Antitumor profiles and cardiac electrophysiological effects of aurora kinase inhibitor ZM447439

Aurora kinases inhibitors, including ZM447439 (ZM), which suppress cell division, have attracted a great deal of attention as potential novel anti-cancer drugs. Several recent studies have confirmed the anti-cancer effects of ZM in various cancer cell lines. However, there have been no studies regarding the cardiac safety of this agent. We performed several cytotoxicity, invasion and migration assays to examine the anti-cancer effects of ZM. To evaluate the potential effects of ZM on cardiac repolarisation, whole-cell patch-clamp experiments were performed with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cells with heterogeneous cardiac ion channel expression. We also conducted a contractility assay with rat ventricular myocytes to determine the effects of ZM on myocardial contraction and/or relaxation. In tests to determine in vitro efficacy, ZM inhibited the proliferation of A549, H1299 (lung cancer), MCF-7 (breast cancer) and HepG2 (hepatoma) cell lines with IC₅₀ in the submicromolar range, and attenuated the invasive and metastatic capacity of A549 cells. In cardiac toxicity testing, ZM did not significantly affect I(Na), I(Ks) or I(K1), but decreased I(hERG) in a dose-dependent manner (IC₅₀: 6.53 µM). In action potential (AP) assay using hiPSC-CMs, ZM did not induce any changes in AP parameters up to 3 µM, but it at 10 µM induced prolongation of AP duration. In summary, ZM showed potent broad-spectrum anti-tumor activity, but relatively low levels of cardiac side effects compared to the effective doses to tumor. Therefore, ZM has a potential to be a candidate as an anti-cancer with low cardiac toxicity.

Incorporación de paciente virtual en portafolio de estudiantes de medicina de pregrado / Introduction of virtual patients to clinical case portfolios for undergraduate medical students

Background: In 2007, a Clinical-Case-Portfolio (CCP) was introduced as a new assessment instrument for fourth grade undergraduate medical students. Since then, several changes have been implemented such as reduction on the number of clinical cases, peer review and the introduction of virtual patient to the portfolio. Aim: To describe the virtual patient model incorporated to the CCP and assess the perception of this change and its effects on the performance of undergraduate students. Material and Methods: Virtual patients were implemented based on prototype clinical cases with specific syndromes. Students’ perceptions about CCP before and after the introduction of virtual patients were evaluated using a validated questionnaire that was answered voluntarily and anonymously. Results: Overall perception of CCP significantly improved after the incorporation of virtual patients (97.1 ± 24.9 and 111.3 ± 25.7 points; 57.8 and 66.2% respectively). The same improvements were observed for the domains “Student Learning”, “Organization and Evaluation”, “Teaching Methodology” and “Integration”. In both years, students obtained high grades in CCP evaluations. However CCP grades were not significantly correlated with integrated final grades. Conclusions: The incorporation of virtual patients improved undergraduate students’ perception of CCP.

Targeted therapy: tailoring cancer treatment / 癌症

Targeted therapies include small-molecule inhibitors and monoclonal antibodies, have made treatment more tumor-specific and less toxic, and have opened new possibilities for tailoring cancer treatment. Nevertheless, there remain several challenges to targeted therapies, including molecular identification, drug resistance, and exploring reliable biomarkers. Here, we present several selected signaling pathways and molecular targets involved in human cancers including Aurora kinases, PI3K/mTOR signaling, FOXO-FOXM1 axis, and MDM2/MDM4-p53 interaction. Understanding the molecular mechanisms for tumorigenesis and development of drug resistance will provide new insights into drug discovery and design of therapeutic strategies for targeted therapies.

Suppression of Aurora-A by RNA interference inhibits laryngeal cancer Hep-2 cell growth / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the effects of knockdown of Aurora-A by RNA interference on laryngeal cancer Hep-2 cell growth in vitro and in vivo.</p><p><b>METHODS</b>A plasmid containing siRNA against Aurora-A was constructed and transfected into human laryngeal cancer cell line Hep-2. Measurements included the CCK-8 assay for viability and proliferation, Transwell assay for invasion, colony formation assay for cell anchorage-independent growth. Western blot and immunohistochemistry assay for protein expression. Tumorigenicity was observed in vivo.</p><p><b>RESULTS</b>In Hep-2 cells transfected by Aurora-A siRNA (designated as siRNA-3), protein expression of Aurora-A was suppressed by 52%. In CCK-8 assay, absorbance value of siRNA-3 cells (3.268 ± 0.106, (x(-) ± s)) was lower than that of Hep-2 cells (3.722 ± 0.152, F = 17.634, P < 0.001). In Transwell assay, the average invasive cells per field in siRNA-3 cells (110.0 ± 18.0) was less than that in Hep-2 cells (236.0 ± 26.0, F = 26.462, P < 0.01). In colony formation assay, the average colony number of siRNA-3 cells (31.0 ± 6.6) was lower than that of Hep-2 cells (104.0 ± 14.0). The average tumor size in siRNA-3 group was (127.77 ± 174.83) mm(3), which was less than Hep-2 cell group (837.26 ± 101.80) mm(3), (F = 28.187, P < 0.001). Silencing of Aurora-A decreased the expression of focal adhesion kinase (FAK) and matrix metalloproteinase-2 (MMP-2), key regulators in cell adhesion and invasion.</p><p><b>CONCLUSIONS</b>The knockdown of Aurora-A inhibits the growth and invasiveness of Hep-2 cells in vitro and in vivo, which may be a promising therapeutic strategy for LSCC.</p>

Killing effect of aurora kinase inhibitor ENMD-2076 on acute myelogenous leukemia cells / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effect of aurora kinase inhibitor ENMD-2076 on human acute myelogenous leukemia (AML) cell lines.</p><p><b>METHODS</b>AML THP-1 and Kasumi-1 cells were treated with ENMD-2076 for 24 h and 48 h,respectively. Cell growth was measured by MTT assay. Apoptosis was determined using Hoechst staining apoptosis detection kit. Activation of Caspase pathway and expression of apoptosis regulator proteins were detected by Western blot.</p><p><b>RESULTS</b>ENMD-2076 significantly induced growth arrest and apoptosis in THP-1 and Kasumi-1 cells. Enhanced apoptosis was observed in ENMD-2076 group evidenced by strong activation of Caspase-9,Caspase-3 and PARP. Furthermore,the ENMD-2076 treatment resulted in down-regulation of anti-apoptotic protein Mcl-1 expression. Also,up-regulated expression of pro-apoptotic protein Bak,Bad and Bax was detected after ENMD-2076 treatment.</p><p><b>CONCLUSION</b>ENMD-2076 can kill effectively AML cells by inhibiting cell growth and inducing apoptosis,which is associated with activation of Caspase pathway and regulation of pro-apoptotic and anti-apoptotic proteins.</p>

Clinical significance of abnormal expression of Aurora-A in human esophageal squamous cell carcinoma with or without lymph node metastasis / 中华肿瘤杂志

<p><b>OBJECTIVE</b>China has the highest incidence and mortality of esophageal carcinoma in the world, and the esophageal squamous cell carcinoma (ESCC) is the major type. In this study, the authors investigated the expression of Aurora-A in stage T3 esophageal squamous cell carcinomas (ESCC) with positive and negative lymph node metastasis, and analyzed its relationship with prognosis of ESCC patients.</p><p><b>METHODS</b>ESCC tissue arrays including 212 specimens had been constructed. The expression of Aurora-A in both ESCC tissues and adjacent normal tissues was determined by immunohistochemical staining. The correlation between Aurora-A protein levels and lymph node status in ESCC and survival rate were statistically analyzed.</p><p><b>RESULTS</b>The positive expression of Aurora-A was 74.07% (140/189) in tumor tissues and 18.52% (35/189) in adjacent normal tissues, showing a significant difference between them (χ(2) = 105.162, P < 0.05). In tumors with positive lymph nodes, strong positive expression of Aurora-A was found in 42.99% (46/107), while only 7.37% (7/95) in tumors with negative lymph nodes, with a statistically significant difference (χ(2) = 36.132, P < 0.05). The cumulative survival rate of the patients with strong Aurora-A-positive tumors was significantly lower than that in patients with Aurora-A-negative tumors (P = 0.0042, P < 0.05).</p><p><b>CONCLUSION</b>The positive expression of Aurora-A in ESCC tissues is much higher than that in adjacent normal tissues. The expression of Aurora-A is higher in lymph node-positive tumors than in the lymph node-negative ones. There is a significantly longer cumulative survival rate in patients with negative Aurora-A expression than that in patients with strong positive Aurora-A expression.</p>

Expression of Aurora-B in human glioma tissue and its significance / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the expression of Aurora-B in human glioma tissue and its significance.</p><p><b>METHODS</b>The total RNA was extracted from 41 human glioma tissues and 11 normal brain tissues by Trizol reagent. After reverse transcription of the total RNA into cDNAs, Aurora-B mRNA expressions in these samples were detected by quantitative real-time PCR. The protein expression in these samples was detected using immunohistochemical staining.</p><p><b>RESULTS</b>Aurora-B mRNA and protein expressions were significantly increased in glioma tissues as compared with those in normal brain tissues.</p><p><b>CONCLUSION</b>Aurora-B mRNA and protein show markedly higher expressions in glioma tissue, suggesting that Aurora-B may be one of the malignant biomarkers in the pathogenesis and progression of human glioma.</p>

Genetic polymorphisms in STK15 and MMP-2 associated susceptibility to esophageal cancer in Mongolian population / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate the frequencies of alleles and the association with risk of esophageal cancer in a Mongolian population, and to compare the allele frequencies of these polymorphisms between the two populations and the susceptibility to esophageal cancer.</p><p><b>METHODS</b>A case-control study was conducted, and 8 single nucleotide polymorphisms (SNP), including FAS - 670G/A, FAS - 1377G/A, FASL -844T/C, COX-2 - 1290A/G, COX-2 - 1195G/A, STK15 Phe31Ile, MMP-2 - 1306C/T and MMP -2 -735C/T, were detected by polymerase chain reaction-based restriction fragment length polymorphism assay (PCR-RFLP) in 188 esophageal cancer cases and 324 normal controls of Mongolian. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression. The results were then compared with the reported data of the Han ethnic Chinese population.</p><p><b>RESULTS</b>In Mongolian, as compared with the STK15 31Ile/Ile genotype, the STK15 31Phe/Phe genotype carriers had an increased risk of esophageal cancer (adjusted OR = 2.20, 95% CI: 1.12-4.31), and the subjects with MMP-2 - 735TT genotype had an increased risk of esophageal cancer as compared with those with the MMP-2 - 735CC genotype (adjusted OR =4.82, 95% CI: 1.59 - 14.60). However, the rest of SNPs were not associated with the susceptibility to esophageal cancer. The allele frequencies of FASL - 844 T/C [0.264(171/648)/0.736 (477/648), 0.323(418/1296)/0.677(878/1296)], COX-2 - 1195G/A [0.431(279/648)/0.569(369/ 648), 0.492(1250/2540)/0.508(1290/2540)], MMP-2 - 1306C/T [0.869(563/648)/0.131(85/ 648), 0.835(1298/1554)/0.165(256/1554)] and MMP-2 - 735C/T [0.789(511/648)/0.211(137/ 648), 0.748(1163/1554)/0.252(391/1554)] were significantly different between the ethnic populations (chi2 = 7.03, 7.84, 3.94, 4.05, respectively, P <0.05).</p><p><b>CONCLUSION</b>These findings suggested that STK15 Phe31Ile and MMP-2 -735C/T polymorphisms might be the genetic susceptibility factors for esophageal cancer in Mongolian and there should be some differences of genetic susceptibility to esophageal cancer in between Han ethnic Chinese and Mongolian population.</p>

Expression of Aurora-B in non-small cell lung cancer and its clinical significance / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the expression of Aurora-B in non-small cell lung cancer (NSCLC) tissues and NSCLC cell lines.</p><p><b>METHOD</b>Aurora-B expression was examined using immunohistochemical SP method in 91 stage I and 69 stage II-III NSCLC tissues and 40 adjacent tissues. The mRNA and protein expressions of Aurora-B in NSCLC cell lines (A549, H460 and H1299) were examined by RT-PCR and Western blotting, respectively.</p><p><b>RESULTS</b>The protein expression of Aurora-B was detected in 77.7% (94/121) of the tumor tissues and 9.8% (4/41) of the adjacent tissues, showing a significant difference between them (P<0.01). The positivity rate of Aurora-B protein was not related with the gender and age of NSCLC patients, but with lymph node metastasis, differentiation and histological type of NSCLC (P<0.05). Aurora-B was expressed in all the NSCLC cell lines (A549, H460 and H1299) at both mRNA and protein levels. A549 cells showed the highest expression of Aurora-B.</p><p><b>CONCLUSION</b>Aurora-B protein is highly expressed in NSCLC tissues and cell lines, and may play a crucial role in the invasion, metastasis and development of NSCLC. The mRNA and protein expression levels of Aurora-B differ significantly between different NSCLC cell lines.</p>

Research progress on aurora kinase inhibitor MK-0457 in therapy for some hematological malignancies -- review / 中国实验血液学杂志

Recent work indicates that an Aurora kinase inhibitor MK-0457 (VX-680), a small-molecule inhibitor of Aurora kinases A, B, C and BCR-ABL, FLT-3, JAK-2, can block the progression of cell growth cycle, causing apoptosis in a range of human tumors. MK-0457 has the activity against expressions of wild-type and mutated bcr-abl gene, including the T315I mutant, and can inhibit the activity of FLT-3, JAK-2 and their mutated types as well. Clinical applications suggest that the MK-0457 has therapeutic effect on the highly refractory CML and CML with poor prognosis, Ph(+) ALL with T315I mutant, relapse refractory AML and JAK-2 positive myeloproliferative diseases (MPD). The intensive preclinical studies and the on-going phase II clinical trials will open up a new vista of therapy for some hematological malignancies. This review focuses on the pharmacologic action of MK-0457 and its clinical trial as well as combined application.

Recent advance in the study of novel anti-tumor targets and drugs--aurora kinase and Pin1 / 药学学报

Malignant tumor, one of the most refractory diseases, plays a threaten role in human health, the therapy and research on malignant tumor have taken a long way to go. The anti-tumor drugs which are the essential therapy strategies upgrade with the development of new anti-tumor targets and the research on tumor pathogenesis. Aurora kinase and Pin1, the novel anti-tumor targets, maintain the important relationship with tumor. Many new compounds designed on these targets have excellent anti-tumor effects and also enter into phase I or phase II clinical trial.

Study on the association between STK15 Phe31Ile polymorphisms and esophageal squamous cell carcinoma / 中华流行病学杂志

<p><b>OBJECTIVE</b>To study the relation between single nucleotide polymorphism(SNP) at the 91T-->A(Phe31Ile) position of the STK15 gene and the susceptibility of esophageal squamous cell carcinoma (ESCC) in She county--a ESCC high incidence region in North China.</p><p><b>METHODS</b>Polymerase-chain reaction(PCR)-restriction fragment length polymorphism (RFLP) analysis was used to detect the genotypes of STKl5 Phe31Ile(91T-->A) SNP, and the samples came from 296 ESCC patients and 302 healthy controls.</p><p><b>RESULTS</b>The risk of ESCC significantly increased in the group which had been smoking or having a family history of upper gastrointestinal cancer (UGIC) (the OR = 1.68 and 1.77, 95% CI: 1.34-2.10 and 1.44-2.19, respectively). Rates of the three genotypes (Phe/Phe, Phe/Ile, Ile/Ile) of the STK15 Phe31Ile (91T-->A) SNPs in ESCC patients were 11.5%, 34.8% and 53.7%, respectively, and were not significantly different from that in the healthy group (11.9%, 36.8% and 51.3%) (chi2 = 0.35, P = 0.84). When compared to Phe/Phe genotype, Phe/Ile and Ile/Ile of STK15 91T-->A(Phe31Ile)did not show effect on the risk of ESCC according to the odds ratio results which were 0.98 (95% CI: 0.57-1.69) and 1.09 (0.65-1.82) respectively. STK15 91T-->A (Phe31Ile) SNP also did not significantly influence on the development of ESCC even the samples were stratified by sex, smoking status and family history of upper gastrointestinal cancer.</p><p><b>CONCLUSION</b>The STK15 Phe31Ile(91T-->A) polymorphisms seemed irrelevant with the risk of ESCC in She county.</p>

The investigation of STK15 gene amplification and overexpression in laryngeal squamous cell carcinoma / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the role of STK15 gene amplification and overexpression to genesis and development of laryngeal squamous cell carcinoma (LSCC).</p><p><b>METHODS</b>STK15 gene amplification in 40 cases carcinoma tissues and normal tissues as control was detected by differential PCR approach. STK15 mRNA and protein levels were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry method.</p><p><b>RESULTS</b>In 40 LSCC cases, STK15 gene amplification was found in 14 tumor tissues(35%), mRNA overexpression in 27 tumor tissues(67.5%), and protein upregulated in 29 tumor tissues(72.5%). Statistics analysis showed that STK15 gene amplification and mRNA overexpression were obviously associated to differentiation degree of LSCC, and protein overexpression was closely associated with both differentiation degree and pathological grades of LSCC.</p><p><b>CONCLUSION</b>This research results suggest that STK15 gene amplification contributes to its mRNA and protein overexpression through affecting the exact replication of centrosome and separation of chromosomes. STK15 gene thus plays a role in LSCC oncogenesis and malignant progression.</p>

Analysis of gene expression profiles in gastric cancer cell cycle / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To detect the gene expression profile in gastric cancer cell cycle and explain the mechanism of gastric cancer cell proliferation by a genomic study.</p><p><b>METHODS</b>Gastric cancer cells MKN45 were synchronized at G2/M and G1/S point by nocodazole-thymidine and double thymidine methods. The synchronizing degree of cells was monitored by flow cytometry. The gene expression profiles at G2/M point, M/G1 transition, G1 early phase, G1 late phase, G1/S point, S early phase, S late phase, G2 early phase and G2 late phase in MKN45 cell cycling were examined using cDNA microarray chips. Hierarchy analysis was conducted with a professional software package and the up-regulated genes at G1 late and G2 phase were analyzed according to gene database. Furthermore, the mRNA level of cyclin E, cyclin B, plk1 and STK15 in above mentioned nine points were measured by quatitative PCR.</p><p><b>RESULTS</b>2001 genes were detected to be available at all 9 points via software processing, out of which 959 appeared up-regulated or down-regulated. 379 genes showed to be up-regulated at late G1 (147) or G2 phases (232), 40 at S and M phases (also up-regulated at G1 late and G2 phases). The 147 up-regulated genes at G1 late phase are involved in DNA metabolism, transcription and translation, protein transportation, ubiquitination and signal transduction, etc. The 232 up-regulated genes in G2 phase are involved in RNA synthesis and processing, intracellular protein transportation, cytoskeleton synthesis, signal transduction, apoptosis and anti-apoptosis, transcription regulation, ubiquitination, mitosis regulation and oncogene expression, etc. The mRNA level of 4 genes detected by quantitative PCR during cell cycle was in agreement with that detected by microarray.</p><p><b>CONCLUSION</b>During MKN45 cell cycling, the preparation for DNA synthesis and chromosome separation are conducted in G1 and G2, which are implicated in multiple genes, may be the main impetus of driving MKN45 cell cycle. Some of these genes may be related to tumor over-proliferation. The cDNA microarray technique has characteristic features such as reliability and can provide a great deal for future research on cell cycle related genes in gastric cancer.</p>

Inhibition of serine/threonine kinase 15 gene expression induces apoptosis of gastric cancer cells / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To observe the effect of inhibition of serine/threonine kinase15 (STK15) gene expression on apoptosis induction in gastric cancer cell line-MKN45 and discuss the role of STK15 in viability of gastric cancer cells.</p><p><b>METHODS</b>The STK15 expression was inhibited by chemically synthesized siRNA. The STK15 mRNA and protein level were respectively measured by real-time quantitative PCR and western blotting,the change of cell cycle distribution and apoptosis rate were detected by flow-cytometry, cell morphological change was observed by Hoechst staining,and pro-caspase 3 level was also detected by western blot.</p><p><b>RESULTS</b>After treatment by siRNA targeting STK15 after 48 h, STK15 mRNA and protein level decreased obviously. More MKN45 cells accumulated at G(2)/M phase (P< 0.05). The apoptosis rate of STK15 siRNA treated MKN45 cells was higher than that of control cells(P< 0.05) with the pro-caspase 3 level decreased.</p><p><b>CONCLUSIONS</b>Inhibition of STK15 gene expression may induce apoptosis in MKN45 cells through the pathway of caspase3. STK15 gene play a key role in proliferation and viability of MKN45 cells.</p>

Association between genetic polymorphism in STK15 and risk of colorectal cancer in a Chinese population / 中华肿瘤杂志

<p><b>OBJECTIVE</b>This case-control study was designed to detect the association between STK15 Phe31Ile polymorphism and colorectal cancer.</p><p><b>METHODS</b>Genotypes were determined in 283 patients with colorectal cancer and 283 controls. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression model.</p><p><b>RESULTS</b>The frequency of the STK15 Ile/Ile genotype was significantly higher in cancer cases than in controls (50.2% vs. 36.8%; P = 0.02). Subjects with the Ile/Ile genotype had an increased risk for the occurrence of colorectal cancer compared with those with the STK15 Phe/Phe genotype (adjusted OR, 1.92; 95% CI, 1.13 - 3.27). No significant association was observed between this STK15 polymorphism and risk of metastasis of the cancer.</p><p><b>CONCLUSION</b>These findings suggest that STK15 Phe/Ile polymorphism may be a genetic susceptibility factor for colorectal cancer among Chinese.</p>

Mitotic arrest of gastric cancer cells induced by silencing of STK15 gene / 中华病理学杂志

<p><b>OBJECTIVE</b>To investigate the role of STK15 in regulating mitosis of gastric cancer cells (MKN45) by gene silencing through RNA interference mechanism.</p><p><b>METHODS</b>RNA interference technique was used to inhibit STK15 expression in MKN45 cells. The expression levels of STK15 mRNA and protein were measured by real-time quantitative RT-PCR and Western blot respectively and cell morphological changes were investigated by reverse microscopy. In addition, cell cycle distribution and cellular proliferation were determined by flow-cytometry and MTT assay respectively. Finally, the mitotic phenotype of MKN45 cells was studied by immunofluorescence staining and confocal microscopy.</p><p><b>RESULTS</b>Silencing of STK15 gene by RNA interference was confirmed by marked decrease of STK15 mRNA and protein levels in the treated MKN45 cells. This silencing correlated with rounding of the cells, decreasing of DNA content in G(2) phase (P < 0.05) and a lowered proliferation index (P < 0.05), along with alterations of mitotic phenotype of MKN45 (P < 0.05).</p><p><b>CONCLUSION</b>STK15 gene may play a key role in regulating cellular mitosis and its inhibition by RNA interference leading to mitosis arrest in MKN45 cells.</p>

Mutation of p53 and overexpression of STK15 in laryngeal squamous-cell carcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the relationship between p53 gene mutations and STK15 abnormal expression in the development of human laryngeal squamous-cell carcinoma (LSCC).</p><p><b>METHODS</b>LSCC tissues and matched normal tissues were taken during operation from 55 patients without previous chemotherapy or radiotherapy. Following polymerase chain reaction amplification direct sequencing single strand conformational polymorphism (PCR-SSCP) combined with silver staining were used to detect mutations of p53 gene in exons 7 and 8 (p53E7 and p53E8) using genomic DNA from 110 specimens including 55 LSCC tissues and 55 matched normal tissues. STK15 expression were evaluated by RT-PCR with beta-actin as internal control.</p><p><b>RESULTS</b>The mutation rate of p53E7 was 30.9% (compared to normal tissues, chi(2) = 8.66, P < 0.01). There was no mutation in p53E8. In 38 of the 55 cases (69.1%), the STK15 mRNA expression level was higher than that of the paired normal tissue. The STK15 to beta-actin ratio of average density value was 1.22 +/- 0.49 in the cancer tissue, and 0.99 +/- 0.54 in the normal tissues (t = 4.539, P < 0.01). In 14 of the 17 cases (82.4%) with p53E7 mutations, the STK15 expression was higher than that of normal tissue. In the 38 cases with STK15 over-expression, p53E7 mutation was found in 14 cases (36.8%). The rate of concurrence of p53E gene mutations and STK15 over-expression (25.5%) was higher than that of only p53E gene mutations (chi(2) = 26.025, P < 0.01).</p><p><b>CONCLUSION</b>There is significant association between p53 gene mutation and STK15 over-expression in laryngeal squamous-cell carcinoma.</p>

Deletion of p15 and pl6 genes and overexpression of STK15 gene in primary hepatocellular carcinoma / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the association of p15 and pl6 genes deletion and STKI5 gene overexpression in primary hepatocellular carcinoma (PHC).</p><p><b>METHODS</b>The carcinoma tissue and the adjacent normal tissue were taken from 30 PHC patients during operations who had had neither chemotherapy nor radiotherapy preoperatively. DNA was extracted from the tissues and PCR was used to determine the homozygous deletion of p15 exon2 (pl5E2) and pl6 exon 2 (pl6E2). RNA was extracted, cDNA was synthesized by RT-PCR, and the expression of STKI5 gene was tested by PCR. Beta-actin was used as an internal control. Average density value (ADV) of STK15 gene and that of beta-actin gene were determined in both carcinoma tissue and the adjacent normal tissue.</p><p><b>RESULTS</b>The rate of p15E2 deletion was 13.3% (4/30) and the rate of p16E2 deletion was 16.7% (5/30) in the carcinoma tissue. The p15E2 and pl6E2 co-deletion rate was 6.7% (2/30). In 19 of the 30 cases (63.3%) the expression of STK15 gene in carcinoma tissue was higher than that in the adjacent normal tissue. The ratio of ADV of STK15 gene to ADV of beta-actin gene (1.53+/-0.31) in the carcinoma tissue was significantly higher than that (0.91+/-0.25) in the paired adjacent normal tissue (t = 2.86).</p><p><b>CONCLUSION</b>The homozygous deletion of p15E2 and p16E2 and overexpression of STKI5 gene may play a role in the oncogenesis and malignant progression of PHC.</p>

Study on STK15 gene abnormality and centrosomal amplification in laryngeal carcinoma / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate STK15 gene abnormality and centrosomal amplification in laryngeal carcinoma.</p><p><b>METHODS</b>STK15 gene mRNA expressional level was tested in 62 cases of laryngeal squamous cell carcinoma and laryngeal squamous cell carcinoma cell line Hep-2 by reverse transcription-polymerase chain reaction(RT-PCR); the mutation of STK15 gene exon 6 and exon 7 in the same tissues and cells was detected by PCR-single strand conformation polymorphism. Immunofluorescent antibodies were used to test centrosomal amplification in Hep-2 cell line as an example.</p><p><b>RESULTS</b>STK15 gene overexpressed in 39 cases of laryngeal carcinoma (63%) and Hep-2 cell line. No mutation was found in exon 6 and exon 7 of STK15 gene in the above tissues and cells. Centrosomal amplification was apparent in Hep-2 cell line. The number of centrosome in a single cell changed from 1 to 7, and Hep-2 cells with amplified centrosomes (more than 2 in one cell) were 11%-23%.</p><p><b>CONCLUSION</b>STK15 gene overexpression and centrosomal amplification were first found in human laryngeal squamous cell carcinoma, which indicated that STK15 gene overexpression leading to centrosomal amplification might occur in the early stage of human laryngeal carcinogenesis and be one of the key mechanisms for the occurrence of laryngeal carcinoma.</p>