Changes of PI3K/AKT/mTOR signaling pathway in the progression of cervical cancer and its target genes

Objective: To study the changes of PI3K/AKT/mTOR signaling pathway in the progression of cervical cancer and explore its target genes. Methods: The patients who underwent surgical resection and were diagnosed with cervical cancer by postoperative pathology in the First People's Hospital of Jiangxia District Wuhan City between June 2014 and December 2017 were selected, and the cervical cancer lesion tissues and lesion tissues adjacent to cervical cancer were kept;patients who underwent conization and were diagnosed with cervical intraepithelial neoplasia by postoperative pathology in the First People's Hospital of Jiangxia District Wuhan City during the same period were selected, and the cervical intraepithelial neoplasia tissues were kept. The protein levels of PI3K/AKT/mTOR signaling molecules as well as the mRNA expression of proliferation genes and invasion genes were determined. Results: p-PI3K, p-AKT, mTOR, p70S6K and p-4EBP1 protein levels as well as CyclinD1, Survivin, Piwil2, RACK1, EFEMP1 and VEGF mRNA expression in cervical cancer lesion tissues were significantly higher than those in adjacent lesion tissues and cervical intraepithelial neoplasia tissues whereas THBS2, Beclin1, E-cadherin, TIMP1 and TIMP2 mRNA expression were significantly lower than those in adjacent lesion tissues and cervical intraepithelial neoplasia tissues;p-PI3K, p-AKT, mTOR, p70S6K and p-4EBP1 protein levels in cervical cancer lesion tissues were positively correlated with CyclinD1, Survivin, Piwil2, RACK1, EFEMP1 and VEGF mRNA expression, and negatively correlated with THBS2, Beclin1, E-cadherin, TIMP1 and TIMP2 mRNA expression. Conclusion: Excessive activation of PI3K/AKT/mTOR signaling pathway during the progression of cervical cancer can change the expression of multiple proliferation and invasion genes to promote the proliferation and invasion of cancer cells.

Osteopontin promotes gastric cancer progression via phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway

BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors.Osteopontin(OPN)is thought to be closely related to the occurrence,metastasis and prognosis of many types of tumors.AIM To investigate the effects of OPN on the proliferation,invasion and migration of GC cells and its possible mechanism.METHODS The mRNA and protein expression of OPN in the GC cells were analyzed by realtime quantitative-reverse transcription polymerase chain reaction and western blotting,and observe the effect of varying degree expression OPN on the proliferation and other behaviors of GC.Next,the effects of OPN knockdown on GC cells migration and invasion were examined.The short hairpin RNA(shRNA)and negative control shRNA targeting OPN-shRNA were transfected into the cells according to the manufacturer’s instructions.Non transfected cells were classified as control in the identical transfecting process.24 h after RNA transfection cell proliferation activity was detected by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay,and cell invasiveness and migration were detected by Trans well assay.Meanwhile,the expression of protein kinase B(AKT),matrix metalloproteinase 2(MMP-2)and vascular endothelial growth factor(VEGF)in the human GC cell lines was detected by reverse transcription polymerase chain reaction and western blotting.RESULTS The results of this study revealed that OPN mRNA and protein expression levels were highly expressed in SGC-7901 cells.OPN knockdown by specific shRNA noticeably reduced the capabilities of proliferation,invasion and migration of SGC-7901 cells.Moreover,in the experiments of investigating the underlying mechanism,results showed that OPN knockdown could down-regulated the expression of MMP-2 and VEGF,it also decreased the phosphorylation of AKT.Meanwhile,the protein expression levels of MMP-2,VEGF and phosphorylated AKT was noticeable lower than that in control group in the GC cells after they were added to phosphatidylinositol-3-kinase(PI3K)inhibitor(LY294002).CONCLUSION These results suggested that OPN though PI3K/AKT/mammalian target of rapamycin signal pathway to upregulate MMP-2 and VEGF expression,which contribute SGC-7901 cells to proliferation,invasion and migration.Thus,our results demonstrate that OPN may serve as a novel prognostic biomarkers as well as a potential therapeutic targets for GC.

Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer

Pancreatic cancer is one of the most aggressive and difficult cancers to treat.Despite numerous research efforts,limited success has been achieved in the therapeutic management of patients with this disease.In the current review,we focus on one component of morphogenesis signaling,Hedgehog(Hh),with the aim of developing novel,effective therapies for the treatment of pancreatic cancer.Hh signaling contributes to the induction of a malignant phenotype in pancreatic cancer and is responsible for maintaining pancreatic cancer stem cells.In addition,we propose a novel concept linking Hh signaling and tumor hypoxic conditions,and discuss the effects of Hh inhibitors in clinical trials.The Hh signaling pathway may represent a potential therapeutic target for patients with refractory pancreatic cancer.

Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer

Fibroblast growth factor receptors(FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer.

Core signaling pathways and new therapeutic targets in pancreatic cancer

Objective Pancreatic cancer is a highly aggressive malignancy that has been resistant to treatment. Advances in cancer genetics have improved our understanding of this disease, but the genetics of pancreatic cancer remain poorly understood. A better understanding of the pathogenic role of specific gene mutations and core signaling pathways would propel the development of more effective treatments. The objective in this review was to highlight recent research that shows promise for new treatments for pancreatic cancer. Data sources All articles cited in this review were mainly searched from PubMed, which were published in English from 1993 to 2009. Study selection Original articles and critical reviews selected were relevant to the molecular mechanisms of pancreatic cancer. Results Dysregulation of core signaling pathways and processes through frequently genetic alterations can explain the major features of pancreatic tumorigenesis. New therapeutic targets based on recent research are emerging that hold promise for the future management of pancreatic cancer. Conclusion New agents used in conjunction with standard radiotherapy and chemotherapy might help to overcome drug resistance by targeting multiple signaling pathways to induce responsiveness of pancreatic cancer cells to death signals.

<i>STYK1/NOK</i>—A Potential Radiotherapeutic Target and Biomarker for Gastric Cancer and Cervical Cancer

This article introduced the STYK1/NOK, including its origin, chemical composition and biological function, and the expression of STYK1/NOK in various cancer cell lines was reviewed. Furthermore, our recent study showed that STYK1/NOK protein was also over expressed in gastric cancer and cervical cancer specimens, and STYK1/NOK expression increased after tumor cells were irradiated with γ ray. These results indicated that STYK1/NOK might be involved in the occurrence and progress of gastric cancer and cervical cancer, and contribute to the radioresistance of tumor cells. Thus, STYK1/NOK might be a potential therapeutic target and diagnostic marker for gastric cancer and cervical cancer.

Effects of different administration routes of neoadjuvant chemotherapy on cancer cell growth signal pathway function in cervical cancer

Objective:To study the effects of different administration routes of neoadjuvant chemotherapy on cancer cell growth signal pathway function in cervical cancer.Methods: Patients with cervical cancer who received neoadjuvant chemotherapy in Fufeng People's Hospital between July 2008 and July 2016 were selected as the research subjects and randomly divided into intervention group and intravenous group who accepted the neoadjuvant interventional arterial chemotherapy and neoadjuvant intravenous chemotherapy respectively. After surgical resection, the contents of PI3K/AKT/mTOR, Wnt/β-catenin and MEK/ERK signaling pathway in cervical cancer lesions were determined.Results:p-PI3K, p-AKT, mTOR, MMP2, VEGF,β-catenin, CyclinD1, Twist, Slug, Snail, MEK1, MEK2, ERK1/2 and Bcl-2 protein levels in cervical cancer lesion of intervention group were significantly lower than those of intravenous group whereas E-cadherin and Bax protein levels were significantly higher than those of intravenous group.Conclusion: Neoadjuvant interventional arterial chemotherapy can be more effective than neoadjuvant intravenous chemotherapy to inhibit the cancer cell growth mediated by PI3K/AKT/mTOR, Wnt/β-catenin and MEK/ERK signaling pathway in cervical cancer.

Correlation of serum STMN1 and Cath-D levels with the invasive growth of cervical cancer

Objective:To study the correlation of serum stathmin 1 (STMN1) and cathepsin D (Cath-D) levels with the invasive growth of cervical cancer.Methods: The patients with cervical cancer and those with uterine fibroids who underwent surgical resection in the Second People's Hospital of Yichang between January 2013 and November 2017 were selected and enrolled in the malignant group and the benign group of the study respectively;the serum was collected before operation to detect the contents of STMN1 and Cath-D;the cervical cancer lesion tissues were collected from the malignant group and the normal cervical tissues were collected from the benign group to measure the expression of STMN1, Cath-D, invasion genes and invasion signal molecules.Results:STMN1 and Cath-D contents in serum as well as STMN1 and Cath-D mRNA expression in lesion tissue of malignant group were significantly higher than those of benign group, and serum STMN1 and Cath-D contents of malignant group were positively correlated with STMN1 and Cath-D mRNA expression in lesion tissue;RACK1, Twist, MMP9, mTOR, S6K1, Wnt andβ-catenin mRNA expression in lesion tissue of malignant group were significantly higher than those of benign group whereas E-cadherin, GRIM19 and GSK-3β mRNA expression were significantly lower than those of benign group, and serum STMN1 and Cath-D contents of malignant group were positively correlated with RACK1, Twist, MMP9, mTOR, S6K1, Wnt andβ-catenin mRNA expression in lesion tissue, and negatively correlated with E-cadherin, GRIM19 and GSK-3β mRNA expression. Conclusion:The abnormally elevated STMN1 and Cath-D in serum of patients with cervical cancer can evaluate the invasive growth of the lesion.

Nanocarrier of Pin1 inhibitor based on supercritical fluid technology inhibits cancer metastasis by blocking multiple signaling pathways

Cancer metastasis is the primary cause of all cancer-related deaths due to the lack of effective targeted drugs that simultaneously block multiple signaling pathways that drive the dissemination and growth of cancer cells.The unique proline isomerase Pin1 activates numerous cancer pathways,but its role in cancer metastasis and the inhibitory efficacy of Pin1 inhibitors on cancer metastasis are unknown.Moreover,the applicability of Pin1 inhibitor-all-trans retinoic acid(ATRA)is limited due to its several drawbacks.Herein,uniform ATRA-loaded polylactic acid-polyethylene glycol block copolymer nanoparticles(ATRA-NPs)with high encapsulation efficiency,good cellular uptake,excellent controlled release performance and pharmacokinetics are developed using supercritical carbon dioxide processing combined with an optimized design.ATRA-NPs exhibited excellent biosafety and significant inhibition on the growth and metastasis of hepatocellular carcinoma.Pin1 played a key role in cancer metastasis and was the main target of ATRA-NPs.ATRA-NPs exerted their potent anti-metastatic effect by inhibiting Pin1 and then simultaneously blocking multiple signaling pathways and cancer epithelial-mesenchymal progression.Since ATRA-NPs could effectively couple the inhibition of cancer cell dissemination with cancer growth,it provided a novel therapeutic strategy for efficiently inhibiting cancer metastasis.

Prostate cancer： the need for biomarkers and new therapeutic targets

Prostate cancer （PCa） incidence and mortality have decreased in recent years. Nonetheless, it remains one of the most prevalent cancers in men, being a disquieting cause of men＇s death worldwide. Changes in many cell signaling pathways have a predominant role in the onset, development, and progression of the disease. These include prominent pathways involved in the growth, apoptosis, and angiogenesis of the normal prostate gland, such as an- drogen and estrogen signaling, and other growth factor signaling pathways. Understanding the foundations of PCa is leading to the discovery of key molecules that could be used to improve patient management. The ideal scenario would be to have a panel of molecules, preferably detectable in body fluids, that are specific and sensitive biomarkers for PCa In the early stages, androgen deprivation is the gold standard therapy. However, as the cancer progresses, it even- tually becomes independent of androgens, and hormonal therapy fails. For this reason, androgen-independent PCa is still a major therapeutic challenge. By disrupting specific protein interactions or manipulating the expression of some key molecules, it might be possible to regulate tumor growth and metastasis formation, avoiding the systemic side effects of current therapies. Clinical trials are already underway to assess the efficacy of molecules specially designed to target key proteins or protein interactions. In this review, we address that recent progress made towards under- standing PCa development and the molecular pathways underlying this pathology. We also discuss relevant molecular markers for the management of PCa and new therapeutic challenges.

Treating non-small cell lung cancer by targeting the PI3K signaling pathway

The phosphosphatidylinositol-3-kinase(PI3K)signaling pathway is one of the most important intracellular signal transduction pathways affecting cell functions,such as apoptosis,translation,metabolism,and angiogenesis.Lung cancer is a malignant tumor with the highest morbidity and mortality rates in the world.It can be divided into two groups,non-small cell lung cancer(NSCLC)and small cell lung cancer(SCLC).NSCLC accounts for>85%of all lung cancers.There are currently many clinical treatment options for NSCLC;however,traditional methods such as surgery,chemotherapy,and radiotherapy have not been able to provide patients with good survival benefits.The emergence of molecular target therapy has improved the survival and prognosis of patients with NSCLC.In recent years,there have been an increasing number of studies on NSCLC and PI3K signaling pathways.Inhibitors of various parts of the PI3K pathway have appeared in various phases of clinical trials with NSCLC as an indication.This article focuses on the role of the PI3K signaling pathway in the occurrence and development of NSCLC and summarizes the current clinical research progress and possible development strategies.

Current therapeutic modalities and chemopreventive role of natural products in liver cancer:Progress and promise

Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year,with an estimated 5-year survival rate of 30%–35%after diagnosis.Hepatocellular carcinoma(HCC)constitutes a significant subtype of liver cancer(approximate75%)and is considered primary liver cancer.Treatment for liver cancer mainly depends on the stage of its progression,where surgery including,hepatectomy and liver transplantation,and ablation and radiotherapy are the prime choice.For advanced liver cancer,various drugs and immunotherapy are used as first-line treatment,whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins.Sorafenib and lenvatinib are first-line therapies,while regorafenib and ramucirumab are secondline therapy.Various metabolic and signaling pathways such as Notch,JAK/STAT,Hippo,TGF-β,and Wnt have played a critical role during HCC progression.Dysbiosis has also been implicated in liver cancer.Drug-induced toxicity is a key obstacle in the treatment of liver cancer,necessitating the development of effective and safe medications,with natural compounds such as resveratrol,curcumin,diallyl sulfide,and others emerging as promising anticancer agents.This review highlights the current status of liver cancer research,signaling pathways,therapeutic targets,current treatment strategies and the chemopreventive role of various natural products in managing liver cancer.

Role of exosomes in metastasis and therapeutic resistance in esophageal cancer

Esophageal cancer(EC)has a high incidence and mortality rate and is emerging as one of the most common health problems globally.Owing to the lack of sensitive detection methods,uncontrollable rapid metastasis,and pervasive treatment resistance,EC is often diagnosed in advanced stages and is susceptible to local recurrence.Exosomes are important components of intercellular communication and the exosome-mediated crosstalk between the cancer and surrounding cells within the tumor microenvironment plays a crucial role in the metastasis,progression,and therapeutic resistance of EC.Considering the critical role of exosomes in tumor pathogenesis,this review focused on elucidating the impact of exosomes on EC metastasis and therapeutic resistance.Here,we summarized the relevant signaling pathways involved in these processes.In addition,we discussed the potential clinical applications of exosomes for the early diagnosis,prognosis,and treatment of EC.

Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells

Colorectal cancer(CRC)represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.The modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells(CSCs),which present both pluripotency and self-renewal properties.These cells are considered responsible for the progression of the disease,recurrence and tumor resistance.Interestingly,some cell signaling pathways participate in CRC survival,proliferation,and selfrenewal properties,and most of them are dysregulated in CSCs,including the Wingless(Wnt)/β-catenin,Notch,Hedgehog,nuclear factor kappa B(NF-κB),Janus kinase/signal transducer and activator of transcription(JAK/STAT),peroxisome proliferator-activated receptor(PPAR),phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin(PI3K/Akt/mTOR),and transforming growth factor-β(TGF-β)/Smad pathways.In this review,we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways,which will contribute to the study of potential therapeutic schemes,combining conventional drugs with CSC-targeting drugs,and allowing better cure rates in anti-CRC therapy.

Small-molecule chemical probes for the potential therapeutic targets in alcoholic liver diseases

Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.

Deoxyribonucleic acid methylation driven aberrations in pancreatic cancer-related pathways

Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target.Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails.Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients.Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies.Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance.Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions,and novel pharmacological strategies that target these components could potentially lead to breakthroughs.We aim to highlight the possibilities that exist and the potential therapeutic interventions.

The p38/MAPK pathway as a therapeutic target to prevent therapeutic escape of breast cancer stem cells

Cancer stem cells(CSCs)play an important role in metastasis development,tumor recurrence,and treatment resistance,and are essential for the eradication of cancer.Currently,therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape,which leads to enhanced aggressive behaviors compared with CSCs that have never been treated.However,the underlying mechanisms regulating the therapeutic escape remain unknown.To this end,we established a model to isolate the therapeutic escaped CSCs(TSCSCs)from breast CSCs and performed the transcription profile to reveal the mechanism.Mechanistically,we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway,resulting in TSCSCs exhibiting enhanced motility and metastasis.Notably,blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo,which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition(EMT)-related proteins vimentin and N-cadherin.The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.

Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics

Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells(CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.

Developmental pathways associated with cancer metastasis:Notch,Wnt,and Hedgehog

Master developmental pathways, such as Notch, Wnt, and Hedgehog, are signaling systems that control proliferation, cell death,motility, migration, and stemness. These systems are not only commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also in primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, indicating these signaling pathways as particularly attractive targets for efficient anticancer therapies, especially in advanced primary tumors and metastatic cancers. Metastasis is the worst feature of cancer development. This feature results from a cascade of events emerging from the hijacking of epithelial-mesenchymal transition, angiogenesis, migration, and invasion by transforming cells and is associated with poor survival, drug resistance, and tumor relapse. In the present review, we summarize and discuss experimental data suggesting pivotal roles for developmental pathways in cancer development and metastasis, considering the therapeutic potential. Emerging targeted antimetastatic therapies based on Notch, Wnt, and Hedgehog pathways are also discussed.

Scorpiones,Scolopendra and Gekko Inhibit Lung Cancer Growth and Metastasis by Ameliorating Hypoxic Tumor Microenvironment via PI3K/AKT/mTOR/HIF-1αSignaling Pathway

Objective:To investigate whether Buthus martensii karsch(Scorpiones),Scolopendra subspinipes mutilans L.Koch(Scolopendra)and Gekko gecko Linnaeus(Gekko)could ameliorate the hypoxic tumor microenvironment and inhibit lung cancer growth and metastasis by regulating phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin/hypoxia-inducible factor-1α(PI3K/AKT/mTOR/HIF-1α)signaling pathway.Methods:Male C57BL/6J mice were inoculated with luciferase labeled LL/2-luc-M38 cell suspension to develop lung cancer models,with rapamycin and cyclophosphamide as positive controls.Carboxy methyl cellulose solutions of Scorpiones,Scolopendra and Gekko were administered intragastrically as 0.33,0.33,and 0.83 g/kg,respectively once daily for 21 days.Fluorescent expression were detected every 7 days after inoculation,and tumor growth curves were plotted.Immunohistochemistry was performed to determine CD31 and HIF-1αexpressions in tumor tissue and microvessel density(MVD)was analyzed.Western blot was performed to detect the expression of PI3K/AKT/mTOR/HIF-1αsignaling pathway-related proteins.Enzyme-linked immunosorbent assay was performed to detect serum basic fibroblast growth factor(bFGF),transforming growth factor-β1(TGF-β1)and vascular endothelial growth factor(VEGF)in mice.Results:Scorpiones,Scolopendra and Gekko prolonged the survival time and inhibited lung cancer metastasis and expression of HIF-1α(all P<0.01).Moreover,Scorpiones,Scolopendra and Gekko inhibited the phosphorylation of AKT and ribosomal protein S6 kinase(p70S6K)(P<0.05 or P<0.01).In addition,they also decreased the expression of CD31,MVD,bFGF,TGF-β1 and VEGF compared with the model group(P<0.05 or P<0.01).Conclusion:Scorpiones,Scolopendra and Gekko all showed beneficial effects on lung cancer by ameliorating the hypoxic tumor microenvironment via PI3K/AKT/mTOR/HIF-1αsignaling pathway.