Prevalencia y análisis clinicopatológico de pacientes con mutación en el gen PIK3CA con cáncer de mama avanzado Rh+/Her2- en el Instituto Oncológico Nacional De Panamá

Antecedentes: La vía de señalización de la fosfoisitol 3-quinasa (PI3K), que promueve el crecimiento y el metabolismo de las células cancerosas, es la vía mutada con mayor frecuencia en el cáncer de mama y es asociada con quimio resistencia y mal pronóstico. En este estudio presentamos el primer análisis en población panameña y de la región, con ataciones precisas de la mutación PIK3CA, las características clinicopatológicas y pronóstico. Métodos: Estudio exploratorio, donde se recolectaron prospectivamente tumores de 74 pacientes con cáncer de mama metastásico RH+/Her2- del Instituto Oncológico Nacional entre 2022 y 2023. Se realizó un ensayo de PCR en tiempo real para análisis de mutación en ADN extraído del material tumoral fijado en formalina e incluido en parafina para detectar mutaciones en los exones 1, 4, 7, 9 y 20 del gen PIK3CA. Resultados: La mediana de edad de las pacientes estudiadas fue 59 años. La mutación en PIK3CA se encontró en 33.8% (25/74) de pacientes con cáncer de mama, entre ellas 44% fueron mutaciones en el exón 20, 38% en el exón 9, 13% en el exón 4 y 5% en el exón 1. Se observó una correlación significativa entre la mutación y el  tener historia de cáncer en la familia (p= 0.005), y en pacientes postmepáusicas (P = 0.045).  encontramos asociación entre la mutación y el tipo histológico, grado, tamaño tumoral ni estatus axilar al momento del diagnóstico. La mediana de supervivencia libre de progresión  se alcanzó en ambos grupos y tampoco demostró una diferencia significativa. Conclusión: La prevalencia de la mutación es relativamente alta comparada con escenarios internacionales, puede ofrecer una ventaja para elegir las mejores opciones de tratamiento por lo que debe evaluarse de forma rutinaria durante las intervenciones clínicas. (provisto por Infomedic International)

Background: The phosphoisitol 3-kinase (PI3K) signaling pathway, which promotes cancer cell growth and metabolism, is the most frequently mutated pathway in breast cancer and is associated with chemoresistance and poor progsis. In this study we present the first analysis in Panamanian and regional population, with precise antations of the PIK3CA mutation, clinicopathological characteristics and progsis. Methods: Exploratory study, where tumors were prospectively collected from 74 patients with RH+/Her2- metastatic breast cancer from the Instituto Oncológico Nacional between 2022 and 2023. A real-time PCR assay for mutation analysis was performed on DNA extracted from formalin-fixed, paraffin-embedded tumor material to detect mutations in exons 1, 4, 7, 9 and 20 of the PIK3CA gene. Results: The median age of the patients studied was 59 years. The mutation in PIK3CA was found in 33.8% (25/74) of patients with breast cancer, among them 44% were mutations in exon 20, 38% in exon 9, 13% in exon 4 and 5% in exon 1. A significant correlation was observed between the mutation and having  history of cancer in the family (P = 0.005), and in postmepausal patients (P = 0.045). We found  association between the mutation and histologic type, grade, tumor size or axillary status at diagsis. Median progression-free survival was t reached in both groups and did t show a significant difference. Conclusion: The prevalence of the mutation is relatively high compared to international settings, it may offer an advantage in choosing the best treatment options and should be routinely evaluated during clinical interventions. (provided by Infomedic International)

Research progress in anti-tumor drugs targeting PIK3CA mutations / 中国肿瘤生物治疗杂志

@#[摘 要] PI3K-Akt信号通路作为肿瘤相关十大信号通路之一，在调控肿瘤恶性进展中扮演着重要角色。PIK3CA编码PI3K复合体蛋白催化亚基P110α，是一种典型的致癌突变，对实体瘤的发生和发展至关重要。PIK3CA突变可导致肿瘤对一线抗癌药物产生耐药性，其机制可能与PIK3CA突变激活PI3K-Akt信号通路相关。目前，几种靶向PIK3CA突变的抑制剂在临床研究中取得了一定进展，特别是PI3Kα特异性抑制剂阿培利司已被FDA批准作为PIK3CA突变乳腺癌的治疗药物。本文就PIK3CA突变促进肿瘤药物耐药的机制，以及逆转耐药的治疗策略作一综述，以期更全面了解PIK3CA突变在肿瘤耐药方面的进展以及最新治疗策略。

Clínica, auxología y calidad de vida en cincuenta niños, niñas y adolescentes con síndromes de sobrecrecimiento corporal segmentario de un único centro / Clinical and auxological characteristics and quality of life of 50 children and adolescents with segmental overgrowth syndromes at a single center

Introducción. Los síndromes de sobrecrecimiento corporal segmentario son un grupo de enfermedades poco frecuentes caracterizadas por exceso de crecimiento en una o más partes del cuerpo relacionadas, en su mayoría, con mutaciones en mosaico en la vía de señalización AKT/PI3K/mTOR y RAS-MAPK. Nuestro objetivo fue analizar las características clínicas y auxológicas, y la calidad de vida relacionada a salud (CVRS) en este grupo de pacientes en un hospital de tercer nivel de atención. Población y métodos. Estudio transversal de una cohorte en seguimiento. Se analizaron edad, sexo, datos sociodemográficos, mediciones antropométricas del segmento afectado y del contralateral, complicaciones, tratamiento, calidad de vida (PedsQL4.0) y dolor. Se calcularon medidas centrales y de dispersión. Se realizó análisis univariado entre calidad de vida y variables incluidas. Resultados. Se incluyeron 50 pacientes, 29 varones. Mediana de edad 9,95 (r 1,44-17,81) años. El diagnóstico más frecuente fue síndrome de sobrecrecimiento relacionado a PIK3CA (PROS) (37/50). Mediana de número de segmentos afectados 2 (r: 1-7) por niño. Cuarenta casos presentaron malformación vascular; 20, capilar. El dolor (24/50) fue la complicación más frecuente. Treinta y un pacientes mostraron asimetría de longitud de miembros inferiores, < 5 cm. La estatura se ubicó entre los centilos 50 y 97 en la mayoría de los niños. Menor CVRS se observó en mujeres, en pacientes con malformación vascular compleja y necesidades básicas insatisfechas (NBI). Conclusiones. PROS fue el diagnóstico más frecuente. El dolor fue una complicación frecuente. La CVRS fue menor en mujeres, pacientes con malformación vascular combinada y NBI.

Introduction. Segmental overgrowth syndromes are a group of rare diseases characterized by overgrowth in one or more parts of the body, mostly related to mosaic mutations in the AKT/PI3K/mTOR and RASMAPK signaling pathway. Our objective was to analyze the clinical and auxological characteristics and health-related quality of life (HRQoL) in this group of patients at a tertiary care hospital. Population and methods. Cross-sectional study of a follow-up cohort. Age, sex, sociodemographic data, anthropometric measurements of the affected and contralateral segments, complications, treatment, quality of life (PedsQL 4.0), and pain were analyzed. Central and dispersion measures were estimated. A univariate analysis between the quality of life and study variables was done. Results. A total of 50 patients were included; 29 were males. Median age: 9.95 (r: 1.44­17.81) years. The most common diagnosis was PIK3CA-related overgrowth spectrum (PROS) (37/50). The median number of affected segments was 2 (r: 1­7) per patient. Vascular malformations were observed in 40, and capillary malformations, in 20 patients. Pain was the most common complication (24/50). An asymmetry of the lower extremities of < 5 cm was observed in 31 patients. In most children, height was between the 50th and 97th percentiles. A lower HRQoL was observed among girls, patients with complex vascular malformations, and those with unmet basic needs (UBNs). Conclusions. PROS was the most common diagnosis. Pain was the most common complication. HRQoL was lower among girls, patients with combined vascular malformations, and those with UBNs.

Relationships between PIK3CA gene status and clinical features and prognosis in triple-negative breast cancer / 国际肿瘤学杂志

Objective:To detect the status of PIK3CA in triple-negative breast cancer (TNBC) , and to analyze the relationships between PIK3CA mutation and clinical features and its impact on prognosis.Methods:From January 1, 2016 to December 31, 2018, 50 patients with primary TNBC admitted to Xinxiang Central Hospital of Henan Province were collected. The PIK3CA mutation status was detected, and the relationships between PIK3CA mutation and clinical characteristics of patients with TNBC and its impact on prognosis were analyzed.Results:PIK3CA gene mutation was detected in 9 of 50 TNBC patients, with a mutation frequency of 18.0%. H1047R mutation was found in 4 cases, E545K mutation in 3 cases and E542K mutation in 2 cases. PIK3CA gene mutation was not associated with age ( χ2=3.55, P=0.060) , tumor location ( χ2=1.01, P=0.315) , tumor size ( χ2<0.01, P>0.999) , lymph node status ( χ2=0.76, P=0.385) , clinical stage ( χ2=0.65, P=0.420) , Ki-67 value ( χ2<0.01, P>0.999) , P53 status ( χ2=0.02, P=0.894) and human epidermal growth factor receptor-2 (HER-2) status ( χ2=1.65, P=0.200) . Prognostic analysis showed that 3-year disease-free survival rates of wild-type PIK3CA patients was significantly higher than that of mutant PIK3CA patients (80.5% vs. 11.1%, χ2=28.23, P<0.001) . Conclusion:The frequency of PIK3CA gene mutation is higher in TNBC patients. There is no correlation between PIK3CA mutation and clinicopathologic features in TNBC patients. PIK3CA gene mutation may be significantly associated with poor prognosis of TNBC patients.

Views on the Current Diagnosis and Treatment of PIK3CA-Related Overgrowth Spectrum / 罕见病研究

PIK3CA-related overgrowth spectrum (PROS) is a rare condition characterized by disproportionate overgrowth of head, neck, trunk, or extremity, caused by PIK3CA gene mutation. This condition has negative impact on the physical appearance, functions, and psychosocial well-being of the patients. The condition causes social and economic burden, too. The gold standard for the diagnosis of PROS is the genetic testing using somatic tissue, but detecting low-level mosaic mutations of PIK3CA gene remains a challenge. There is no specific treatment now. Supportive management including surgery and other interventions have limited effects in improving cosmetic outcome and functions. Multidisciplinary collaboration is the key to the success of managing PROS. Targeted gene therapy is promising in improving the outcome for patients with severe PROS. Patients diagnosed with negative genetics test by the clinical measures are often ineligible for novel gene therapy. This article reviews the clinical manifestations, diagnosis, and treatments of PROS, aiming to improve the current understanding of this rare condition.

Plasma exosome-derived miR-20a-5p affects bone metastasis in estrogen receptor-positive breast cancer cells by targeting PIK3R1 / 中华内分泌外科杂志

Objective:To investigate the effects of plasma exosome-derived miR-20a-5p on bone metastases in estrogen receptor-positive breast cancer (ER (+) BC) by targeting PIK3R1.Methods:The data sets related to ER (+) BC bone metastasis were retrieved with the help of bioinformatics website, miR-20a-5p was included in the study. The plasma of 90 ER (+) BC patients and the corresponding healthy people were collected to detect the expression of PIK3R1 in the plasma, and exosomes were extracted from the plasma to detect expression of miR-20a-5p in exosomes. The dual-luciferase reporter assay was used to verify the targeting regulation relationship between miR-20a-5p and PIK3R1. The exosomes transfected with NC-inhibitor and miR-inhibitor or ER (+) BC cells transfected with si-NC and si-PIK3R1 were injected into the left ventricle of mice, respectively, and the bone tissue was scanned by Micro-CT and bone tissue TRAP staining was performed. After co-culturing NC-inhibitor and miR-inhibitor-transfected exosomes with si-NC and si-PIK3R1-transfected ER (+) BC cells, Western blot was used to detect the expression of osteoclast molecules c-fos and NFATc1.Results:qRT-PCR assay showed that compared with normal plasma exosomes (1±0.26) or cells (1±0.13) , miR-20a-5p was significantly increased in ER (+) BC plasma exosomes (1.49±0.27) ( t=12.40, P<0.001) and BC cell line MCF-7 (1.64±0.13) ( t=6.03, P=0.004) , BT474 (1.49±0.11) ( t=4.98, P=0.008) , T47D (1.98±0.15) ( t=8.55, P=0.001) . But compared with normal plasma exosomes (1±0.25) or cells (1±0.10) , expression of PIK3R1 in ER (+) BC plasma exosomes (0.69±0.24) ( t=8.48, P<0.001) and ER (+) BC cell lines MCF-7 (0.73±0.05) ( t=4.18, P=0.014) , BT474 (0.61±0.05) ( t=6.04, P=0.004) , and T47D (0.34±0.04) ( t=10.61, P<0.001) was inhibited. PIK3R1 was confirmed as a target gene of miR-20a-5p. Compared with mice in NC-inhibitor group, trabecular bone tissue volume ( t=3.32, P=0.029) , trabecular bone area volume ( t=6.24, P=0.003) , bone volume fraction ( t=7.35, P=0.002) and bone mineral density ( t=13.72, P<0.001) of mice in miR-inhibitor group were both increased, the number of mature osteoclasts was decreased. Compared with NC inhibitor group, expression of c-fos ( t=9.04, P=0.001) and NFATc1 ( t=13.42, P<0.001) in miR-inhibitor group was decreased. Compared with miR-inhibitor+si-NC group, trabecular bone tissue volume ( t=3.03, P=0.039) , trabecular bone area volume ( t=6.37, P=0.003) , bone volume fraction ( t=3.36, P=0.028) and bone mineral density ( t=6.92, P=0.002) were decreased, the number of mature osteoclasts was increased, and expressionof c-fos ( t=7.75, P= 0.002) and NFATc1 ( t=9.65, P=0.001) was increased in miR-inhibitor+si-PIK3R1 group. Conclusion:PlasmaExosome-derived miR-20a-5p from ER (+) BC patients promotes ER (+) BC bone metastasis by inhibiting the expression of PIK3R1.

Germline and Somatic mutations in postmenopausal breast cancer patients

OBJECTIVES: In breast cancer (BC) patients, the frequency of germline BRCA mutations (gBRCA) may vary according to the ethnic background, age, and family history of cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the second most common somatic mutated gene in BC; however, the association of mutations in both genes with cancer has not been thoroughly investigated. Thus, our aims were to investigate gBRCA mutation frequency in a cohort of postmenopausal Brazilian BC patients and the association of gBRCA1/BRCA2 and PIK3CA somatic mutations. METHODS: Forty-nine postmenopausal (>55 years) and forty-one young (≤35 years) BC patients were included in this study. The postmenopausal group included patients who reported a positive family history of cancer. For these patients, gBRCA1/BRCA2 were sequenced using next-generation sequencing (NGS) or Sanger sequencing. Data for gBRCA in young patients were already available from a previous study. DNA from formalin-fixed, paraffin-embedded (FFPE) tumors was obtained from 27 postmenopausal and 41 young patients for analyzing exons 9 and 20 of PIK3CA. The association between gBRCA1/BRCA2 and somatic mutations in PIK3CA was investigated. RESULTS: The overall frequency of gBRCA1/BRCA2 among the 49 postmenopausal patients was 10.2%. The frequencies of somatic mutations in PIK3CA in the postmenopausal and young patients were 37% and 17%, respectively (ns). The most common PIK3CA mutation was found to be E454A. Nonsense and frameshift mutations, which may counteract the oncogenic potential of PIK3CA were also detected. Regardless of age, 25% of BRCA1/BRCA2 mutation carriers and non-carriers , each, had PIK3CA somatic mutations. CONCLUSIONS: Data obtained indicate that BRCA1/BRCA2 gene testing may be considered for postmenopausal patients with BC who have a family history of cancer. Although some of them are not considered pathogenic, somatic variants of PIK3CA are frequently observed in BC patients, especially in postmenopausal patients.

SHORT syndrome in a child caused by PIK3R1 gene mutation / 中华实用儿科临床杂志

The clinical data of a child with SHORT syndrome caused by PIK3R1 gene mutation in Children′s Hospital of Nanjing Medical University was retrospectively analyzed.The patient was a 11 years old and 5 months Chinese girl initially hospitalized due to polyuria, polyphagia and polydipsia in the past 2 months.Physical examination showed decreased subcutaneous fat on the face, a triangular-shaped face, ocular depression, a wide nose bridge, hypoplastic nasal alae, columnar depression in the low part of the nose, downturned lips, hyperpigmentation of the skin of the neck, axillae, cubital and popliteal fossae and groins (acanthosis nigricans). Besides, slight cubitus valgus and hyperextension were observed.Laboratory tests showed diabetes mellitus with insulin resistance.Whole exome sequencing identified a de novo heterozygous PIK3R1 mutation (c.1945C>T, p.Arg649Trp), SHORT syndrome is a rare autosomal dominant disorder, characterized by special facial appearance, lipodystrophy and insulin resistance.Molecular analysis of the PIK3R1 gene permits confirmation of the diagnosis.The patients with SHORT syndrome require multidisciplinary management, and early diagnosis can prevent complications and reduce the burden on the family.

Clinical characteristics of 170 cases of macrodactyly / 北京大学学报(医学版)

OBJECTIVE@#To analyze the clinical characteristics of 170 cases of macrodactyly.@*METHODS@#Medical records of 170 macrodactyly patients at Beijing Jishuitan Hospital between March 2006 and October 2019, including demographic characteristics, clinical presentations, anatomical distributions, X-rays, pathological findings, and treatments, were reviewed. PIK3CA mutation analyses of 12 patients were also reviewed.@*RESULTS@#Disease incidence was similar across sex and geographical regions. Multiple-digit involvement was 3.9 times more frequent than single-digit involvement. In upper deformit: ies, the index finger, middle finger and thumb were mostly involved, and the second and third toes were the most affected on the foot. Two digits were affected more often than three digits, with the affected multiple digits were adjacent most time. The cases of progressive macrodactyly, in which the affected digits grew at a faster rate than the unaffected digits, were found more than static type. Most of progressive macrodactyly were noticed at birth. In terms of nerve involvement, affected fingers mostly occurred in the median nerve innervation area (79.4%) accompanied by median nerve and brunches enlargement and fat infiltration, i.e., nerve territory oriented; affected toes mostly occurred in the medial plantar nerve innervation area (89.1%), marked with overgrowth of adipose tissue with a lesser degree of neural overgrowth, i.e., lipomatous. Only 17 cases had comorbid of syndactyly. The metacarpal bones were involved only in progressive type of macrodactyly. Ten of the 12 cases subjected to PIK3CA mutation analysis were positive. Among all tested specimens, PIK3CA mutation levels ranged from 7% to 27%. In terms of tissue sources in which a mutation was found, adipose tissue had the highest mutation detection rate, followed by nerve and skin. All the DNA samples of blood from the 12 PIK3CA mutation-positive patients were negative.@*CONCLUSION@#Macrodactyly fingers mostly occurred in the median nerve innervation area accompanied by median nerve and brunches enlargement and fat infiltration. The index and middle fingers were mostly involved. Macrodactyly toes mostly occurred in the medial plantar nerve innervation area, marked with overgrowth of adipose tissue with a lesser degree of neural overgrowth. The second and third toes were the most affected on the foot. A high proportion (83%) of isolated macrodactyly patients carry activating PIK3CA mutations. Adipose, nerve, and skin tissues provide the highest PIK3CA mutation detection yield among all types of tissue studied.

Silencing the PIK3CA Gene Enhances the Sensitivity of Childhood Leukemia Cells to Chemotherapy Drugs by Suppressing the Phosphorylation of Akt

PURPOSE: This study aimed to investigate the effects of PIK3CA on the sensitivity of acute B lymphocytic leukemia cells (Nalm-6 cells) to chemotherapy drugs. MATERIALS AND METHODS: Children's normal B lymphocytes and Nalm-6 cells were cultured. Nalm-6 cells were transfected with PIK3CA siRNA (siPIK3CA group) or its negative control (PIK3CA-Control group). Normal Nalm-6 cells were named Mock group. Nalm-6 cells transfected by PIK3CA siRNA were treated with Akt inhibitor (siPIK3CA+Akti-1/2 group). mRNA and protein expression was detected by qRT-PCR and Western blot. Proliferation and sensitivity to chemotherapeutic drugs was detected by MTT assay. Cell cycle and apoptosis was explored by low cytometry. Transwell assay was performed to test invasion. RESULTS: PIK3CA mRNA (p=0.008) and protein (p=0.006) expression was higher in Nalm-6 cells than that in normal B lymphocytes. Compared with the Mock group and PIK3CA-Control group, Nalm-6 cells of the siPIK3CA group had lower OD495 values (all p < 0.05) and invasion cell numbers (p=0.03 and p=0.025), as well as a higher proportion of G0/G1 phase cells (p=0.020 and p=0.022), percentage of apoptosis (p=0.016 and p=0.022), and inhibition rate (all p < 0.05). pAkt expression in the siPIK3CA group (p=0.026 and p=0.031) and siPIK3CA+Akti-1/2 group (p=0.019 and p=0.023) was lower than that in the Mock group. CONCLUSION: PIK3CA silencing inhibited Nalm-6 cell proliferation and invasion, and promoted their apoptosis and sensitivity to chemotherapeutic drugs, potentially through regulation of the PI3K/AKT signaling pathway.

PIK3R3 Regulates Lipid Metabolism and Proliferation of Hepatocellular Carcinoma Cells by Regulating PPARA / 华中科技大学学报(医学版)

Objective@#To explore whether PIK3R3 is dependent on PPARA to regulate fat metabolism and proliferation of liver cancer cells.@* Methods@#The PIK3R3 overexpression plasmids and its specific siRNA were transfected into hepatocellular carcinoma cells HepG2 and SMMC-7721. The level of PPARA was detected by Western blotting（WB）and the ketone body content in supernatant was measured by colorimetric method.DNA synthesis and proliferation of hepatocellular carcinoma cells were detected by BrdU/PI incorporation method and CCK8 method. Then we used PIK3R3 overexpression or silenced hepatocellular carcinoma cell lines to observe the effect of PIK3R3 on the proliferation of hepatocellular carcinoma cells by plate cloning experiments. We intervened the expression of PIK3R3 and then observed the lipid metabolism and cell proliferation，so as to determine whether the role of PIK3R3 in hepatocellular carcinoma cells depends on PPARA. Finally, we added MG132（proteasome inhibitor）or CHX（cycloheximide）to PIK3R3 overexpression or silencing hepatocellular carcinoma cells to detect the level of PPARA by WB，next we constructed the plasmids of PPARA promoter luciferases and observed the effect of PIK3R3 on the activity of PPARA promoter. @*Results@#PIK3R3 influenced the expression of PPARA，lipid metabolism and proliferation of hepatocellular carcinoma cells，and PPARA partly reversed the effects of PIK3R3.@*Conclusion@#PIK3R3 can regulate the fat metabolism and proliferation of hepatoma cells by regulating the expression of PPARA.

Prevalence and Prognostic Role of PIK3CA/AKT1 Mutations in Chinese Breast Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The prevalence of PIK3CA in Chinese breast cancer patients may be underestimated. Therefore, we investigated the distribution of somatic PIK3CA/AKT1 mutations in Chinese breast cancer patients and explored their roles in tumor phenotypes and disease prognosis. MATERIALS AND METHODS: Tumors from 507 breast cancer patients were prospectively collected from the West China Hospital between 2008 and 2013. Whole exons of AKT1 and PIK3CA were detected in fresh-frozen tumors using next-generation sequencing, and correlations between PIK3CA/AKT1 mutations and clinicopathological features were analyzed. RESULTS: The AKT1 mutation was found in 3.6% (18/507) of patients. Tumors from patients that carried the AKT1 mutation were estrogen receptor (ER)+/progesterone receptor (PR)+/human epidermal growth factor receptor 2 (HER2)‒ and were more likely to have high expression levels of Ki67. The prevalence of the PIK3CA mutation was 46.5% (236/507), and 35 patients carried two or three variants of the PIK3CA gene. PIK3CA mutations were associated with ER+/PR+/HER2‒ status. The prognosis of patients with one mutation in PIK3CA (or PIK3CA/AKT1) was not significantly different than that of patients with wild-type PIK3CA (or PIK3CA/AKT1), while patients with two or three variants in PIK3CA (or PIK3CA/AKT1) exhibited poorer outcomes in the entire group and in all three subgroups (ER+, HER2‒, Ki67 high), particularly with respect to overall survival. CONCLUSION: A high frequency of somatic PIK3CA mutations was detected in Chinese breast cancer patients. In addition to the mutation frequency, the tumor mutational burden of the PIK3CA and AKT1 genes should also be of concern, as they may be associated with poor prognosis.

Overexpression of PIK3R1 promotes hepatocellular carcinoma progression

BACKGROUND: Phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1) could regulate cancer cell proliferation important for cancer cell proliferation; however, its role in Hepatocellular carcinoma (HCC) remains largely unknown. Here, we investigated the role of PIK3R1 in HCC and examined the underlying molecular mechanisms. METHODS: The expression of PIK3R1 was evaluated by immunohistochemistry and qRT-PCR in a series of HCC tissues. The mRNA and protein expression of PIK3R1 was used by qRT-PCR and western blot assays in a series of human HCC cell lines, and then we choose MHCC97H and HCCLM3 cells as a model to investigate the effect of PIK3R1 on HCC progression. The effects of PIK3R1 knowdown on cell proliferation, migration, apoptosis of HCC were assessed by the MTT assay, clonogenic assays, wound healing assay and flow cytometry in vitro. Western blot assay was performed to assess the expression changes of PI3K/AKT/mTOR signaling pathway. RESULTS: Our results found that PIK3R1 was highly expressed in HCC tissues compared with adjacent normal tissues. Knockdown of PIK3R1 inhibited the proliferation, migration and promoted apoptosis of HCC cell lines. In addition, we proved that knockdown of PIK3R1 downregulated p-PI3K, p-AKT, and p-mTOR expressions in MHCC97H and HCCLM3 cells. CONCLUSIONS: In conclusion, PIK3R1 providing potential novel targets for the treatment of HCC.

BRAF/ KRAS and PIK3CA mutation characteristics and clinical significance in primary small cell lung caner / 中华放射肿瘤学杂志

Objective To detect the frequency of BRAF/ KRAS and PIK3CA mutations in the small cell lung cancer (SCLC) specimens from a large population of Chinese patients and to analyze the gene mutation and clinical characteristics. Methods A total of 557 samples were collected from SCLC patients from 2009 to 2014.BRAF,KRAS,PIK3CA,NRAS and MEK1 gene mutations were detected by the dideoxy sequencing. Chi-square test was adopted to analyze the correlation between clinical factors and gene mutation. Kaplan-Meier method was utilized for survival analysis. Cox model was used for multivariate prognostic analysis. Results BRAF mutations were detected in 13 out of 557 specimens. The mutation types included V600E (n= 5) ,V600A (n= 2) ,V600M (n= 1) ,D594G (n= 1),G464E (n= 1),K601R (n= 2) and S605N (n= 1).KRAS mutation was detected in 6 cases including G12C (n= 3),G12A (n= 1),G12D (n=1) andG13D (n= 1).PIK3CA mutation was observed in 4 samples including E545G (n= 2) and H1047R (n= 2).Besides,NRAS mutation (Q61R) was detected in 1 case and MEK1 mutation (D61Y) was noted in 1 case. These gene mutations were not significantly correlated with the age, gender, smoking status and clinical staging of the patients. Univariate survival analysis demonstrated the median survival time of patients with gene mutation was (10.30±0. 751) months (95％CI:8. 829-11. 771 months),significantly shorter than (12.80±0. 543) months (95％CI:11. 736-13. 864 months) of their counterparts without gene mutation (P=0. 011). Conclusions BRAF/ KRAS and PIK3CA gene mutation is detected in a small proportion of SCLC patients. These gene mutations are not significantly correlated with the clinical characteristics. Univariate survival analysis demonstrates that negative these gene mutations are negatively correlated with the clinical prognosis of SCLC patients.

Molecular characterizations and possible treatment strategies for Epstein-Barr virus-as-sociated gastric cancer / 中国肿瘤临床

In 2014, The Cancer Genome Atlas (TCGA) classified gastric cancer into four types based on the genotype include EBV-infect-ed tumors, genomically stable tumors, chromosomally unstable tumors and MSI tumors, among which Epstein-Barr virus-associated gastric cancer (EBVaGC) is expected to be most suitable for immunotherapy because of its molecular characteristics, such as PD-L1/2 amplification or upregulation. Understanding the molecular characterizations of EBVaGC is very important in clinical practice. The re-ported molecular characteristics of EBVaGC include: PD-L1/2 upregulation, PIK3CA mutation, ARID1A mutation, DNA hypermethyl-ation, and rare mutation of TP53. Therefore, the possible therapeutic strategies for EBVaGC include the use of immune checkpoint in-hibitors, PI3K/AKT signaling pathway inhibitors, or antiviral therapy. This review summarizes the important molecular characterizations and possible treatment strategies for EBVaGC.

PIK3CA amplification and PTEN deletion in invasive B-cell lymphoma and their clinico-pathological significance / 中国肿瘤临床

Objective:To investigate the expression of PIK3CA and PTEN in PI3K/Akt/Mtor signaling pathway and its correlation with clinicopathological parameters in invasive B-cell lymphoma.Methods:A total of 235 invasive B-cell lymphoma cases enrolled in First Affliated Hospital of Xinjiang Medical University from January 2008 to December 2012,without any pre-operative treatment,were collected;those included 205 cases of diffuse large B-cell lymphoma(DLBCL),27 cases of Burkitt lymphoma(BL),and the remaining three cases were somewhere between DLBCL and BL,but could not be classified clearly.The expression of PIK3CA and PTEN genes was detected by fluo-rescence in situ hybridization.The relationship between PIK3CA and PTEN genes was analyzed statistically and extended to clinicopathological parameters and prognosis.Results:The positive rate of PIK3CA amplification in invasive B-cell lymphoma was 12.3%(29/235),and the positive rate of clinical stageⅠ-Ⅱ(8.6%,12/139)was much lower than that ofⅢ-Ⅳ(17.7%,17/96),with the difference being statistically significant (P=0.038).The deletion rate of PTEN in invasive B cell lymphoma was 13.6%(32/235),which was not correlated with other clinicopathological features.PIK3CA amplification was negatively correlated with PTEN deletion(P=0.046),and neither was found to be significantly associated with survival.Conclusions:PIK3CA amplification and PTEN deletion play a role in the development of invasive B-cell lymphoma,and the former is associated with late stage of the disease.

IL-6 promotes gastric cancer cell proliferation and EMT through regulating miR-152/PIK3R3 pathway / 中南大学学报(医学版)

Objective:To explore the role ofinterleukin (IL)-6 in gastric cancer cells and the mechanisms.Methods:Gastric cancer cells MGC-803 were treated with 50 ng/mL of recombinant IL-6 protein,and then cell viability and cell migration were detected by MTT assay and wound-healing assay,respectively.The mRNA and protein expressions of E-cadherin,N-cadherin,vimentin,Snaill and miR-152 were analyzed by RT-qPCR and Western blot,respectively.Moreover,MGC-803 cells were simultaneously or separately treated with IL-6 and transfected with miR-152 mimics,and then the mRNA expression of PIK3R3 and the protein levels of PIK3R3,Akt and p-Akt were determined.Results:IL-6 stimulation significantly promoted cell proliferation and migration,reduced the expression of E-cadherin and miR-152,and increased the expression of N-cadherin,vimentin,Snaill,PIK3R3 and p-Akt (All P＜0.05).The protein levels of PIK3R3 and p-Akt were significantly decreased after transfecting miR-152 mimics into MGC-803 cells (P＜0.01).miR-152 overexpression down-regulated IL-6-induced the protein expression of PIK3R3 and p-Akt (P＜0.01).The levels of Akt in each group were not changed.Conclusion:IL-6 up-regulates PIK3R3 expression and activates PI3K/Akt signaling pathway through down-regulating miR-152 expression,which consequently promotes gastric cancer cell proliferation,migration,and epithelial-mesenchymal transition.

Expression of 3 markers and its correlation with prognosis of patients with non-small cell lung cancer / 国际检验医学杂志

Objective To investigate the expressions of ALCAM,IL-17RA and PIK3CA in patients with non-small cell lung cancer,and to investigate the correlation between the above-mentioned indexes and patients′ prognosis.Methods A total of 65 patients with non-small cell lung cancer admitted to the third People′s Hospital in Liaocheng City were selected and were served as study objects.Immunohistochemical staining(S-P) method was used to detect the expression of ALCAM,IL-17RA and PIK3CA in tissues to analyze the difference of expression between different pathological parameters.And 65 patients were followed up after the operation to compare the survival time of patients in the negative expression group and the positive expression group,and to analyze the correlation between ALCAM,IL-17RA and PIK3CA and the prognosis of the disease.Results Among the 65 cases of patients,47 cases were positive for ALCAM with the positive rate of 72.3%,34 cases were positive for IL-17RA with the positive rate of 52.3%;31 cases were positive for PIK3CA with the positive rate of 47.7%.There was significant difference in the expression of ALCAM,IL-17RA and PIK3CA in patients with different pathological types,TNM staging and lymph node metastasis(P0.05).The median survival time of patients with positive results of ALCAM,IL-17RA and PIK3CA were lower than those of negative group,and the differences were statistically significant(P<0.05).Conclusion The expression of ALCAM,IL-17RA and PIK3CA increased in non-small cell lung cancer tissues to remind the higher degree of malignancy and poor prognosis.

c-Myc promoted migration and invasion of malignant melanoma B16-F10 cells through regulating PIK3 R3 / 中国免疫学杂志

Objective:To investigate the effect and the related mechanism of c-Myc on the proliferation,invasion and migration ability of malignant melanoma B16-F10 cells. Methods:We detected the expression of PIK3R3 in malignant melanoma and normal tis-sues. Efficiency of gene silencing of c-Myc and PIK3R3 was determined by qPCR and Western blot. We detected the proliferate ability of B16-F10 cells after silencing c-Myc and PIK3R3 using EdU assay. We detected the migration and invasion ability of B16-F10 cells after silencing c-Myc and PIK3R3 using wound healing assays and Transwell matrigel invasion assays. The expression of miR-199a after silencing c-Myc and PIK3R3 using qPCR. The expression of c-Myc and PIK3R3 was detected by qPCR after transfecting miR-199a mimics or miR-199a inhibitor. Dual-luciferase reporter assay system was used to detect miR-199a regulating c-Myc and PIK3R3. Results:Compared normal skin tissue,expression of PIK3R3 was significantly increased in malignant melanoma tissue;after silencing c-Myc and PIK3R3 gene,the proliferation,invasion and metastasis of melanoma cell line B16-F10 were significantly reduced;expression of miR-199a upregulated after silencing c-Myc and PIK3R3 genes, expression of c-Myc and PIK3R3 decreased after transfecting miR-199a mimics, expression of c-Myc and PIK3R3 upregulated after transfecting miR-199a inhibitor, dual luciferase reporter system test results revealed miR-199a can directly regulate c-Myc and PIK3R3 transcription activity. Conclusion: miR199a regulated the expression of c-Myc,then promote proliferation,migration and invasion in malignant melanoma cells.

Correlation of KRAS and PIK3CA gene status between primary tumors and paired metastases in colorectal cancer / 临床与实验病理学杂志

Purpose To investigate the mutation status of KRAS and PIK3CA gene in colorectal cancer (CRC) primary lesions and corresponding liver metastasis and its clinical significance.Methods The gene mutations of KRAS and PIK3CA were detected in 58 cases of primary lesions of CRC and corresponding liver metastasis tissue by real-time PCR.Results The mutation rates of KRAS were 31.03％ (18/58) and 25.86％ (15/58) in primary lesions of CRC and corresponding liver metastasis tissue,respectively,in which G12D was most commonly detected.The mutation rates of PIK3CA were 8.62％ (5/58) and 10.34％ (6/58) respectively,in which the most common mutation site was E545K.Only one case carried simultaneously both mutations of KRAS (G12D) and PIK3CA (E545K).The mutation of KRAS and PIK3CA had a good consistency between primary lesions and liver metastasis.Univariate analysis showed that the mutation of KRAS was related to the primary lesion of tumor location,the quantity of metastasis and the types of tumor (P ＜ O.05),PIK3 CA mutation was associated with the synchronous/metachronous liver metastasis and the quantity of metastasis (P ＜ 0.05).Multivariate Cox regression analysis showed that synchronous/metachronous liver metastasis and the mutation of KRAS were influencing factors for prognosis of CRC.The overall survival of patients with CRC who had simultaneous liver metastases was longer than those with heterotopic liver metastases;the overall survival of KRAS wild-type mutant patients was longer than those of mutant patients (P ＜ 0.05).Conclusion The G12D site of KRAS gene has the highest mutation frequency in CRC,KRAS/PIK3CA mutation has a good consistency of the primary lesions of CRC and corresponding liver metastasis.Primary lesions can be as the source of molecular detection.To achieve individualized treatment,we need to reassess the genetic status of metastasis based on the choice of targeted therapy for precision medicine.