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Cytoskeleton-associated protein 4 (CKAP4) acts as a key transmembrane protein that connects the endoplasmic reticulum (ER) to microtubule dynamics. Researchers have not examined the roles of CKAP4 in nasopharyngeal carcinoma (NPC). The study aimed at evaluating the prognostic value and metastasis-regulating effect of CKAP4 in NPC. CKAP4 protein could be observed in 86.36% of 557 NPC specimens but not in normal nasopharyngeal epithelial tissue. According to immunoblot assays, NPC cell lines presented high CKAP4 expression relative to NP69 immortalized nasopharyngeal epithelial cells. Moreover, CKAP4 was highly expressed at the NPC tumor front and in matched liver, lung, and lymph node metastasis samples. Furthermore, high CKAP4 expression reported poor overall survival (OS) and presented a positive relevance to tumor (T) classification, recurrence, and metastasis. According to multivariate analysis, CKAP4 could independently and negatively predict patients’ prognosis. Stable knockdown of CKAP4 expression in NPC cells inhibited cell migration, invasion and metastasis in vitro and in vivo. Moreover, CKAP4 promoted epithelial-mesenchymal transition (EMT) in NPC cells. CKAP4 knockdown was followed by the downregulation of the interstitial marker vimentin, and upregulation of the epithelial marker E-cadherin. In NPC tissues, high CKAP4 expression exhibited a positive relevance to vimentin expression and a negative relevance to E-cadherin expression. In conclusion, CKAP4 is an independent predictor of NPC, and CKAP4 might contribute NPC progression and metastasis, which may be involved in EMT with vimentin and E-cadherin.

Supplemental material, sj-docx-4-tub-10.1177_1010428317709638 for Oncogene mutation profile predicts tumor regression and survival in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy and radical surgery by Jianhong Peng, Junzhong Lin, Miaozhen Qiu, Yujie Zhao, Yuxiang Deng, Jianyong Shao, Peirong Ding, Huizhong Zhang, Desen Wan, Zhenhai Lu and Zhizhong Pan in Tumor Biology

Supplemental material, sj-docx-3-tub-10.1177_1010428317709638 for Oncogene mutation profile predicts tumor regression and survival in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy and radical surgery by Jianhong Peng, Junzhong Lin, Miaozhen Qiu, Yujie Zhao, Yuxiang Deng, Jianyong Shao, Peirong Ding, Huizhong Zhang, Desen Wan, Zhenhai Lu and Zhizhong Pan in Tumor Biology

Supplemental material, sj-docx-2-tub-10.1177_1010428317709638 for Oncogene mutation profile predicts tumor regression and survival in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy and radical surgery by Jianhong Peng, Junzhong Lin, Miaozhen Qiu, Yujie Zhao, Yuxiang Deng, Jianyong Shao, Peirong Ding, Huizhong Zhang, Desen Wan, Zhenhai Lu and Zhizhong Pan in Tumor Biology

Supplemental material, sj-docx-1-tub-10.1177_1010428317709638 for Oncogene mutation profile predicts tumor regression and survival in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy and radical surgery by Jianhong Peng, Junzhong Lin, Miaozhen Qiu, Yujie Zhao, Yuxiang Deng, Jianyong Shao, Peirong Ding, Huizhong Zhang, Desen Wan, Zhenhai Lu and Zhizhong Pan in Tumor Biology

Objective: To evaluate the diagnostic value of fluorescence in situ hybridization (FISH) in bladder cancer. Methods: We enrolled healthy volunteers and patients who were clinically suspected to have bladder cancer and conducted FISH tests and cytology examinations from August 2007 to December 2008. Receiver operating characteristic (ROC) curve analysis was performed and the area under curve (AUC) values were calculated for both the FISH and urine cytology tests. Results: A cohort of 988 healthy volunteers was enrolled to establish a reference range for the normal population. A total of 4807 patients with hematuria were prospectively, randomly enrolled for the simultaneous analysis of urine cytology, FISH testing, and a final diagnosis as determined by the pathologic findings of a biopsy or a surgically-excised specimen. Overall, the sensitivity of FISH in detecting transitional-cell carcinoma was 82.7%, while that of cytology was 33.4% (p

Distant metastasis is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure while epithelial-mesenchymal transition (EMT) is the critical process of NPC invasion and metastasis. However, tumor-suppressor genes involved in the EMT and metastasis of NPC have not been explored clearly compared with the oncogenes. In the present study, the expression of pigment epithelium-derived factor (PEDF), a potent endogenous antitumor factor, was diminished in human NPC tissues and associated with clinicopathological and EMT features. The knockdown of PEDF induced EMT in lower metastatic NPC cell lines and overexpression of PEDF restored epithelial phenotype in higher metastatic NPC cell lines with typical EMT. The inhibition of PEDF mediated NPC cell spontaneous metastasis in vivo. LRP6/GSK3β/β-catenin signal pathway rather than AKT/GSK3β pathway was involved in the effects of PEDF on EMT. The expression of PEDF was directly downregulated by elevated miR-320c in NPC. In conclusion, our findings indicate for the first time that PEDF functions as tumor-suppressor gene in the occurrence of EMT and metastasis in NPC. PEDF could serve as a promising candidate for NPC diagnosis, prognosis and treatment.

Background Prostate adenocarcinoma (PCa) is a complex genetic disease, and the implementation of personalized treatment in PCa faces challenges due to significant inter- and intrapatient tumor heterogeneities. Objective To systematically explore the genomic complexity of tumor cells with different Gleason scores (GSs) in PCa. Design, setting, and participants We performed single-cell whole genome sequencing of 17 tumor cells from localized lesions with distinct GS and matched four normal samples from two prostatectomy patients. Outcome measurements and statistical analysis All classes of genomic alterations were identified, including substitutions, insertions/deletions, copy number alterations, and rearrangements. Results and limitations Significant spatial, intra- and intertumoral heterogeneities were observed at the cellular level. In the patient 1, all cells shared the same TP53 driver mutation, implying a monoclonal origin of PCa. In the patient 2, only a subpopulation of cells contained the TP53 driver mutation, whereas other cells carried different driver mutations, indicating a typical polyclonal model with separate clonal cell expansions. The tumor cells from different sides of prostate owned various mutation patterns. Considerable neoantigens were predicted among different cells, implying unknown immune editing components helping prostate tumor cells escaping from immune surveillance. Conclusions There is a significant spatial genomic heterogeneity even in the same PCa patient. Our study also provides the first genome-wide evidence at single-cell level, supporting that the origin of PCa could be either polyclonal or monoclonal, which has implications for treatment decisions for prostate cancer. Patient summary We reported the first single-cell whole genomic data of prostate adenocarcinoma (PCa) from different Gleason scores. Identification of these genetic alterations may help understand PCa tumor progression and clonal evolution.

Objective: To detect the expression of survivin in subtypes of lymphoma and its value in classifying subtypes of lymphoma. Methods: Paraffin-embedded samples collected from 219 cases of lymphoma and 13 cases of lymph node reactive proliferation from affiliated hospitals of Sun Yat-sen University during 2001-2003 were examined for the expression of survivin by using immunohistochemical staining. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the mRNA expression of survivin in K562, HL60, Raji, and Jurkat cell lines. Semi-quantitative assay was used to evaluate the quantity of survivin protein and mRNA expression in subtypes of lymphoma. Results: Protein expression of survivin was high and strong in diffuse large B-cell lymphoma (DLBL) (88.6%, 70/79), Burkitt lymphoma (BL) (100%, 2/2), and lymphoblastic lymphoma (LBL) (92.3%, 12/13), while their expression was always lower and weaker in follicular lymphoma (FL) (18.2%), extranodal marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue (MALT lymphoma) (40.9%) and marginal zone lymphoma (MZL) (33.3%). There was a significant difference between the higher expression group (DLBL, BL and LBL) and lower one (FL, MZL, and MALT) in the expression of survivin (Chi-square test, χ2=24.77, P

Various molecular analytical techniques have providedmore and more information which is necessary for theaccurate classification of diseases. Such informationhas enabled researchers to shift from morphology-based classification to molecular characteristics-basedclassification, also known as molecular classification.Molecular classifications of diseases can be carried outat the DNA, RNA, and protein levels. At the DNA level,for example,molecular classification canbe done basedon genetic mutation, polymorphisms, cytogeneticchanges in genomes or DNA methylation differences.Classification based on different mRNA expressionprofiles is currently a key research approach. Since itsintroduction in the 1990s, biochip technology, as a high-throughput large-scale analytic technology, has beenincreasingly applied in research on functional genomics,disease genomics, and pharmacogenomics. Rapidadvances in molecular classification have shed lighton the establishment of guidelines for the molecularclassification of tumors and personalized diagnosis andtreatment.Tumors are a heterogeneous group of systemicdiseases that develop in multiple steps/phases.Although loss of genomic stability and evading immunedestruction are two milestone events that may beobserved throughout the occurrence and developmentof tumors, the pathogenesis of tumors differs widelyamong different cancers and individuals. Dramaticadvances in basic research over the last 30 yearshave enabled practitioners to understand the pathogen-esis of malignancies at the molecular level and providedsolid bases for the prevention and treatment of tumors.The prognoses of most malignancies, advancedmalignant tumors in particular, have unfortunately notbeen fundamentally improved.Histopathology has long been the “gold standard” oftumor diagnosis and the basis for clinical treatment;however, for tumors of the same phases and stages,treatment responses and prognoses may differ vastlyamong patients even after application of the sametherapeutic strategy. In fact, malignant tumors are highlyheterogeneous at the molecular level. Tumors with thesame morphology may contain varied changes inmolecular genetics, resulting in diversity in treatmentresponses and prognoses. Individualized treatmentbased on molecular differences is thus a new directionfor tumor treatment, and molecular classification is thebasis of individualized therapy.One of the challenges in the new century is todetermine specific targeted therapies aimed at tumortypes with the same pathological origin so as tomaximize the efficacy and minimize the toxicity oftherapy. Accurate classification of tumors will obviouslybe vital toward achieving this endeavor.In our laboratory, we employed high-throughputmolecular techniques, such as gene chip and tissuemicroarray to detect 18 molecular markers by immuno-histochemistry and determined that the combinedexpression levels of seven proteins, including latencymembrane protein 1 (LMP1), CD147, caveolin-1,phospho-P70S6 kinase, survivin, matrix metalloprotei-nase 11 (MMP11), and secreted protein acidic and richin cysteine (SPARC), in tumors, together with patientsex, can distinguish patients with nasopharyngealcarcinoma (NPC) into low- and high-risk groups forprediction of NPC survival [1]. For these two groups ofpatients, the division indicates the clinical application ofindividualizedtherapy soasto preventover-treatment ofthe low-risk group and ensure appropriate treatment ofthe high-risk group. We also detected cancer stem cellsin NPC and proposed that genomic instability and DNAdamage are among the main causes of cancer stem cellformation [2,3]. In fact, the expressions of manyimportant genes, including p63, RASSF1A, VEGF,CCND1, and Hsp70, significantly differ in NPC tissue

Distant metastasis is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure while epithelial–mesenchymal transition (EMT) is the critical process of NPC invasion and metastasis. However, tumor-suppressor genes involved in the EMT and metastasis of NPC have not been explored clearly compared with the oncogenes. In the present study, the expression of pigment epithelium-derived factor (PEDF), a potent endogenous antitumor factor, was diminished in human NPC tissues and associated with clinicopathological and EMT features. The knockdown of PEDF induced EMT in lower metastatic NPC cell lines and overexpression of PEDF restored epithelial phenotype in higher metastatic NPC cell lines with typical EMT. The inhibition of PEDF mediated NPC cell spontaneous metastasis in vivo. LRP6/GSK3β/β-catenin signal pathway rather than AKT/GSK3β pathway was involved in the effects of PEDF on EMT. The expression of PEDF was directly downregulated by elevated miR-320c in NPC. In conclusion, our findings indicate for the first time that PEDF functions as tumor-suppressor gene in the occurrence of EMT and metastasis in NPC. PEDF could serve as a promising candidate for NPC diagnosis, prognosis and treatment.

Objective: The nm23 gene is one of the tumor metastatic suppressor genes. The expression of nm23-H1 has been reported to be inversely associated with metastatic potentiality in a number of human carcinomas, including breast, colorectal, gastric, hepatocellular and gallbladder carcinomas. In this study, the immunohistochemical staining of nm23-H1 protein in human nasopharyngeal carcinoma (NPC) was examined, and the relationship between nm23-H1 and both metastasis and prognosis of patients with NPC was also investigated. Methods: Routine LSAB immunohistochemistry with the nm23-H1 monoclonal murine antibody was employed to study the expression of nm23-H1 protein in 95 paraffinembedded specimens of NPC treated at our hospital. The clinical pathologic data and results of follow-up were also retrieved. Comparisons between patients with and without expression of nm23-H1 protein with respect to metastasis, Ioco-regional recurrence and survival were performed using Log rank test. Multivariate prognostic analyses were performed by using Cox's regression model. Results: Nm23-H1 negative expressive tumors were associated with a higher incidence of lymph-node metastasis (86.7%) than those of nm23-H1 positive (48.6%, P

The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement is almost in mutual exclusion to epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, with rare exceptions. This study aimed to search for the coexisting gene alterations in Chinese patients with lung adenocarcinoma (LAC).We detected mutations in the EGFR, KRAS, and ALK gene rearrangements in samples from 131 Chinese patients with LAC. ALK rearrangements were identified by fluorescent in situ hybridization. Mutations in EGFR (exons 19 to 21) and KRAS (codons 12 and 13) were determined by real time polymerase chain reaction.All patients were classified into four distinct genotype groups: EGFR mutations (n = 63; 48.1%), ALK rearrangements (n = 9; 6.9%), KRAS mutations (n = 8; 6.1%), and the wild-type (unmutated) genotype of all three genes (WT/WT/WT) (n = 53; 40.5%). Interestingly, two never-smoking women (2/131, 1.5%) harbored coexisting ALK rearrangement and EGFR mutation. ALK rearrangement occurred more frequently in young patients (8/9) (P = 0.687), non-smokers (8/9) (P = 0.077), and those who had no family history of LAC (8/9) (P = 1.000); all KRAS mutations occurred in the EGFR wild type (P = 0.007). KRAS mutations were generally detected in young patients (6/8) (P = 0.658) and in those who had no family history (7/8) (P = 1.000); EGFR mutations correlated with gender (P = 0.001), and smoking status (P0.001).Two patients harboring both EGFR mutation and EML4-ALK rearrangement were detected in this study. Our data was apparently inconsistent with the traditional view that the EML4-ALK fusion gene in patients is resistant to EGFR-TKIs.

To evaluate the diagnostic value of serum miR-103 for breast cancer and its correlation to the clinicopathological features of the patients.We collected the serum samples and corresponding formalin-fixed paraffin-embedded (FFPE) surgical specimens from 50 breast cancer patients, using the serum samples from 50 healthy women as the control. The total RNA was extracted from the samples for quantitative analysis of miR-103 using real-time RT-PCR.The serum levels of miR-103 expression were significantly higher in the cancer patients than in the healthy control group (P0.01). In the cancer patients, high miR-103 expression was significantly correlated to advanced clinical stage (P0.05) and lymph node metastasis (P0.05). miR-103 showed a receiver operating characteristic (ROC) curve area of 84.3%, and a sensitivity of 84% and a specificity of 70% in discriminating breast cancer patients from the control subjects.Serum miR-103 can serve as a potential diagnostic marker for breast cancer and provides useful information of the clinicopathological features of the patients.

To investigate the loss of heterozygosity (LOH) on chromosomal arms 13q and 14q in nasopharyngeal carcinoma (NPC) using 21 microsatellite polymorphic markers and to study whether there is a correlation between LOH and clinicopathologic parameters and/or Epstein-Barr virus (EBV) infection in NPC.Sixty cases of NPC were studied using polymerase chain reaction based microsatellite analysis with genescan and genotyping techniques.LOH was detected on 13q in 78% of NPC tumors, high frequency LOH loci (more than 30%) clustered to 13q12.3-q14.3 and 13q32. On chromosome 14q, LOH was detected in 80% of NPC tumors; high frequency LOH loci clustered to 14q11-q13, 14q21-q24 and 14q32. High frequency LOH at 13q31-q32 correlated with a lower level of EBV infection; LOH on chromosome 14q was closely associated with poor differentiation of NPC tumor cells.Our results suggest that in NPC, LOH on chromosome 13q and 14q are common genetic events, and putative tumor suppressor genes (TSG) residing in these regions may be involved in tumorigenesis.