Despite development of novel agents targeting oncogenic pathways, matching targeted therapies to the genetic status of individual tumors is proving to be a daunting task for clinicians To improve the clinical efficacy and to reduce the toxic side effects of treatments, a deep characterization of genetic alterations in different tumors is required The mutational profile often evidences a gain of function or hyperactivity of phosphoinositide 3-kinases (PI3Ks) in tumors These enzymes are activated downstream tyrosine kinase receptors (RTKs) and/or G proteins coupled receptors (GPCRs) and, via AKT, are able to induce mammalian target of rapamycin (mTOR) stimulation Here, we elucidate the impact of class I (p110α, β, γ, and δ) catalytic subunit mutations on AKT-mediated cellular processes that control crucial mechanisms in tumor development Moreover, the interrelation of PI3K signaling with mTOR, ERK, and RAS pathways will be discussed, exploiting the potential benefits of PI3K signaling inhibitors in clinical use

https://www.tandfonline.com/doi/pdf/10.3109/07853890.2014.912836

PI3K/AKT signaling pathway and cancer: an updated review.

PTEN is among the most frequently inactivated tumour suppressor genes in sporadic cancer. PTEN has dual protein and lipid phosphatase activity, and its tumour suppressor activity is dependent on its lipid phosphatase activity, which negatively regulates the PI3K-AKT-mTOR pathway. Germline mutations in PTEN have been described in a variety of rare syndromes that are collectively known as the PTEN hamartoma tumour syndromes (PHTS). Cowden syndrome is the best-described syndrome within PHTS, with approximately 80% of patients having germline PTEN mutations. Patients with Cowden syndrome have an increased incidence of cancers of the breast, thyroid and endometrium, which correspond to sporadic tumour types that commonly exhibit somatic PTEN inactivation. Pten deletion in mice leads to Cowden syndrome-like phenotypes, and tissue-specific Pten deletion has provided clues to the role of PTEN mutation and loss in specific tumour types. Studying PTEN in the continuum of rare syndromes, common cancers and mouse models provides insight into the role of PTEN in tumorigenesis and will inform targeted drug development.

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PTEN loss in the continuum of common cancers, rare syndromes and mouse models

The efficacy of computed tomography (CT) screening for early lung cancer detection in heavy smokers is currently being tested by a number of randomized trials. Critical issues remain the frequency of unnecessary treatments and impact on mortality, indicating the need for biomarkers of aggressive disease. We explored microRNA (miRNA) expression profiles of lung tumors, normal lung tissues and plasma samples from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive follow-up. miRNA expression patterns significantly distinguished: (i) tumors from normal lung tissues, (ii) tumor histology and growth rate, (iii) clinical outcome, and (iv) year of lung cancer CT detection. Interestingly, miRNA profiles in normal lung tissues also displayed remarkable associations with clinical features, suggesting the influence of a permissive microenvironment for tumor development. miRNA expression analyses in plasma samples collected 1–2 y before the onset of disease, at the time of CT detection and in disease-free smokers enrolled in the screening trial, resulted in the generation of miRNA signatures with strong predictive, diagnostic, and prognostic potential (area under the ROC curve ≥ 0.85). These signatures were validated in an independent cohort from a second randomized spiral-CT trial. These results indicate a role for miRNAs in lung tissues and plasma as molecular predictors of lung cancer development and aggressiveness and have theoretical and clinical implication for lung cancer management.

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MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer

PTEN is a potent tumour suppressor, and its loss of function is frequently observed in both heritable and sporadic cancers. PTEN has phosphatase-dependent and phosphatase-independent (scaffold) activities in the cell and governs a variety of biological processes, including maintenance of genomic stability, cell survival, migration, proliferation and metabolism. Even a subtle decrease in PTEN levels and activity results in cancer susceptibility and favours tumour progression. Regulation of PTEN has therefore emerged as a subject of intense research in tumour biology. Recent discoveries, including the existence of distinct PTEN isoforms and the ability of PTEN to form dimers, have brought to light new modes of PTEN function and regulation. These milestone findings have in turn opened new therapeutic avenues for cancer prevention and treatment through restoration of PTEN tumour suppressor activity.

The functions and regulation of the PTEN tumour suppressor: new modes and prospects

PTEN is the most important negative regulator of the PI3K signaling pathway. In addition to its canonical, PI3K inhibition-dependent functions, PTEN can also function as a tumor suppressor in a PI3K-independent manner. Indeed, the PTEN network regulates a broad spectrum of biological functions, modulating the flow of information from membrane-bound growth factor receptors to nuclear transcription factors, occurring in concert with other tumor suppressors and oncogenic signaling pathways. PTEN acts through its lipid and protein phosphatase activity and other non-enzymatic mechanisms. Studies conducted over the past 10 years have expanded our understanding of the biological role of PTEN, showing that in addition to its ability to regulate proliferation and cell survival, it also plays an intriguing role in regulating genomic stability, cell migration, stem cell self-renewal and tumor microenvironment. Changes in PTEN protein levels, location, and enzymatic activity through various molecular mechanisms can generate a continuum of functional PTEN levels in inherited syndromes, sporadic cancers and other diseases. PTEN activity can indeed, be modulated by mutations, epigenetic silencing, transcriptional repression, aberrant protein localization, and posttranslational modifications. This review will discuss our current understanding of the biological role of PTEN, how PTEN expression and activity are regulated, and the consequences of PTEN dysregulation in human malignant tumors.

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PTEN: Multiple Functions in Human Malignant Tumors

MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC)

Background: MicroRNAs have been identified to play important role in the development of human esophageal squamous carcinoma (ESCC). In this study, we examined the regulatory effects of microRNA-26b (miR-26b) on ESCC proliferation, cell-cycle transition and migration. Methods: Expressions of miR-26a and miR-2bb were analyzed in 8 ESCC cell lines, and 27 human ESCC tissues and paired adjacent non-tumor tissues. MiR-26a and miR-26b were either upregulated or downregulated in ESCC cell lines TE-1 and Kyse140 cells. Their effects on ESCC in vitro growth, cell-cycle transition and migration were analyzed by proliferation assay, cell-cycle assay and invasion assay, respectively. The association of miR-26b and its downstream target gene, tumor necrosis factor receptor-associated factor 5 (TRAF5), was analyzed by luciferase reporter assay and qRT-PCR. TRAF5 was downregulated in TE-1 and Kyse140 cells to analyze its direct effect on miR-26b downregulation induced ESCC inhibition. Results: MiR-26b expression was aberrantly upregulated in ESCC cell lines and human ESCC tissues, whereas miR-26a expression was unchanged. In TE-1 and Kyse140 cells, miR-26b downregulation had tumor-suppressive effect, whereas miR-26b downregulation or miR-26a upregulation/downregulation had no significant effect, on ESCC proliferation, cell-cycle transition and migration. TRAF5 is confirmed to be the downstream target of miR-26b in ESCC. SiRNA-mediated TRAF5 downregulation inversely regulated the inhibition of miR-26b downregulation on ESCC proliferation, cell-cycle transition and migration. Conclusion: our study demonstrates that miR-26b downregulation, through the inverse regulation on TRAF5, had tumor-suppressive effect on human ESCC.

MicroRNA-26b regulates cancer proliferation migration and cell cycle transition by suppressing TRAF5 in esophageal squamous cell carcinoma

The aim of this study was to discover and identify potential protein biomarkers specific for non-small cell lung cancer (NSCLC). Two hundred and thirty five (235) Serum samples with 112 NSCLC and 123 controls were randomly divided into a training set and a blind testing set. Serum proteomic profiles were analyzed using surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy (SELDI-TOF-MS). Candidate protein biomarkers were purified by high Performance Liquid Chromatography (HPLC) and identified by liquid chromatography tandem mass spectrometry (LC-MS/MS) and validated using ProteinChip immunoassays. A total of 3 peaks (m/z with 6628, 9191 and 11412 Da) were screened out by SVM to construct the classification model with the high discriminatory power in the training set. The sensitivity and specificity of the model were 96.56% and 94.79% respectively in the blind testing set. The candidate biomarker with m/z of 6628 Da was found down-regulated in NSCLC patients, and identified as apolipoprotein C-I. Another two candidate biomarkers (9191 and 11412 Da) were found up-regulated in serum of NSCLC patients and identified as haptoglobin alpha-1 chain and S100A4, respectively. We have identified a set of biomarkers that could discriminate NSCLC from non-cancer controls. An efficient strategy, including SELDI-TOF-MS analysis, HPLC purification, MALDI-TOF-MS trace and LC-MS/MS identification, has been proved successfully.

https://journals.sagepub.com/doi/pdf/10.1177/153303460900800607

Detection and identification of potential biomarkers of non-small cell lung cancer.

The present study investigated the effect of tetrandrine on lung cancer cell growth and apoptosis, and its possible underlying molecular mechanism. A549 human lung cancer cells were incubated with between 2.5 and 10 µM tetrandrine for 12, 24 and 48 h, following which the effect of tetrandrine on cell viability and apoptosis were assessed using an MTT assay and flow cytometry. ELISA and western blotting were used to analyze VEGF activity, and the expression of poly (ADP-ribose) polymerase (PARP), phosphorylated protein kinase B (Akt), Bcl-2-associated X protein (Bax), hypoxia inducible factor (HIF)-1α and inter-cellular adhesion molecule-1 (ICAM-1). Tetrandrine effectively suppressed the growth of and induced apoptosis in A549 lung cancer cells. The expression of PARP, Bax, intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF) was significantly upregulated, and the phosphorylation of Akt and expression of HIF-1α was significantly suppressed in A549 lung cancer cells. Therefore, tetrandrine may suppress cell viability and induce apoptosis via the VEGF/HIF-1α/ICAM-1 signaling pathway.

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Tetrandrine suppresses lung cancer growth and induces apoptosis, potentially via the VEGF/HIF-1α/ICAM-1 signaling pathway

ABSTRACT Long non-coding RNA (lncRNA) OPA-interacting protein 5 antisense transcript 1 (OIP5-AS1) plays an oncogenic role in several types of cancer, but whether it is involved in non-small-cell lung cancer (NSCLC) is unclear. Our preliminary sequencing analysis revealed the upregulation of OIP5-AS1 in NSCLC. In this study, gene expression levels were analyzed by RT-qPCR. RNA-RNA pull-down assay was applied to detect direct interactions between RNAs. Overexpression assays were performed to explore the relationship between miR-34a and OIP5-AS1. CCK-8 assay and colony formation assay were applied to evaluate cell proliferation. In NSCLC cells (H23), overexpression of OIP5-AS1 increased the expression levels of programmed death-ligand 1 (PD-L1). In addition, inhibition of OIP5-AS1 and overexpression of miR-34a decreased the expression levels of PD-L1, and miR-34a significantly blocked the role of overexpression of OIP5-AS1. Overexpression of OIP5-AS1 and PD-L1 promoted H23 and H22 cells proliferation, while silencing of miR-34a and OIP5-AS1 played opposite roles and eliminated the effects of overexpression of OIP5-AS1 on cell proliferation. Therefore, OIP5-AS1 was upregulated to enhance the expression of oncogenic PD-L1 by sponging miR-34a in NSCLC, leading to promoted NSCLC cell proliferation. Our study also demonstrated that OIP5-AS1 was upregulated while miR-34a was downregulated in NSCLC.

https://www.tandfonline.com/doi/pdf/10.1080/21655979.2022.2036904?needAccess=true

Feng Zhao

Papers

MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC)

MicroRNA-26b regulates cancer proliferation migration and cell cycle transition by suppressing TRAF5 in esophageal squamous cell carcinoma

Detection and identification of potential biomarkers of non-small cell lung cancer.

Tetrandrine suppresses lung cancer growth and induces apoptosis, potentially via the VEGF/HIF-1α/ICAM-1 signaling pathway

Long non-coding RNA Opa interacting protein 5-antisense RNA 1 binds to micorRNA-34a to upregulate oncogenic PD-L1 in non-small cell lung cancer