDCD4) in multiple myeloma (MM) development remains unknown. Here, we investigated its role and action mechanism in MM. Bioinformatic analysis indicated that patients with MM and high PDCD4 expression had higher overall survival than those with low PDCD4 expression. PDCD4 expression promoted MM cell apoptosis and inhibited their viability in vitro and tumor growth in vivo. RNA-binding protein immunoprecipitation sequencing analysis showed that PDCD4 is bound to the 5\' UTR of the apoptosis-related genes PIK3CB, Cathepsin Z (CTSZ), and X-chromosome-linked apoptosis inhibitor (XIAP). PDCD4 knockdown reduced the cell apoptosis rate, which was rescued by adding PIK3CB, CTSZ, or XIAP inhibitors. Dual luciferase reporter assays confirmed the internal ribosome entry site (IRES) activity of the 5\' UTRs of PIK3CB and CTSZ. An RNA pull-down assay confirmed binding of the 5\' UTR of PIK3CB and CTSZ to PDCD4, identifying the specific binding fragments. PDCD4 is expected to promote MM cell apoptosis by binding to the IRES domain in the 5\' UTR of PIK3CB and CTSZ and inhibiting their translation. Our findings suggest that PDCD4 plays an important role in MM development by regulating the expression of PIK3CB, CTSZ, and XIAP, and highlight new potential molecular targets for MM treatment.

PIK3CB, one of catalytic subunits of PI3Ks kinase family, is implicated in several cellular processes such as cell growth, proliferation, mobility and neoplastic transformation. Its abnormal expression has been found in several human cancer types. However, the regulation pattern and function of PIK3CB in gastric cancer (GC) are still unclear. Here, we demonstrated that PIK3CB and SP1 (special protein 1) were both upregulated in GC samples compared to adjacent non-cancerous stomach tissues at mRNA and protein levels. The expression of the two genes also displayed a significant positive correlation in GC samples. Dual-luciferase assays and chromatin immunoprecipitation (ChIP) assays revealed that SP1 could bind to the -771~-605 region of the promoter of PIK3CB and enhance transcription. Furthermore, we discovered that SP1 induced AKT activation through PIK3CB and accelerated GC cell proliferation and migration in a PIK3CB/AKT signaling dependent manner. TGX-221, a PIK3CB-selective inhibitor, which can block this signaling transduction pathway, was found to inhibit the growth of GC cells and induce apoptosis in vitro, implying that it may act as a potential development agent for GC. These collective findings provide a new insight into PI3K/AKT signaling that SP1 may function as an upstream factor on PI3K, forming a new signaling axis to promote the progression of GC or other malignancies.

Loss of PTEN function leads to increased PI3Kβ signaling. AZD8186, a selective PI3Kβ/δ inhibitor, has shown anti-tumor activity in PTEN-deficient preclinical models. Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed in advanced gastric cancer with PTEN loss.
In the phase Ib dose-escalation, subjects with advanced solid tumors received oral AZD8186 (60 mg or 120 mg; twice daily (BID); 5 days on/2 days off) plus intravenous paclitaxel (70 mg/m2 or 80 mg/m2; days 1, 8, and 15) every 4 weeks. In the phase II part, MRGC patients with PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received recommended phase II dose (RP2D) of AZD8186 plus paclitaxel. Primary endpoints were to determine maximum tolerated dose (MTD) and RP2D in phase Ib and 4-month progression-free survival (PFS) rate in phase II.
In phase Ib, both MTD and RP2D were determined at paclitaxel 80 mg/m2 and AZD8186 120 mg BID. In phase II, 18 patients were enrolled [PTEN loss (n = 18) and PIK3CB mutation (n = 1)]. The 4-month PFS rate was 18.8% (3 of 16 evaluable patients) and further enrollment stopped due to futility.
Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed.ClinicalTrials.gov Identifier: NCT04001569.

PIK3CB is abnormally expressed in various carcinomas and affects the proliferation, invasion and drug resistance of cancer cells. However, its role in oesophageal squamous cell carcinoma (ESCC) is still unclear. In this study, PIK3CB was found to be highly expressed in ESCC tissues and cells and positively correlated with the poor prognosis of ESCC. Silencing PIK3CB inhibited the proliferation of ESCC cells, arrested the cell cycle, and promoted apoptosis. Mechanistic studies showed that the tumour-promoting effect of PIK3CB was achieved through PI3K/AKT/mTOR signalling pathway activation. Moreover, the high PIK3CB expression level in ESCC may be closely associated with the hypomethylation status of the gene promoter. In conclusion, PIK3CB promotes ESCC by activating the PI3K/AKT/mTOR signalling axis. PIK3CB may be a potential target in ESCC.

OBJECTIVE: The aim of this study was to explore the expression and prognostic significance of PIK3CB in lung adenocarcinoma (LUAD) and to analyse the possible molecular mechanism that promotes LUAD development.
METHODS: Differences of PIK3CB expression at transcriptional level between LUAD and normal tissues were analysed with the Timer and UALCAN databases. Then, immunohistochemical staining was performed to investigate PIK3CB expression at the protein level, and relationships between PIK3CB and clinical characteristics were accessed. Univariate and multivariate Cox regression were performed to identify the independent prognostic risk factors for LUAD. Genetic alterations were analysed using the cBioPortal database. The main coexpressed genes and enrichment pathways of PIK3CB were estimated with the LinkedOmics database.
RESULTS: Compared with normal tissues, PIK3CB was higherly expressed in LUAD at the transcriptional level and protein level, respectively. PIK3CB expression was closely related to prognosis of LUAD patients, and PIK3CB protein expression was associated with lymph node metastasis and pathological differentiation, but not related to sex, age, pleural invasion, vascular invasion, tumour site, tumour size or clinical stage. PIK3CB and tumour size were independent risk factors for LUAD patients. The expression of PIK3CB was negatively correlated with AKT1 and AKT2, but there was no significant correlation with AKT3, and strong positive correlations with ARMC8, DNAJC13 and PIK3R4. The main enrichment pathways of PIK3CB and related genes included adherens junctions and the phosphatidylinositol signalling pathways, ErbB signalling pathways, Hedgehog signalling pathways, and C-type lectin receptor signalling pathways. Therefore, we hypothesized that PIK3CB expression did not promote LUAD development through the classical PI3K/AKT pathway.
CONCLUSIONS: High PIK3CB expression was associated with the development of LUAD and worse prognosis. PIK3CB was an independent risk factor for LUAD patients. Therefore, this study provides a reliable reference for the prognostic assessment and targeted therapy for LUAD patients.

The human liver fluke Opisthorchis viverrini (Ov), the primary risk factor for cholangiocarcinoma (CHCA), is a parasite endemic to southeast Asian countries. With no effective treatments for CHCA currently available, early diagnosis and treatment of Ov infection remains the only practical method for the prevention of CHCA. In this study, plasma phosphoproteomes of patients in the non-Ov infection, non-cholangiocarcinoma subject group (non-OVCCA), the asymptomatic Ov infected group (OV), and the CHCA group (CCA), were investigated to identify potential biomarkers for Ov infection and CHCA. The AKT signalling pathway was found to be up-regulated. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (PIK3CB), an upstream signalling molecule, was selected as a potential biomarker and evaluated using indirect enzyme-linked immunosorbent assay (ELISA). Results demonstrated evidence that levels of PIK3CB in both the OV group and CCA group was statistically different compared to the non-OVCCA group (P < 0.01). However, the levels of PIK3CB between the OV group and the CCA group were found not to be statistically different. Sensitivity and specificity for OV using OD450 cut-off at >1.570 was 76 and 72%, respectively. For CCA, sensitivity and specificity using OD450 cut-off at >1.398 was 68 and 76%, respectively. Application of indirect ELISA detecting plasma PIK3CB will be of great benefit for screening of opisthorchiasis and CHCA.

OBJECTIVE: Preeclampsia (PE) is a pregnancy-specific multisystem disease as well as an important cause of maternal and perinatal death. This study aimed to analyze the placental transcriptional data and clinical information of PE patients available in the published database and predict the target genes for prevention of PE.
METHODS: The clinical information and corresponding RNA data of PE patients were downloaded from the GEO database. Cluster analysis was performed to examine the correlation between different genotyping genes and clinical manifestations. Then, bioinformatic approaches including GO, KEGG, WGCNA, and GSEA were employed to functionally characterize candidate target genes involved in pathogenesis of PE.
RESULTS: Two PE datasets GSE60438 and GSE75010 were obtained and combined, thereby providing the data of 205 samples in total (100 non-PE and 105 PE samples). After eliminating the batch effect, we grouped and analyzed the integrated data, and further performed GSEA analysis. It was found that the genes in group 1 and group 2 were different from those in normal samples. Moreover, WGCNA analysis revealed that genes in group 1 were up-regulated in turquoise module, including SASH1, PIK3CB and FLT-1, while genes in group 2 were up-regulated in the blue and brown modules. We further conducted GO and KEGG pathway enrichment analyses and found that the differential genes in turquoise module were mainly involved in biological processes such as small molecular catabolic process, while being highly enriched in pathways, including MAPK signaling pathway and Rap1 signaling pathway.
CONCLUSIONS: FLT-1 was conventionally used to predict PE risk, and sFLT-1 could also be used as an indicator to evaluate PE treatment effect. As a candidate biomarker for predicting PE, SASH1 may participate in proliferation, migration, invasion and epithelial mesenchymal transformation of human trophoblast cells by regulating MAPK pathway and Rap1 signaling pathway, thus affecting the progression of PE. The mechanism allowing PIK3CB to regulate PE development was not clear, while the gene could be another candidate biomarker for PE risk prediction. This is an exploratory study and our findings were still required verification in further studies.

Pancreatic adenocarcinoma (PAAD) is an aggressive malignancy, with a major mortality resulting from the rapid progression of metastasis. Unfortunately, no effective treatment strategy has been developed for PAAD metastasis to date. Thus, unraveling the mechanisms involved in PAAD metastatic phenotype may facilitate the treatment for PAAD patients.
PIK3CB is an oncogene implicated in cancer development and progression but less is known about whether PIK3CB participates in PAAD metastasis. Therefore, the objective of this study is to explore the mechanism(s) of PIK3CB in PAAD metastasis.
In our study, we examined the PIK3CB expression pattern using bioinformatic analysis and clinical material derived from patients with PAAD. Subsequently, a series of biochemical experiments were conducted to investigate the role of PIK3CB as potential mechanism(s) underlying PAAD metastasis in vivo using nude mice and in vitro using cell lines.
We observed that PIK3CB was involved in PAAD progression. Notably, we identified that PIK3CB was involved in PAAD metastasis. Downregulation of PIK3CB significantly reduced PAAD metastatic potential in vivo. Furthermore, a series of bioinformatic analyses showed that PIK3CB was involved in cell adhesion in PAAD. Notably, PIK3CB depletion inhibited invasion potential specifically via suppressing cell adhesion to collagen I in PAAD cells.
Collectively, our findings indicate that PIK3CB is involved in PAAD metastasis through cell-matrix adhesion. We proposed that PIK3CB is a potential therapeutic target for PAAD therapy.

The class I phosphoinositide 3-kinase (PI3K) catalytic subunits p110α and p110β are ubiquitously expressed but differently targeted in tumours. In cancer, PIK3CB (encoding p110β) is seldom mutated compared with PIK3CA (encoding p110α) but can contribute to tumorigenesis in certain PTEN-deficient tumours. The underlying molecular mechanisms are, however, unclear. We have previously reported that p110β is highly expressed in endometrial cancer (EC) cell lines and at the mRNA level in primary patient tumours. Here, we show that p110β protein levels are high in both the cytoplasmic and nuclear compartments in EC cells. Moreover, high nuclear:cytoplasmic staining ratios were detected in high-grade primary tumours. High levels of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P 3] were measured in the nucleus of EC cells, and pharmacological and genetic approaches showed that its production was partly dependent upon p110β activity. Using immunofluorescence staining, p110β and PtdIns(3,4,5)P 3 were localised in the nucleolus, which correlated with high levels of 47S pre-rRNA. p110β inhibition led to a decrease in both 47S rRNA levels and cell proliferation. In conclusion, these results present a nucleolar role for p110β that may contribute to tumorigenesis in EC.This article has an associated First Person interview with Fatemeh Mazloumi Gavgani, joint first author of the paper.

The most common PIK3CA mutation, producing the H1047R mutant of p110α, arises in myriad malignancies and is typically observed in low-grade breast tumours. In contrast, amplification is observed for wild-type PIK3CB, encoding p110β, and occurs at low frequency but in aggressive, high-grade metastatic tumours. We hypothesized that mutant p110αH1047R and wild-type p110β give rise to distinct transformed phenotypes. We show that p110αH1047R and wild-type p110β, but not wild-type p110α, transform MCF-10A cells and constitutively stimulate phosphoinositide 3-kinase (PI3K)-AKT pathway signalling. However, their resultant morphological transformed phenotypes are distinct. p110αH1047R induced an epithelial-to-mesenchymal transition (EMT) commensurate with SNAIL (also known as SNAI1) induction and loss of E-cadherin. Upon p110β expression, however, E-cadherin expression was maintained despite cells readily delaminating from epithelial sheets. Distinct from the prominent filopodia in p110αH1047R-expressing cells, p110β induced formation of lamellipodia, and these cells migrated with significantly greater velocity and decreased directionality. p110β-induced phenotypic alterations were accompanied by hyperactivation of RAC1; the dependency of transformation of p110β-binding to Rac1 revealed using a Rac1-binding mutant of p110β. Thus, PIK3CB amplification induces a transformed phenotype that is dependent upon a p110β-Rac1 signalling loop and is distinct from the transformed phenotype induced by p110αH1047R.