Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. Enormous efforts have been dedicated to the development of drugs targeting PI3K signaling, many of which are currently employed in clinical trials evaluation, and it is becoming increasingly clear that PI3K inhibitors are effective in inhibiting tumor progression. PI3K inhibitors are subdivided into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors. In this review, we performed a critical review to summarize the role of the PI3K pathway in tumor development, recent PI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3K inhibition.

/pdf/targeting-pi3k-in-cancer-mechanisms-and-advances-in-clinical-4ituoao2ez.pdf

Targeting PI3K in cancer: mechanisms and advances in clinical trials

The incidence and mortality rate of cancer has been quickly increasing in the past decades. At present, cancer has become the leading cause of death worldwide. Most of the cancers cannot be effectively diagnosed at the early stage. Although there are multiple therapeutic treatments, including surgery, radiotherapy, chemotherapy, and targeted drugs, their effectiveness is still limited. The overall survival rate of malignant cancers is still low. It is necessary to further study the mechanisms for malignant cancers, and explore new biomarkers and targets that are more sensitive and effective for early diagnosis, treatment, and prognosis of cancers than traditional biomarkers and methods. Long non-coding RNAs (lncRNAs) are a class of RNA transcripts with a length greater than 200 nucleotides. Generally, lncRNAs are not capable of encoding proteins or peptides. LncRNAs exert diverse biological functions by regulating gene expressions and functions at transcriptional, translational, and post-translational levels. In the past decade, it has been demonstrated that the dysregulated lncRNA profile is widely involved in the pathogenesis of many diseases, including cancer, metabolic disorders, and cardiovascular diseases. In particular, lncRNAs have been revealed to play an important role in tumor growth and metastasis. Many lncRNAs have been shown to be potential biomarkers and targets for the diagnosis and treatment of cancers. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis of certain malignant cancers, including lung, breast, liver, and colorectal cancers, as well as hematological malignancies and neuroblastoma.

https://www.mdpi.com/2073-4409/8/9/1015/pdf

Long Non-Coding RNA in the Pathogenesis of Cancers.

Long non-coding RNAs (LncRNAs) represent a novel class of noncoding RNAs that are longer than 200 nucleotides without protein-coding potential and function as novel master regulators in various human diseases, including cancer. Accumulating evidence shows that lncRNAs are dysregulated and implicated in various aspects of cellular homeostasis, such as proliferation, apoptosis, mobility, invasion, metastasis, chromatin remodeling, gene transcription, and post-transcriptional processing. However, the mechanisms by which lncRNAs regulate various biological functions in human diseases have yet to be determined. HOX antisense intergenic RNA (HOTAIR) is a recently discovered lncRNA and plays a critical role in various areas of cancer, such as proliferation, survival, migration, drug resistance, and genomic stability. In this review, we briefly introduce the concept, identification, and biological functions of HOTAIR. We then describe the involvement of HOTAIR that has been associated with tumorigenesis, growth, invasion, cancer stem cell differentiation, metastasis, and drug resistance in cancer. We also discuss emerging insights into the role of HOTAIR as potential biomarkers and therapeutic targets for novel treatment paradigms in cancer.

/pdf/hotair-an-oncogenic-long-non-coding-rna-in-human-cancer-2jjkhanz7k.pdf

HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer.

Noncoding RNAs (ncRNAs) represent a large segment of the human transcriptome and have been shown to play important roles in cellular physiology and disease pathogenesis. Increasing evidence on the functional roles of ncRNAs in cancer progression emphasizes the potential of ncRNAs for cancer treatment. Here, we summarize the roles of ncRNAs in disease relapse and resistance to current standard chemotherapy and radiotherapy; the current research progress on ncRNAs for clinical and/or potential translational applications, including the identification of ncRNAs as therapeutic targets; therapeutic approaches for ncRNA targeting; and ncRNA delivery strategies in potential clinical translation. Several ongoing clinical trials of novel RNA-based therapeutics were also emphasized. Finally, we discussed the perspectives and obstacles to different target combinations, delivery strategies, and system designs for ncRNA application. The next approved nucleic acid drug to treat cancer patients may realistically be on the horizon.

/pdf/noncoding-rnas-in-cancer-therapy-resistance-and-targeted-3trdx2xa7w.pdf

Noncoding RNAs in cancer therapy resistance and targeted drug development

HOTAIR LncRNA: A novel oncogenic propellant in human cancer.

Objectives: Imatinib, a breakpoint cluster region-Abelson murine leukemia tyrosine kinase inhibitor, has revolutionized the treatment of chronic myelogenous leukemia (CML). However, the development of multidrug resistance (MDR) limits the clinical application of imatinib. In this study, we aimed to investigate the mechanisms of long noncoding RNA (lncRNA) HOTAIR in CML resistance to imatinib.Methods: Thirty-four CML patients were divided into multidrug resistance protein 1 (MRP1)-low and MRP1-high groups according to the median expression. Real-time PCR (qPCR) was used to detect the expression of lncRNA HOTAIR in CML patients, and MTT assay and flow cytometry assay were employed to detect the biological function of silencing lncRNA HOTAIR on the cell survival rate and apoptotic rate. An imatinib-resistant human CML cell line K562 (K562-R) was established, and western blot was used to detect the impact of lncRNA HOTAIR on the activation of PI3K/Akt signaling pathway.Results: Our results showed that...

https://www.tandfonline.com/doi/pdf/10.1080/10245332.2016.1258152

The role of long noncoding RNA HOTAIR in the acquired multidrug resistance to imatinib in chronic myeloid leukemia cells.

The histone demethylase JMJD1C is associated with human platelet counts. The JMJD1C knockout in zebrafish and mice leads to the ablation of megakaryocyte–erythroid lineage anemia. However, the specific expression, function, and mechanism of JMJD1C in megakaryopoiesis remain unknown. Here, we used cell line models, cord blood cells, and thrombocytopenia samples, to detect the JMJD1C expression. ShRNA of JMJD1C and a specific peptide agonist of JMJD1C, SAH-JZ3, were used to explore the JMJD1C function in the cell line models. The actin ratio in megakaryopoiesis for the JMJDC modulation was also measured. Mass spectrometry was used to identify the JMJD1C-interacting proteins. We first show the JMJD1C expression difference in the PMA-induced cell line models, the thrombopoietin (TPO)-induced megakaryocyte differentiation of the cord blood cells, and also the thrombocytopenia patients, compared to the normal controls. The ShRNA of JMJD1C and SAH-JZ3 showed different effects, which were consistent with the expression of JMJD1C in the cell line models. The effort to find the underlying mechanism of JMJD1C in megakaryopoiesis, led to the discovery that SAH-JZ3 decreases F-actin in K562 cells and increases F-actin in MEG-01 cells. We further performed mass spectrometry to identify the potential JMJD1C-interacting proteins and found that the important Ran GTPase interacts with JMJD1C. To sum up, JMJD1C probably regulates megakaryopoiesis by influencing the actin network.

/pdf/jmjd1c-regulates-megakaryopoiesis-in-in-vitro-models-through-231bam7n.pdf

JMJD1C Regulates Megakaryopoiesis in In Vitro Models through the Actin Network

Macroautophagy (hereafter referred to as autophagy) is a highly conserved self‑digestion process that is critical for maintaining homeostasis in response to various stresses. The autophagy‑related protein family, including the GABA type A receptor‑associated protein (GABARAP) and microtubule‑associated protein 1 light chain 3 subfamilies, is crucial for autophagosome biogenesis. Although the regulatory machinery of autophagy in the cytoplasm has been widely studied, its transcriptional and epigenetic regulatory mechanisms still require more targeted investigations. The present study identified histone lysine demethylase 3B (KDM3B) as a crucial component of autophagy on a panel of leukemia cell lines, including K562, THP1 and U937, resulting in transcriptional activation of the autophagy‑related gene GABA type A receptor‑associated protein like 1 (GABARAPL1). KDM3B expression promoted autophagosome formation and affected the autophagic flux in leukemia cells under the induction of external stimuli. Notably, RNA‑sequencing and reverse transcription‑quantitative PCR analysis showed that KDM3B knockout inhibited the expression of GABARAPL1. Chromatin immunoprecipitation‑quantitative PCR and luciferase assay showed that KDM3B was associated with the GABARAPL1 gene promoter under stimulation and enhanced its transcription. The present findings demonstrated that KDM3B was critical for regulating the GABARAPL1 gene and influencing the process of autophagy in leukemia cells. These results provide a new insight for exploring the association between autophagy and KDM3B epigenetic regulation in leukemia.

/pdf/histone-lysine-demethylase-3b-regulates-autophagy-via-3bb1usyk.pdf

Haiying Wang

Papers

The role of long noncoding RNA HOTAIR in the acquired multidrug resistance to imatinib in chronic myeloid leukemia cells.

JMJD1C Regulates Megakaryopoiesis in In Vitro Models through the Actin Network

Histone lysine demethylase 3B regulates autophagy via transcriptional regulation of GABARAPL1 in acute myeloid leukemia cells.

FOXK2 regulates PFKFB3 in promoting glycolysis and tumorigenesis in multiple myeloma.