The potential role of regulatory microRNAs of RAS/MAPK signaling pathway in the pathogenesis of colorectal cancer

Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Dysregulation of RAS/MAPK signaling axis is frequently found in CRC patients. The RAS/MAPK axis regulates cancer cell proliferation, apoptosis, inflammation, migration, and metastasis. Oncogenic or tumor-suppressor microRNAs (miRNAs) for RAS/MAPK signaling play a key role in the pathogenesis of CRC and are considered as novel potential biomarkers for diagnosis and prognosis of human malignancies. This review summarizes the current knowledge of mechanisms of action of RAS/MAPK miRNAs in the development and progression of CRC for a better understanding and hence a better management of this disease.     

Prolactin-stimulated activation of ERK1/2 mitogen-activated protein kinases is controlled by PI3-kinase/Rac/PAK signaling pathway in breast cancer cells

There is strong evidence that deregulation of prolactin (PRL) signaling contributes to pathogenesis and chemoresistance of breast cancer. Therefore, understanding cross-talk between distinct signal transduction pathways triggered by activation of the prolactin receptor (PRL-R), is essential for elucidating the pathogenesis of metastatic breast cancer.In this study, we applied a sequential inhibitory analysis of various signaling intermediates to examine the hierarchy of protein interactions within the PRL signaling network and to evaluate the relative contributions of multiple signaling branches downstream of PRL-R to the activation of the extracellular signal-regulated kinases ERK1 and ERK2 in T47D and MCF-7 human breast cancer cells.Quantitative measurements of the phosphorylation/activation patterns of proteins showed that PRL simultaneously activated Src family kinases (SFKs) and the JAK/STAT, phosphoinositide-3 (PI3)-kinase/Akt and MAPK signaling pathways. The specific blockade or siRNA-mediated suppression of SFK/FAK, JAK2/STAT5, PI3-kinase/PDK1/Akt, Rac/PAK or Ras regulatory circuits revealed that (1) the PI3-kinase/Akt pathway is required for activation of the MAPK/ERK signaling cascade upon PRL stimulation; (2) PI3-kinase-mediated activation of the c-Raf-MEK1/2-ERK1/2 cascade occurs independent of signaling dowstream of STATs, Akt and PKC, but requires JAK2, SFKs and FAK activities; (3) activated PRL-R mainly utilizes the PI3-kinase-dependent Rac/PAK pathway rather than the canonical Shc/Grb2/SOS/Ras route to initiate and sustain ERK1/2 signaling. By interconnecting diverse signaling pathways PLR may enhance proliferation, survival, migration and invasiveness of breast cancer cells.     

PLS3 predicts poor prognosis in pancreatic cancer and promotes cancer cell proliferation via PI3K/AKT signaling

Plastin-3 plays a key role in cancer cell proliferation and invasion, but its prognostic value in pancreatic cancer (PACA) remains poorly defined. In this study, we show that PLS3 messenger RNA is overexpressed in PACA tissue compared with normal tissue. We accumulated 207 cases of PACA specimens to perform immunohistochemical analysis and demonstrated that PLS3 levels correlate with T-classification (p < .001) and pathology (p < .001). Furthermore, overall survival rates (p < .001) in tumors with high PLS3 expression were poor, as assessed through Kaplan–Meier survival analysis. PLS3 was found to be an independent prognostic factor for PACA through multivariate Cox regression analysis. Moreover, we found that PLS3 enhances the proliferation and invasion of tumor cells as assessed through Cell Counting Kit-8, wounding healing assays, and Transwell assays. The upregulation of PLS3 also led to enhanced phosphatidylinositol-3 kinase/protein kinase B signaling in PACA cells. These data suggest that PLS3 is a biomarker to estimate PACA progression and represents a molecular target for PACA therapy.     

Importance of PI3-kinase pathway in response/resistance to aromatase inhibitors

Endocrine therapy has been the most effective treatment modality for hormone receptor positive breast cancer. However, its efficacy has been limited by either de novo or acquired resistance. Recent data indicates that activation of the phosphatidylinositol 3-kinase (PI3K) signaling is associated with the poor outcome luminal B subtype of breast cancer and accompanied by the development of endocrine therapy resistance. Importantly, inhibition of PI3K pathway signaling in endocrine resistant breast cancer cell lines reduces cell survival and improves treatment response to endocrine agents. Interestingly, mutations in PIK3CA, the alpha catalytic subunit of the class IA PI3K, which renders cells dependent on PI3K pathway signaling, is the most common genetic abnormality identified in hormone receptor positive breast cancer. The synthetic lethality observed between estrogen deprivation and PI3K pathway inhibition in estrogen receptor positive (ER+) breast cancer cell lines provides further scientific rational to target both estrogen receptor and the PI3K pathway in order to improve the outcome of ER+ breast cancer.     

Effects of streptozotocin-induced type 1 maternal diabetes on PI3K/AKT signaling pathway in the hippocampus of rat neonates

Diabetes in pregnancy impairs hippocampus development in offspring, leading to behavioral problems and learning deficits. Phosphatidylinositol 3-kinase/protein kinase B (PKB/Akt) signaling pathway plays a pivotal role in the regulation of neuronal proliferation, survival and death. The present study was designed to examine the effects of maternal diabetes on PKB/Akt expression and phosphorylation in the developing rat hippocampus. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was killed at first postnatal day (P1). The hippocampal expression and phosphorylation level of PKB/Akt, one of the key molecules in PI3K/AKT signaling pathway, was evaluated using real-time polymerase chain reaction (PCR) and western blot analysis. We found a significant bilateral downregulation of AKT1 gene expression in the hippocampus of pups born to diabetic mothers (p?<?0.05). Interestingly, our results revealed a marked upregulation of Akt1 gene in insulin-treated group compared with other groups (p?<?0.05). The western blot analysis also showed the reduction of phosphorylation level of all AKT isoforms in both diabetic and insulin-treated groups compared with control (p?<?0.05). Moreover, the results showed a significant increase in phosphorylation level of AKT in insulin-treated group compared with the diabetic group. These results represent that diabetes during pregnancy strongly influences the regulation of PKB/AKT in the developing rat hippocampus. Furthermore, although the control of glycemia by insulin administration is not sufficient to prevent the alterations in PKB/Akt expression, it modulates the phosphorylation process, thus ultimately resulting in a situation comparable to that found in the normal condition.     

PI3K regulates the activation of NLRP3 inflammasome in atherosclerosis through part-dependent AKT signaling pathway

PI3K is a downstream target of multiple cell-surface receptors, which acts as a crucial modulator of both cell polarization and survival. PI3K/AKT signaling pathway is commonly involved in cancer, atherosclerosis, and other diseases. However, its role in cardiovascular diseases, especially in atherosclerosis, remains to be further investigated. To determine the effect of PI3K/AKT signaling pathway on cellular inflammatory response and oxidative stress, PI3K inhibitor (GDC0941) and AKT inhibitor (MK2206) were used. First, THP-1 cells were incubated with ox-LDL (100 µg/ml) to establish an in vitro atherosclerosis model. The inflammatory factors and foam cell formation were then evaluated to ascertain and compare the effects of PI3K and AKT inhibition. ApoE^−/− mice fed a high-fat diet were used to assess the roles of PI3K and AKT in aortic plaque formation. Our results showed that the inhibition of PI3K or AKT could suppress the activation of NLRP3, decreased the expression levels of p-p65/p65 and reduced the production of mitochondrial reaction oxygen species (mitoROS) in THP-1 cells. Inhibition of PI3K or AKT could also reduced atherosclerosis lesion and plaque area, and decreased the levels of NLRP3 and IL-1β in ApoE^−/− mice. The effect of PI3K inhibition was more significant than AKT. Therefore, PI3K inhibition can retard the progress of atherosclerosis. Besides, there may be other AKT-independent pathways that regulate the formation of atherosclerosis.     

PI3K/AKT/mTOR信号通路及其在卵巢癌治疗中的应用

卵巢癌是女性生殖系统常见的恶性肿瘤,发病率居于妇科恶性肿瘤第三位,死亡率居于妇科恶性肿瘤之首。目前对卵巢癌的标准治疗包括肿瘤细胞减灭术及卡铂和紫杉醇的联合化疗。PI3K/AKT/mTOR信号通路在卵巢癌的细胞增殖、侵袭、细胞周期进展、血管生成及耐药中发挥重要作用,是卵巢癌中最常发生改变的细胞内途径。本文对PI3K/AKT/mTOR信号通路及其在卵巢癌增殖和进展中的影响、PI3K/AKT/mTOR信号通路抑制剂在卵巢癌中的治疗应用做简要综述。     

Low-dose naltrexone plays antineoplastic role in cervical cancer progression through suppressing PI3K/AKT/mTOR pathway

The incidence of cervical cancer is increasing annually worldwide. Low-dose naltrexone (LDN) has been reported to delay tumor progression, but the mechanism remains unclear. Here, we found that low-dose naltrexone could upregulate the expression of OGFr. Additionally, LDN could suppress the abilities of colony formation, migration and invasion in cervical cancer cells. LDN could also inhibit cervical cancer progression in mice model. Moreover, LDN indirectly reduced the expressions of PI3K, pAKT and mTOR in vitro and in vivo. Therefore, LDN may be considered a potential treatment option for cervical cancer.     

Structure-based design of thienobenzoxepin inhibitors of PI3-kinase

Starting from thienobenzopyran HTS hit 1, co-crystallization, molecular modeling and metabolic analysis were used to design potent and metabolically stable inhibitors of PI3-kinase. Compound 15 demonstrated PI3K pathway suppression in a mouse MCF7 xenograft model.     

Retracted: MicroRNA-99b suppresses human cervical cancer cell activity by inhibiting the PI3K/AKT/mTOR signaling pathway

Cervical cancer is common cancer among women with high morbidity. MicroRNAs (miRs) are involved in the progression and development of cervical cancer. This study aimed to explore the effect of miR-99b-5p (miR-99b) on invasion and migration in cervical cancer through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway. The microarray-based analysis was used to screen out differentially expressed miRNAs. Expression of miR-99b, PI3K, AKT, mTOR, and ribosomal protein S6 kinase (p70S6K) was determined in both cervical cancer tissues and paracancerous tissues. Next, alteration of miR-99b expression in cervical cancer was conducted to evaluate levels of PI3K, AKT, mTOR, p70S6K matrix metallopeptidase 2, epithelial cell adhesion molecule, and intercellular adhesion molecule 1, as well as the effect of miR-99b on cell proliferation, invasion, migration, cell cycle distribution, and apoptosis. The results demonstrated that miR-99b expression was decreased and levels of PI3K, AKT, mTOR, and p70S6K were elevated in cervical cancer tissues. More important, overexpressed miR-99b repressed the PI3K/AKT/mTOR signaling pathway, inhibited cell proliferation, invasion, and migration, blocked cell cycle entry, and promoted apoptosis in cervical cancer. These results indicate that miR-99b attenuates the migration and invasion of human cervical cancer cells through downregulation of the PI3K/AKT/mTOR signaling pathway, which provides a therapeutic approach for cervical cancer treatment.     

PI3K-Akt pathway: Its functions and alterations in human cancer

Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase and generates phosphatidylinositol-3,4,5-trisphosphate (PI(3, 4, 5)P3). PI(3, 4, 5)P3 is a second messenger essential for the translocation of Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (PDK) 1 and PDK2. Activation of Akt plays a pivotal role in fundamental cellular functions such as cell proliferation and survival by phosphorylating a variety of substrates. In recent years, it has been reported that alterations to the PI3K-Akt signaling pathway are frequent in human cancer. Constitutive activation of the PI3K-Akt pathway occurs due to amplification of the PIK3C gene encoding PI3K or the Akt gene, or as a result of mutations in components of the pathway, for example PTEN (phosphatase and tensin homologue deleted on chromosome 10), which inhibit the activation of Akt. Several small molecules designed to specifically target PI3K-Akt have been developed, and induced cell cycle arrest or apoptosis in human cancer cells in vitro and in vivo . Moreover, the combination of an inhibitor with various cytotoxic agents enhances the anti-tumor efficacy. Therefore, specific inhibition of the activation of Akt may be a valid approach to treating human malignancies and overcoming the resistance of cancer cells to radiation or chemotherapy.     

胃癌病灶内幽门螺杆菌感染与病理特征、凋亡侵袭基因和PI3K/AKT信号通路的关系

目的 探讨胃癌病灶内幽门螺杆菌（H. pylori）感染与病理特征、凋亡侵袭基因、PI3K/AKT信号通路的相关性。方法 选择我院2016年9月至2019年1月间经胃镜检查、病灶组织病理学证实为原发性胃癌的患者117例作为胃癌组,选择同期在我院进行胃镜检查并明确无恶性病变的志愿者100例为非胃癌组。检测两组对象H. pylori阳性情况并进一步分为Hp阳性组（n＝59）和Hp阴性组（n＝58）。对比不同H. pylori感染情况胃癌患者的病理特征及病灶组织中凋亡侵袭基因、PI3K/AKT信号通路相关分子的表达差异。结果 胃癌组患者H. pylori感染率显著高于非胃癌组（P＜0.05）。H. pylori阳性组中肿瘤直径≥5 cm、TNM分期为Ⅲ~Ⅳ期、组织分化程度为低—中分化和淋巴结转移的比例均显著高于Hp阴性组患者,差异均有统计学意义（P＜0.05）。Hp阳性组患者胃癌病灶中凋亡相关基因p53、Bax的表达量低于Hp阴性组,Survivin、Bcl-2的表达量高于Hp阴性组;侵袭相关基因BOP1、MUC17、SIRT2 mRNA的表达量高于Hp阴性组（P＜0.05）。Hp阳性组患者胃癌病灶中PI3K/AKT信号通路相关分子PI3K和AKT的表达量高于Hp阴性组（P＜0.05）。结论 胃癌合并H. pylori感染者的病情相对较重,可能与H. pylori能上调PI3K/AKT信号通路活性、影响癌细胞相关凋亡及侵袭基因的表达有关。     

PI3-kinase activation by GM-CSF in endothelium is upstream of Jak/Stat pathway: role of alphaGMR

GM-CSF has been identified as a growth factor for endothelial cells. In this study, we investigated the role of PI3-kinase pathway in mediating GM-CSF induced angiogenesis. GM-CSF induced tube formation in human umbilical vein endothelial cells, as examined using Matrigel assay, was inhibited by specific inhibitors of PI3-kinase, wortmannin, and LY294002. The regulatory subunit of PI3-kinase (p85) interacted with alphaGMR via its C-SH2 domain in a GM-CSF-dependent fashion with concomitant phosphorylation of p85 and activation of PI3-kinase pathway. p85 binding site on the alphaGMR was essential to induce GM-CSF receptor-dependent Stat activation. Furthermore, inhibition of PI3-kinase activity also abrogated GM-CSF induced Stat activation. These studies underscore the significance of the GM-CSF mediated PI3-kinase activation and its role in angiogenesis.     

PI3K/Akt信号通路的调控与肿瘤血管生成

肿瘤对人类的生存危害极大,恶性肿瘤的治疗一直是世界性的难题。肿瘤血管生成是肿瘤赖以生长、转移的基础,受多种因子的调节。目前发现有多条信号网络参与调控肿瘤血管生成,PI3K/Akt是其中比较重要的一条信号传导途径,该通路与肿瘤的发生发展密切相关。本文介绍了PI3K/Akt信号通路的结构组成与活性调控,并重点阐述PI3K/Akt信号途径与肿瘤血管生成的关系。