1.PIK3CA gene mutations in Chinese women with HR+/HER2- breast cancer.
Sha Fei WU ; Xue Fei WANG ; Yuan Yuan LIU ; Chuan XIA ; Zhi Yong LIANG ; Xuan ZENG
Chinese Journal of Pathology 2022;51(12):1246-1250
Objective: To investigate the spectrum of PIK3CA gene mutations in Chinese women with hormone receptor positive and HER2 negative (HR+/HER2-) breast cancer, to provide the genetic evidence for identifying potential beneficiaries from specific PI3K isoform inhibitors in Chinese women with breast cancer and to develop detection strategies. Methods: A total of 365 breast cancer specimens archived at the Peking Union Medical College Hospital, Beijing, China from January 2017 to October 2017 were screened. Among these patients, 186 HR+/HER2- women with invasive breast cancer were collected. PIK3CA gene mutations were detected using next generation sequencing technology. The gene variant features were then analyzed and compared with reported data. Results: Among the 186 HR+/HER2- breast cancer cases, 40 (21.5%,40/186) cases harbored PIK3CA gene mutations. Exons 9 and 20 of PIK3CA mutations occurred in 92.5%(37/40)of the tumors, which included E545K, E545G, Q546K, E542K, Q546R, P539R, E547D, H1047R, H1047L, H1047Q and N1044Y. Only one case harbored the exon 7 C420R mutation. Additionally, exons 1 (F83C) and 5 (G364R) uncommon mutations were discovered respectively in 2 cases. Based on the finding, 85.0% (34/40) of cases with known mutations could be detected using companion diagnostic methods. Moreover, 25.0% (10/40) of patients had two or three variants, which were composed of E726K/N345K, H1047Q/N345K, H1047R/G364R, H1047R/E453K, E545G/E726K, E542K/E726K, E542K/H1047R, E545K/H1047R/H1047L and E545K/E547D. The lymph node positive rate in these patients with PIK3CA mutation was remarkably higher than those without (i.e., wild type, <i>Pi><0.05). Conclusions: In this group of HR+/HER2- breast cancer patients, common PIK3CA gene mutations account for the vast majority of the mutations. New rare variants in PIK3CA are also identified while their clinical significance needs to be further studied in a large cohort and/or multi-center study.
Humans
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Female
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Breast Neoplasms/genetics*
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East Asian People
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China
;
Class I Phosphatidylinositol 3-Kinases/genetics*
3.Chitosan/PIK3CA siRNA nanoparticle-mediated PIK3CA gene interference decreases the invasive capacity of gastric cancer cells in vitro.
Xinke ZHOU ; Lu HE ; Min LIANG ; Jifang LIU
Journal of Southern Medical University 2014;34(10):1503-1506
OBJECTIVETo investigate the effect of PIK3CA/siRNA chitosan nanoparticle on the invasiveness of gastric carcinoma and the potential value of PIK3CA/siRNA chitosan nanoparticle in suppressing the metastasis of gastric carcinoma.
METHODSGastric cancer cells were treated with PIK3CA/siRNA nanoparticle (with a diameter of 350 nm), and the efficiency of PIK3CA gene interference was evaluated using Western blotting and real-time PCR. The changes of the invasive capacity of the treated cells was assessed with Transwell assay.
RESULTSPIK3CA/siRNA chitosan nanoparticle efficiently lowered the expression level of PIK3CA and significantly decreased the invasion of BGC823 cells.
CONCLUSIONPIK3CA gene interference mediated by PIK3CA/siRNA chitosan nanoparticle can decrease the invasive capacity of gastric cancer cells in vitro.
Cell Line, Tumor ; Cell Proliferation ; Chitosan ; Class I Phosphatidylinositol 3-Kinases ; Humans ; Nanoparticles ; Phosphatidylinositol 3-Kinases ; genetics ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Stomach Neoplasms ; pathology
4.Multiple oncogenic mutations related to targeted therapy in nasopharyngeal carcinoma.
Jian-Wei ZHANG ; ; Tao QIN ; ; Shao-Dong HONG ; ; Jing ZHANG ; ; Wen-Feng FANG ; ; Yuan-Yuan ZHAO ; ; Yun-Peng YANG ; ; Cong XUE ; ; Yan HUANG ; ; Hong-Yuan ZHAO ; ; Yu-Xiang MA ; ; Zhi-Huang HU ; ; Pei-Yu HUANG ; ; Li ZHANG ;
Chinese Journal of Cancer 2015;34(4):177-183
INTRODUCTIONAn increasing number of targeted drugs have been tested for the treatment of nasopharyngeal carcinoma (NPC). However, targeted therapy-related oncogenic mutations have not been fully evaluated. This study aimed to detect targeted therapy-related oncogenic mutations in NPC and to determine which targeted therapy might be potentially effective in treating NPC.
METHODSBy using the SNaPshot assay, a rapid detection method, 19 mutation hotspots in 6 targeted therapy-related oncogenes were examined in 70 NPC patients. The associations between oncogenic mutations and clinicopathologic factors were analyzed.
RESULTSAmong 70 patients, 12 (17.1%) had mutations in 5 oncogenes: 7 (10.0%) had v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) mutation, 2 (2.8%) had epidermal growth factor receptor (EGFR) mutation, 1 (1.4%) had phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, 1 (1.4%) had Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, and 1 (1.4%) had simultaneous EGFR and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations. No significant differences were observed between oncogenic mutations and clinicopathologic characteristics. Additionally, these oncogenic mutations were not associated with tumor recurrence and metastasis.
CONCLUSIONSOncogenic mutations are present in NPC patients. The efficacy of targeted drugs on patients with the related oncogenic mutations requires further validation.
Carcinoma ; Class I Phosphatidylinositol 3-Kinases ; Humans ; Mutation ; Nasopharyngeal Neoplasms ; Neoplasm Recurrence, Local ; Oncogenes ; Pharmacogenetics ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins B-raf ; Receptor, Epidermal Growth Factor
5.Effects of class I( phosphatidylinositol-3-kinases inhibitor on gastric cancer cell xenografts in nude mice.
Ru-Lu LIU ; Kui ZHAO ; Jia-Lei SUN ; Li-Yan YU ; Bao-Song ZHU ; Xiao-Dong YANG ; Chun-Gen XING
Chinese Journal of Gastrointestinal Surgery 2013;16(5):484-488
OBJECTIVETo investigate the effect of recombinant adenovirus (phosphatidylinositol-3-kinases(PI3K)(I()-RNAi-AD which blocks the class I( PI3K signaling pathway on gastric carcinoma cells xenografts in nude mice.
METHODSSubcutaneous tumor models of nude mice were established with SGC7901 cells and randomly divided into PI3K(I()-RNAi-AD group, NC-RNAi-GFP-AD group and control group. The tumor size and the inhibitory rate of tumor growth on days 3, 6, and 9 after cell transplantation were measured. The expression of TNF-α, COX2, P53, PCNA, E-cadherin and nm23/DNPK in tumor tissues were detected by immunohistochemistry.
RESULTSTumor growth was significantly inhibited in the PI3K(I()-RNAi-AD group(14.2%, 21.0%, and 28.1%) on days 3, 6, 9 compared with NC-RNAi-GFP-AD group(1.3%, 1.9%, and 2.0%, all P<0.05). The expressions of TNF-α, P53, E-cadherin and nm23/DNPK were up-regulated, and the expressions of COX2 and PCNA were down-regulated in the PI3K(I()-RNAi-AD group by immunohistochemical staining(all P<0.05).
CONCLUSIONSPI3K(I()-RNAi-AD can inhibit the growth of SGC7901 cell transplantation tumor in vivo in nude mice by inhibiting cell growth, reducing the capacity of tumor invasion and inhibiting tumor angiogenesis.
Adenoviridae ; Animals ; Cell Line, Tumor ; Cell Proliferation ; Class I Phosphatidylinositol 3-Kinases ; Heterografts ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Phosphatidylinositol 3-Kinases ; Phosphatidylinositols ; Stomach Neoplasms
6.Effects of PI3K/Akt Pathway in Wound Healing Process of Mice Skin.
Yan-ling GAO ; Chang-sheng LIU ; Rui ZHAO ; Lin-lin WANG ; Shan-shan LI ; Min LIU ; Miao ZHANG ; Shu-kun JIANG ; Zhi-ling TIAN ; Meng WANG ; Da-wei GUAN
Journal of Forensic Medicine 2016;32(1):7-12
OBJECTIVE:
To investigate the expressions and time-dependent changes of phosphatidylinositol-3-kinase (PI3K), phospho-PI3K (p-PI3K), protein kinase B (PKB/Akt) and phospho-Akt (p-Akt) during wound healing process of mice skin.
METHODS:
The changes of PI3K, p-PI3K, Akt and p-Akt expression in skin wound were detected by immunohistochemistry, Western blotting and real-time PCR.
RESULTS:
Immunohistochemistry showed the expression of PI3K and p-Akt were observed in mononuclear and fibroblast after skin wound, and reached peak in reconstruction. The positive bands of PI3K, p-PI3K, Akt and p-Akt were observed in all time points of the wound healing process by Western blotting. The expression peak of p-PI3K and p-Akt showed in inflammation and proliferation; the expression peak of PI3K and Akt in reconstruction. Real-time PCR showed the expression peak of PI3K mRNA in inflammation and reconstruction and the peak of Akt mRNA in reconstruction.
CONCLUSION
During the wound healing process, the expressions of PI3K, Akt, p-PI3K and p-Akt show different changes with significant correlation to wound time. The expression of PI3K/Akt may be a valuable marker for wound time estimation.
Animals
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Blotting, Western
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Class I Phosphatidylinositol 3-Kinases
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Fibroblasts/metabolism*
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Mice
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Phosphatidylinositol 3-Kinase
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Phosphatidylinositol 3-Kinases/metabolism*
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Phosphorylation
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Proto-Oncogene Proteins c-akt/metabolism*
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Real-Time Polymerase Chain Reaction
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Signal Transduction
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Skin/injuries*
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Wound Healing
7.A study of the relationship between the mutation of PIK3CA, PTEN and the occurrence of liver metastasis of colorectal cancer: survival analysis.
Li LIANG ; Ye WEI ; Li REN ; Yun-shi ZHONG ; Jian-min XU
Chinese Journal of Surgery 2012;50(11):1007-1010
OBJECTIVETo investigate PIK3CA, PTEN status in the primary lesion of colorectal cancer (CRC): relationship with occurrences of liver metastasis and its prognosis.
METHODSPatients with CRC who had the primary tumor resected between 2003 and 2008 were selected and enrolled into three groups according to the occurrence of liver metastasis. The mutations of PIK3CA exon 9 and 20, PTEN exon 5, 7, 8 in primary cancer cells in formalin-fixed, paraffin-embedded specimens were detected by Pyrosequencing, then a statistical analysis was deduced to find out the relationship between PIK3CA, PTEN status and occurrences of liver metastasis as well as the prognosis.
RESULTSOf all the 300 CRC cases, the mutation rates of PIK3CA and PTEN was 18.2% (51/300) and 16.3% (49/300). The multivariate Logistic analysis revealed that exon 5 mutation of PTEN was one of the independent risk factors of occurrence of metachronous liver metastasis in CRC patients (HR = 1.634, 95%CI: 1.796 - 3.355, P = 0.041). Patients with PTEN mutation had a poorer overall survival in group with synchronous liver metastasis (median survival time 62.0 months vs 71.0 months, χ(2) = 12.942, P = 0.048) while CRC patients who had the liver metastasis resected in group of synchronous and metachronous liver metastasis had a poorer disease free survival rates with PIK3CA mutation (median survival time 16.0 months vs 25.0 months, χ(2) = 9.679, P = 0.037).
CONCLUSIONSThe exon 5 mutation of PTEN of CRC is potentially correlated with the occurrence of synchronous liver metastasis. CRC patients who had the liver metatasis resected but with PIK3CA mutation could have a poorer prognosis.
Aged ; Class I Phosphatidylinositol 3-Kinases ; Colorectal Neoplasms ; genetics ; pathology ; Female ; Humans ; Liver Neoplasms ; genetics ; secondary ; Male ; Middle Aged ; Mutation ; PTEN Phosphohydrolase ; genetics ; Phosphatidylinositol 3-Kinases ; genetics ; Prognosis ; Proto-Oncogene Proteins B-raf ; genetics ; Survival Analysis
8.The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer.
Amaury G DUMONT ; Sarah N DUMONT ; Jonathan C TRENT
Chinese Journal of Cancer 2012;31(7):327-334
The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently, this pathway is commonly deregulated in cancer. In particular, mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice. These data underscore the role of this pathway during oncogenesis. Thus, an ongoing, large-scale effort is underway to develop clinically active drugs that target elements of the PI3K pathway. However, conflicting data suggest that gain-of-function PIK3CA mutations may be associated with either a favorable or a poor clinical outcome, compared with the wild-type PIK3CA gene. In the current study, we performed a systematic review of breast cancer clinical studies. Upon evaluation of 2587 breast cancer cases from 12 independent studies, we showed that patients with tumors harboring a PIK3CA mutation have a better clinical outcome than those with a wild-type PIK3CA gene. Importantly, this improved prognosis may pertain only to patients with mutations in the kinase domain of p110α and to postmenopausal women with estrogen receptor-positive breast cancer. We propose three potential explanations for this paradoxical observation. First, PIK3CA mutations may interfere with the metastasis process or may induce senescence, which results in a better outcome for patients with mutated tumors. Secondly, we speculate that PIK3CA mutations may increase early tumor diagnosis by modification of the actin cytoskeleton in tumor cells. Lastly, we propose that PIK3CA mutations may be a favorable predictive factor for response to hormonal therapy, giving a therapeutic advantage to these patients. Ultimately, an improved understanding of the clinical impact of PIK3CA mutations is critical for the development of optimally personalized therapeutics against breast cancer and other solid tumors. This effort will be important to prevent or explain therapeutic failures and select patients who are most likely to respond to new therapies that inhibit the PI3K pathway.
Antineoplastic Agents, Hormonal
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therapeutic use
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Apoptosis
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Breast Neoplasms
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drug therapy
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genetics
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metabolism
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pathology
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Cellular Senescence
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Class I Phosphatidylinositol 3-Kinases
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Disease-Free Survival
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Early Detection of Cancer
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Female
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Humans
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Mutation
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Neoplasm Metastasis
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Phosphatidylinositol 3-Kinases
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antagonists & inhibitors
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genetics
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metabolism
;
Survival Rate
9.Expression and mutations of PIK3CA gene in hepatocellular carcinomas.
Ding-hua YANG ; Zhao-yin FU ; Yu HUANG ; Qi-yan ZENG ; Jie ZHOU
Journal of Southern Medical University 2009;29(12):2517-2522
OBJECTIVETo investigate the expression and mutation of PIK3CA gene in hepatocellular carcinomas (HCC).
METHODSHCC samples and the corresponding adjacent tissues were collected from the surgical patients with pathologically verified diagnosis. The exons 1, 9 and 20 of PIK3CA gene were detected by PCR-SSCP and DNA sequencing. Immnohistochemistry was employed to test the expression of PIK3CA gene in these samples.
RESULTSNo mutation was found in exons 1, 9 or 20 of PIK3CA gene in the HCC tissue and the adjacent tissues by PCR-SSCP and DNA sequencing, while abnormal superimposed peaks were found on the sequence map of exon 9 in 25 cases of HCC tissue. Immunohistochemistry showed that expression of PIK3CA was higher in the HCC tissue than in the corresponding adjacent tissue (50.81% vs 14.75%).
CONCLUSIONPIK3CA gene mutation may exist in HCC in Guangxi, which can be associated with the development of HCC, but the ratio of hotspot mutations is low.
Base Sequence ; Carcinoma, Hepatocellular ; genetics ; Class I Phosphatidylinositol 3-Kinases ; Exons ; genetics ; Female ; Humans ; Liver Neoplasms ; genetics ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation ; Phosphatidylinositol 3-Kinases ; genetics ; metabolism ; Sequence Analysis, DNA
10.Mechanism of Wuling Capsules against hepatic fibrosis based on network pharmacology and animal experiments.
Nan LI ; Su-Juan REN ; Rui ZHOU ; Zhong-Xing SONG ; Yan-Ru LIU ; Zhi-Shu TANG ; Jian-Ping ZHOU ; Zhao-Jun CAO
China Journal of Chinese Materia Medica 2023;48(19):5365-5376
The present study aimed to explore the underlying mechanism of Wuling Capsules in the treatment of hepatic fibrosis(HF) through network pharmacology, molecular docking, and animal experiments. Firstly, the chemical components and targets of Wuling Capsules against HF were searched from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), Traditional Chinese Medicines Integrated Database(TCMID), GeneCards, and literature retrieval. The protein-protein interaction(PPI) network analysis was carried out on the common targets by STRING database and Cytoscape 3.9.1 software, and the core targets were screened, followed by Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses. Enrichment analysis was conducted on the core targets and the "drug-core component-target-pathway-disease" network was further constructed. Subsequently, molecular docking between core components and core targets was conducted using AutoDock Vina software to predict the underlying mechanism of action against HF. Finally, an HF model induced by CCl_4 was constructed in rats, and the general signs and liver tissue morphology were observed. HE and Masson staining were used to analyze the liver tissue sections. The effects of Wuling Capsules on the levels of inflammatory factors, hydroxyproline(HYP) levels, and core targets were analyzed by ELISA, RT-PCR, etc. A total of 445 chemical components of Wuling Capsules were screened, corresponding to 3 882 potential targets, intersecting with 1 240 targets of HF, and 47 core targets such as TNF, IL6, INS, and PIK3CA were screened. GO and KEGG enrichment analysis showed that the core targets mainly affected the process of cell stimulation response and metabolic regulation, involving cancer, PI3K-Akt, MAPK, and other signaling pathways. Molecular docking showed that the core components of Wuling Capsules, such as lucidenic acid K, ganoderic acid B, lucidenic acid N, saikosaponin Q2, and neocryptotanshinone, had high affinities with the core targets, such as TNF, IL6 and PIK3CA. Animal experiments showed that Wuling Capsules could reduce fat vacuole, inflammatory infiltration, and collagen deposition in rat liver, decrease the levels of inflammatory cytokines TNF-α, IL-6, and HYP, and downregulated the expressions of PI3K and Akt mRNA. This study suggests that the anti-HF effect of Wuling Capsules may be achieved by regulating the PI3K-Akt signaling pathway, reducing the levels of TNF-α and IL-6 inflammatory factors, and inhibiting the excessive deposition of collagen.
Animals
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Rats
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Interleukin-6
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Network Pharmacology
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Animal Experimentation
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Tumor Necrosis Factor-alpha
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Molecular Docking Simulation
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Liver Cirrhosis/genetics*
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Medicine, Chinese Traditional
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Capsules
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Class I Phosphatidylinositol 3-Kinases
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Collagen
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Drugs, Chinese Herbal/pharmacology*