Showing papers by "Chien-Feng Li published in 2014"
TL;DR: In summary, ASS1 protein deficiency was seen in approximately a half of NPCs and associated with advanced T classification, DNA methylation, and clinical aggressiveness, consistent with its tumor suppressor role.
Abstract: The risk stratification and final outcomes in patients with nasopharyngeal carcinomas (NPC) still remain suboptimal. Our principal goals were to identify and validate targetable metabolic drivers relevant to pathogenesis of NPC using a published transcriptome. One prominently downregulated gene regulating amino acid metabolism was found to be arginino- succinate synthetase (ASS1). Attributable to epigenetic DNA methylation, ASS1 deficiency may link to the therapeutic sen- sitivity to the arginine-depriving agents and promote tumor aggressiveness through its newly identified tumor suppressor function. ASS1 immunohistochemistry was therefore exam- ined in a well-defined cohort of 124 NPC biopsy specimens and in the neck lymph node metastases of another ten inde- pendent cases. For the latter, bisulphite pyrosequencing was performed to evaluate the extent of ASS1 gene methylation. ASS1 protein deficiency was identified in 64 of 124 cases (51.6 %), significantly related to T3-T4 status (p=0.006), and univariately associated with inferior local recurrence-free sur- vival (p=0.0427), distant metastasis-free survival (DMFS; p=0.0036), and disease-specific survival (DSS; p=0.0069). Together with advanced AJCC stages III-IV, ASS1 protein deficiency was also independently predictive of worse out- comesfor the DFMS(p=0.010,hazardratio=2.241)andDSS (p=0.020, hazard ratio=1.900).ASS1 promoter hypermethy- lation was detected in eight of ten neck nodal metastatic lesions by bisulphite pyrosequencing and associated with ASS1 protein deficiency (p<0.001). In summary, ASS1 pro- tein deficiency was seen in approximately a half of NPCs and associated with advanced T classification, DNA methylation, and clinical aggressiveness, consistent with its tumor suppres- sor role. This aberration may render pegylated arginine deiminase as a promising strategy for ASS1-deficient NPCs.
56 citations
TL;DR: Molecular testing is diagnostic of variant AFHs displaying diverse histomorphological alterations in the architectural patterns, cytomorphology and extracellular matrix.
Abstract: Aims Angiomatoid fibrous histiocytoma (AFH) is histologically typified by nodules of histiocytoid spindle cells with pseudoangiomatoid spaces, fibrous pseudocapsules and lymphocytic cuffs. The principal goal was to expand the spectrum of AFHs through clinicopathological and molecular characterisation. Methods Thirteen AFHs, including 11 with confirmed hallmark translocation, were reappraised for classic features, reactive osteoclasts, mitoses and stromal, architectural and cytomorphological variations, with CD99, desmin and EMA stained in available cases. Results Seven male and six female patients ranged in age from 4 to 63 years (median, 13), including 4 older than 20 years. Tumours were located on the extremities (n=6), trunk (n=4) and scalp (n=3). Although fibrous pseudocapsules were observed in all cases, four showed solid histology without pseudoangiomatoid spaces and another one lacked peripheral lymphoid infiltrates. Nuclear pleomorphism was striking in two cases, moderate in seven and absent in four, with osteoclasts seen in two cases. In three AFHs with sclerotic matrix, one exhibited perivascular hyalinisation and nuclear palisading, reminiscent of a schwannoma. In three varyingly myxoid tumours, one closely resembled a myoepithelioma with prominent reticular arrangement of spindle cells in an abundant myxoid stroma. Besides EWSR1 gene rearrangement detected in four cases by fluorescence in situ hybridisation (FISH), EWSR1-CREB1 fusion was confirmed in nine cases, including a schwannoma-like AFH, and EWSR1-ATF1 fusion detected in a myoepithelioma-like AFH. Immunohistochemically, 56% of AFHs were positive for EMA, 78% for desmin and 100% for CD99. Conclusions Molecular testing is diagnostic of variant AFHs displaying diverse histomorphological alterations in the architectural patterns, cytomorphology and extracellular matrix.
52 citations
TL;DR: Fructose is upregulated in a subset of NPCs, and its increased immunoexpression significantly correlated with advanced features, justifying the potentiality of fibronectin as a theragnostic biomaker of NPC.
Abstract: Despite recent improvements in the diagnosis and treatment, the final outcomes in patients with nasopharyngeal carcinomas (NPC) still remain suboptimal. Through data mining from published transcriptomic database with further bioinformatic validation, fibronectin (FN1) was identified as a differentially upregulated gene in NPC tissues, which implicates the transition from epithelial to mesenchymal phenotype (EMT) and promotes metastasis. Given the roles of fibronectin in risk stratification and in the frontline therapeutics of common carcinomas, such as renal cell cancer, we explored fibronectin immunoexpression status and its associations with clinicopathological variables and survival in a well-defined cohort of NPC patients. Fibronectin immunohistochemistry was retrospectively performed and analyzed using H-score for 124 biopsy specimens from NPC patients who received standard treatment without distant metastasis at initial diagnosis. Those cases with H-score higher than the median value were regarded as fibronectin overexpression. The findings were correlated with clinicopathological variables, EBV latent membrane protein 1 (LMP1) expression, disease-specific survival (DSS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Fibronectin overexpression was significantly associated with American Joint Committee on Cancer (AJCC) stages III-IV (p = 0.019) and LMP1 expression (p = 0.004), and univariately predictive of adverse outcomes for DSS, DMFS, and LRFS (all p < 0.0001). In the multivariate comparison, fibronectin overexpression still remained prognostically independent to portend worse DSS (p < 0.01, hazard ratio = 5.958), DMFS (p < 0.01, hazard ratio = 5.728), and LRFS (p < 0.01, hazard ratio = 5.411) together with a vanced AJCC stages III-IV. Fibronectin is upregulated in a subset of NPCs, and its increased immunoexpression significantly correlated with advanced features, justifying the potentiality of fibronectin as a theragnostic biomaker of NPC.
43 citations
TL;DR: High STMN1 protein level is commonly associated with adverse prognosticators and confers tumor aggressiveness in patients with NPC, and its upregulation might be attributed to E2F1 and/or TFDP1 transactivation.
Abstract: Data mining on public domain identified that stathmin 1 (STMN1) transcript was significantly higher expressed in nasopharyngeal carcinoma (NPC). Also known as the oncoprotein 18, STMN1 performs an important function in regulating rapid microtubule remodeling of the cytoskeleton in response to the cellular conditions. Immunoexpression of STMN1 was retrospectively assessed in biopsies of 124 consecutive NPC patients without initial distant metastasis and treated with consistent guidelines. The outcome was correlated with clinicopathological features and patient survivals. Results indicated that high STMN1 expressions (50 %) were correlated with advanced age (p = 0.027), higher T stage (p = 0.003), and overall clinical stage (p = 0.006) by the 7th American Joint Committee of Cancer Staging. In multivariate analyses, high STMN1 expression emerged as an independent prognosticator for worse disease-specific survival (p = 0.001), distal metastasis-free survival (p = 0.003), and local recurrence-free survival (p = 0.006). Exogenous expression of E2F transcription factor 1 (E2F1) or/and its dimeric partner, transcription factor Dp-1 (TFDP1), notably induced the STMN1 protein level in a NPC-derived cell line, TW01. Accordingly, high STMN1 protein level is commonly associated with adverse prognosticators and confers tumor aggressiveness in patients with NPC, and its upregulation might be attributed to E2F1 and/or TFDP1 transactivation.
41 citations
TL;DR: Overexpressed AMACR in myxofibrosarcomas can be amplification-driven, associated with tumor aggressiveness, and may be relevant as a druggable target.
Abstract: Purpose: Myxofibrosarcomas frequently display arm-level gains on 5p. We characterized the pathogenetic and therapeutic relevance of the α-methylacyl coenzyme A racemase ( AMACR ) at 5p13.3. Experimental Design: AMACR mRNA expression in myxofibrosarcomas was analyzed using the public transcriptome and laser-microdissected sarcoma cells. We performed florescence in situ hybridization (FISH) and immunohistochemistry in independent samples for clinical correlates. In AMACR-overexpressing myxofibrosarcoma cells and xenografts, we elucidated the biologic function of AMACR using RNA interference and explored the therapeutic effect and mechanism of an AMACR inhibitor, ebselen oxide. Results: AMACR protein overexpression and gene amplification were significantly associated with each other ( P P ≤ 0.002), and univariately with worse metastasis-free survival (MFS; both P P = 0.0002 for overexpression; P = 0.0062 for amplification). AMACR protein overexpression also independently portended adverse outcome (DSS, P = 0.007; MFS, P = 0.001). However, 39% of AMACR-overexpression cases did not show gene amplification, implying alternative regulatory mechanisms. In myxofibrosarcoma cell lines, stable AMACR knockdown suppressed cell proliferation, anchorage-independent growth, and expression of cyclin D1 and cyclin T2. These growth-promoting attributes of AMACR were corroborated in the AMACR-silenced xenograft model and AMACR-underexpressed myxofibrosarcomas, showing decreased labeling for cyclin D1, cyclin T2, and Ki-67. Compared with fibroblasts, AMACR-expressing myxofibrosarcoma cells were more susceptible to ebselen oxide, which not only decreased viable cells, promoted proteasome-mediated degradation of AMACR protein, and induced cellular apoptosis in vitro , but also dose-dependently suppressed xenografted tumor growth in vivo . Conclusions: Overexpressed AMACR in myxofibrosarcomas can be amplification-driven, associated with tumor aggressiveness, and may be relevant as a druggable target. Clin Cancer Res; 20(23); 6141–52. ©2014 AACR .
29 citations
TL;DR: Overexpression of CPS1 is associated with poor therapeutic response and adverse outcomes among rectal cancer patients receiving CCRT, justifying the potential theranostic value of CPS 1 for such patients.
Abstract: Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but stratification of risk and final outcomes remain suboptimal. In view of the fact that glutamine metabolism is usually altered in cancer, we profiled and validated the significance of genes involved in this pathway in rectal cancers treated with CCRT. From a published transcriptome of rectal cancers (GSE35452), we focused on glutamine metabolic process-related genes (GO:0006541) and found upregulation of carbamoyl phosphate synthetase 1 (CPS1) gene most significantly predicted poor response to CCRT. We evaluated the expression levels of CPS1 using immunohistochemistry to analyze tumor specimens obtained during colonoscopy from 172 rectal cancer patients. Expression levels of CPS1 were further correlated with major clinicopathological features and survivals in this validation cohort. To further confirm CPS1 expression levels, Western blotting was performed for human colon epithelial primary cell (HCoEpiC) and four human colon cancer cells, including HT29, SW480, LoVo, and SW620. CPS1 overexpression was significantly related to advanced posttreatment tumor (T3, T4; P = 0.006) and nodal status (N1, N2; P < 0.001), and inferior tumor regression grade (P = 0.004). In survival analyses, CPS1 overexpression was significantly associated with shorter disease-specific survival (DSS) and metastasis-free survival (MeFS). Furthermore, using multivariate analysis, it was also independently predictive of worse DSS (P = 0.021, hazard ratio = 2.762) and MeFS (P = 0.004, hazard ratio = 3.897). CPS1 protein expression, as detected by Western blotting, is more abundant in colon cancer cells than nonneoplastic HCoEpiC. Overexpression of CPS1 is associated with poor therapeutic response and adverse outcomes among rectal cancer patients receiving CCRT, justifying the potential theranostic value of CPS1 for such patients.
27 citations
TL;DR: It is found that androgen can activate CEBPD transcription by direct binding of the androgen receptor (AR) to theCEBPD promoter region and caspase 8 (CASP8), an apoptotic initiator, is responsive to CEB PD induction.
Abstract: The survival of prostate cancer (PrCa) patients is associated with the transition to hormone-independent tumor growth and metastasis. Clinically, the dysregulation of androgen action has been associated with the formation of PrCa and the outcome of androgen deprivation therapy in PrCa. CCAAT/enhancer binding protein delta (CEBPD) is a transcription factor that has been reported to act as an oncogene or tumor suppressor, depending on the extra- and intracellular environments following tumorigenesis. We found that androgen can activate CEBPD transcription by direct binding of the androgen receptor (AR) to the CEBPD promoter region. Increases of suppressor of zeste 12 (SUZ12) and enhancer of zeste homolog 2 (EZH2) attenuated the androgen-induced transcription of CEBPD. Importantly, the increases in E2F1, SUZ12 and EZH2 as well as the inactivation of CEBPD were associated with the clinicopathological variables and survival of PrCa patients. We revealed that caspase 8 (CASP8), an apoptotic initiator, is responsive to CEBPD induction. Reporter and in vivo DNA-binding assays revealed that CEBPD directly binds to and activates CASP8 reporter activity. A prodrug system was developed for therapeutic application in AR-independent or androgen-insensitive PrCa to avoid the epigenetic effects on the suppression of CEBPD expression. Our results showed that the combination of a perforin (PF)-CEBPD prodrug (which increases the level of procaspase-8) and a PF-granzyme B prodrug (which activates CASP8 and caspase 3 (CASP3)) showed an additive effect in triggering the apoptotic pathway and enhancing apoptosis in PrCa cells.
24 citations
TL;DR: High expression of FGFR2 is correlated with advanced tumour stage, poor therapeutic response and worse survival in rectal cancer patients receiving neoadjuvant CCRT, indicating that FGFR 2 is a prognostic factor for treating rectal cancers.
Abstract: Aims Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is an increasingly used therapeutic strategy for advanced rectal cancer, but risk stratification and final outcomes remain suboptimal. Recently, the oncogenic role of the fibroblast growth factor/fibroblast growth factor receptor (FGFR) signalling pathway has been recognised; however, its clinical significance in rectal cancer has not been elucidated. In this study, we identify and validate targetable drivers associated with the FGFR signalling pathway in rectal cancer patients treated with CCRT. Methods Using a published transcriptome of rectal cancers, we found FGFR2 gene significantly predicted response to CCRT. The expression levels of FGFR2, using immunohistochemistry assays, were further evaluated in 172 rectal cancer specimens that had not received any treatment. Expression levels of FGFR2 were statistically correlated with major clinicopathological features and clinical survival in this valid cohort. Results High expression of FGFR2 was significantly related to advanced pretreatment tumour (p=0.022) and nodal status (p=0.026), post-treatment tumour (p<0.001) and nodal status (p=0.004), and inferior tumour regression grade (p<0.001). In survival analyses, high expression of FGFR2 was significantly associated with shorter local recurrence-free survival (p=0.0001), metastasis-free survival (MeFS; p=0.0003) and diseasespecific survival (DSS; p<0.0001). Notably, high expression of FGFR2 was independently predictive of worse outcomes for MeFS (p=0.002, HR=5.387) and DSS (p=0.004, HR=4.997). Conclusions High expression of FGFR2 is correlated with advanced tumour stage, poor therapeutic response and worse survival in rectal cancer patients receiving neoadjuvant CCRT. These findings indicate that FGFR2 is a prognostic factor for treating rectal cancer.
23 citations
TL;DR: Hemizygous deletion primarily accounts for the adverse prognostic impact of MTAP deficiency and confers the biological aggressiveness and susceptibility to L-alanosine in myxofibrosarcomas.
Abstract: Myxofibrosarcomas are genetically complex and involve recurrently deleted chromosome 9p, for which we characterized the pathogenically relevant target(s) using genomic profiling. In 12 of the 15 samples, we detected complete or partial losses of 9p. The only aggressiveness-associated, differentially lost region was 9p21.3, spanning the potential inactivated methylthioadenosine phosphorylase (MTAP) that exhibited homozygous (4/15) or hemizygous (3/15) deletions. In independent samples, MTAP gene status was assessed using quantitative- and methylation-specific PCR assays, and immunoexpression was evaluated. We applied MTAP reexpression or knockdown to elucidate the functional roles of MTAP and the therapeutic potential of L-alanosine in MTAP-preserved and MTAP-deficient myxofibrosarcoma cell lines and xenografts. MTAP protein deficiency (37%) was associated with MTAP gene inactivation (P < 0.001) by homozygous deletion or promoter methylation, and independently portended unfavorable metastasis-free survival (P = 0.0318) and disease-specific survival (P = 0.014). Among the MTAP-deficient cases, the homozygous deletion of MTAP predicted adverse outcome. In MTAP-deficient cells, MTAP reexpression inhibited cell migration and invasion, proliferation, and anchorage-independent colony formation and downregulated cyclin D1. This approach also attenuated the tube-forming abilities of human umbilical venous endothelial cells, attributable to the transcriptional repression of MMP-9, and abrogated the susceptibility to L-alanosine. The inhibiting effects of MTAP expression on tumor growth, angiogenesis, and the induction of apoptosis by L-alanosine were validated using MTAP-reexpressing xenografts and reverted using RNA interference in MTAP-preserved cells. In conclusion, homozygous deletion primarily accounts for the adverse prognostic impact of MTAP deficiency and confers the biological aggressiveness and susceptibility to L-alanosine in myxofibrosarcomas.
22 citations
TL;DR: AMACR amplification is a mechanism driving increased mRNA and protein expression and conferring aggressiveness through heightened cell proliferation in gastrointestinal stromal tumors and independently predictive of decreased disease-free survival.
Abstract: // Chien-Feng Li 1,2,3,4 , Li-Tzong Chen 2,3,5,6 , Jui Lan 7 , Fong-Fu Chou 8 , Ching-Yih Lin 9,10 , Yen-Yang Chen 11 , Tzu-Ju Chen 1 , Shau-Hsuan Li 11 , Shih-Chen Yu 7 , Fu-Ming Fang 12 , Hui-Chun Tai 13 and Hsuan-Ying Huang 7 1 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 2 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan 3 Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan 5 Department of Internal Medicine and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 6 Institutes of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan 7 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 8 Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 9 Department of Tourism Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan 10 Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan 11 Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 12 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 13 Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan Correspondence: Hsuan-Ying Huang, email: // Keywords : GIST, 5p, AMACR, amplification, proliferation Received : August 13, 2014 Accepted : October 18, 2014 Published : October 18, 2014 Abstract Non-random gains of chromosome 5p have been observed in clinically aggressive gastrointestinal stromal tumors, whereas the driving oncogenes on 5p remain to be characterized. We used an integrative genomic and functional approach to identify amplified oncogenes on 5p and to evaluate the relevance of AMACR amplification at 5p13.3 and its overexpression in gastrointestinal stromal tumors. Thirty-seven tumor samples, imatinib-sensitive GIST882 cell line, and imatinib-resistant GIST48 cell line were analyzed for DNA imbalances using array-based genomic profiling. Forty-one fresh tumor samples of various risk categories were enriched for pure tumor cells by laser capture microdissection and quantified for AMACR mRNA expression. AMACR- specific fluorescence in situ hybridization and immunohistochemistry were both informative in tissue microarray sections of 350 independent primary gastrointestinal stromal tumors, including 213 cases with confirmed KIT / PDGFRA genotypes. To assess the oncogenic functions of AMACR, GIST882 and GIST48 cell lines were stably silenced against their endogenous AMACR expression. In 59% of cases featuring 5p gains, two major amplicons encompassed discontinuous chromosomal regions that were differentially overrepresented in high-risk cases, including the one harboring the mRNA-upregulated AMACR gene. Gene amplification was detected in 19.7% of cases (69/350) and strongly related to protein overexpression (p<0.001), although 52% of AMACR-overexpressing cases exhibited no amplification. Both gene amplification and protein overexpression were significantly associated with epithelioid histology, larger size, increased mitoses, higher risk levels, and unfavorable genotypes (all p ≦0.03). They were also independently predictive of decreased disease-free survival (overexpression, p <0.001; amplification, p =0.020) in the multivariate analysis. Concomitant with downregulated cyclin D1, cyclin E, and CDK4, AMACR knockdown suppressed cell proliferation and induced G 1 -phase arrest, but did not affect apoptosis in both GIST882 and GIST48 cells. In conclusion, AMACR amplification is a mechanism driving increased mRNA and protein expression and conferring aggressiveness through heightened cell proliferation in gastrointestinal stromal tumors.
22 citations
TL;DR: The results suggest the addition of a MTOR inhibitor may reduce NVP-AUY922 dose requirement and potentially improve its therapeutic index in mutant KIT-expressing GISTs.
Abstract: Our previous study demonstrated NVP-AUY922, a HSP90AA1 inhibitor, could enhance mutant KIT degradation in gastrointestinal stromal tumor (GIST) cells through both proteasome- and autophagy-mediated pathways. Herein, we showed rapamycin, a MTOR inhibitor and autophagy inducer, could reduce total and phospho-KIT expression levels and enhance apoptosis in imatinib-resistant GIST cells. The involvement of autophagy in rapamycin-induced KIT downregulation was further confirmed by co-localization of KIT and autophagosome, and partial recovery of KIT expression level by either siRNA-mediated BECN1 and ATG5 silencing or autophagy inhibitors after rapamycin. Rapamycin and NVP-AUY922 synergistically inhibited GIST cells growth in vitro. The combination of low-dose NVP-AUY922 with rapamycin had comparable effects on reducing KIT expression, increasing MAP1LC3B puncta and tumor necrosis, and inhibiting tumor growth as high-dose NVP-AUY922 did in GIST430 xenograft model. Our results suggest the addition of a MTOR inhibitor may reduce NVP-AUY922 dose requirement and potentially improve its therapeutic index in mutant KIT-expressing GISTs.
TL;DR: It is concluded that high expression of ANXA1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CCRT.
Abstract: Neoadjuvant concurrent chemoradiation therapy (CCRT) is an increasingly common therapeutic strategy for rectal cancer. Clinically, it remains a major challenge to predict therapeutic response and patient outcomes after CCRT. Annexin I (ANXA1), encoded by ANXA1, is a Ca2+/phospholipid-binding protein that mediates actin dynamics and cellular proliferation, as well as suggesting tumor aggressiveness and predicting therapeutic response in certain malignancies. However, expression of ANXA1 has never been reported in rectal cancer receiving CCRT. This study examined the predictive and prognostic impact of ANXA1 expression in patients with rectal cancer following neoadjuvant CCRT. We identified ANXA1 as associated with resistance to CCRT through data mining from a published transcriptomic dataset. Its immunoexpression was retrospectively assessed using H scores on pre-treatment biopsies from 172 rectal cancer patients treated with neoadjuvant CCRT followed by curative surgery. Results were correlated with clinicopathological features, therapeutic response, tumor regression grade (TRG), and metastasis-free survival (MeFS), as well as local recurrent-free survival (LRFS) and disease-specific survival (DSS). High expression of ANXA1 was associated with advanced pre-treatment tumor status (T3, T4, p = 0.022), advanced pre-treatment nodal status (N1, N2, p = 0.004), advanced post-treatment tumor status (T3, T4, p < 0.001), advanced post-treatment nodal status (N1, N2, p = 0.001) and inferior TRG (p = 0.009). In addition, high expression of ANXA1 emerged as an adverse prognosticator for DSS (p < 0.0001), LRFS (p = 0.0001) and MeFS (p = 0.0004). Moreover, high expression of ANXA1 also remained independently prognostic of worse DSS (hazard ratio [HR] = 3.998; p = 0.007), LRFS (HR = 3.206; p = 0.028) and MeFS (HR = 3.075; p = 0.017). This study concludes that high expression of ANXA1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CCRT.
TL;DR: It is found that asparagine synthetase (ASNS) gene significantly predicted the response to CCRT, and findings indicate that ASNS is a prognostic factor with therapeutic potential for treating rectal cancer.
Abstract: Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but risk stratification and final outcomes remain suboptimal. In this study, we identify and validate targetable metabolic drivers relevant to the prognosis of patients with rectal cancer treated with CCRT. Using a published transcriptome of rectal cancers, we found that asparagine synthetase (ASNS) gene significantly predicted the response to CCRT. From 172 patients with rectal cancer, the expression levels of ASNS, using immunohistochemistry assays, were further evaluated in tumor specimens initially obtained by using colonoscopy. Expression levels of ASNS were further correlated with major clinicopathological features and clinical survivals in this valid cohort. ASNS deficiency was significantly related to advanced posttreatment tumor (T3, T4; P = .015) and nodal status (N1, N2; P = .004) and inferior tumor regression grade (P < .001). In survival analyses, ASNS deficiency was significantly associated with shorter local recurrence-free survival (LRFS; P = .0039), metastasis-free survival (MeFS; P = .0001), and disease-specific survival (DSS; P = .0006). Furthermore, ASNS deficiency was independently predictive of worse outcomes for MeFS (P = .012, hazard ratio = 3.691) and DSS (P = .022, hazard ratio = 2.845), using multivariate analysis. ASNS deficiency is correlated with poor therapeutic response and worse survivals in patients with rectal cancer receiving neoadjuvant CCRT. These findings indicate that ASNS is a prognostic factor with therapeutic potential for treating rectal cancer.
TL;DR: This study examined the prognostic impact of REG4 expression in patients with rectal cancer receiving neoadjuvant CCRT and identified Regenerating Gene Type IV (REG4) as the most significantly associated gene with resistance to C CRT.
Abstract: Locally advanced rectal cancers are currently treated with neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery, but stratification of risk and final outcomes remain suboptimal In view of the fact that glutamine metabolism is usually altered in cancer, we profiled and validated the significance of genes involved in this pathway in rectal cancers treated with CCRT From a published transcriptome of rectal cancers (GSE35452), we focused on glutamine metabolic process-related genes (GO:0006541) and found upregulation of carbamoyl phosphate synthetase 1 (CPS1) gene most significantly predicted poor response to CCRT We evaluated the expression levels of CPS1 using immunohistochemistry to analyze tumor specimens obtained during colonoscopy from 172 rectal cancer patients Expression levels of CPS1 were further correlated with major clinicopathological features and survivals in this validation cohort To further confirm CPS1 expression levels, Western blotting was performed for human colon epithelial primary cell (HCoEpiC) and four human colon cancer cells, including HT29, SW480, LoVo, and SW620 CPS1 overexpression was significantly related to advanced posttreatment tumor (T3, T4; P = 0006) and nodal status (N1, N2; P < 0001), and inferior tumor regression grade (P = 0004) In survival analyses, CPS1 overexpression was significantly associated with shorter disease-specific survival (DSS) and metastasis-free survival (MeFS) Furthermore, using multivariate analysis, it was also independently predictive of worse DSS (P = 0021, hazard ratio = 2762) and MeFS (P = 0004, hazard ratio = 3897) CPS1 protein expression, as detected by Western blotting, is more abundant in colon cancer cells than nonneoplastic HCoEpiC Overexpression of CPS1 is associated with poor therapeutic response and adverse outcomes among rectal cancer patients receiving CCRT, justifying the potential theranostic value of CPS1 for such patients
TL;DR: CDK4 overexpression is mostly independent with gene amplification and represents a potential prognostic biomarker in NPC and may indicate tumor aggressiveness through cell cycle dysregulation.
Abstract: Data mining in the public domain demonstrates that cyclin-dependent kinase 4 (CDK4) is highly expressed in nasopharyngeal carcinomas (NPC). Associated with cyclin-D, CDK4 phosphorylates and inactivates retinoblastoma (Rb) protein family members and mediates progression through the G1- to the S-phase of the cell cycle. Amplification and overexpression of CDK4 has been identified in various human malignancies. However, its expression and amplification has never been systemically evaluated in NPC. This study aimed to evaluate the amplification and expression status, correlation with clinicopathological features, and prognostic implications of CDK4 based on public domain dataset and in our well-defined cohort of NPC patients. The association between CDK4 transcript level and gene dosage was explored by analysis of an independent public domain dataset. We retrospectively assessed CDK4 immunoexpression in biopsies of 124 consecutive NPC patients devoid of initial distant metastasis and treated according to consistent guidelines. The results were correlated with clinicopathological features, local recurrence-free survival (LRFS), distant metastasis-free survival (DMeFS), and disease-specific survival (DSS). High levels of CDK4 protein were positively correlated with the T 3, 4 status (p = 0.024); N 2, 3 status (p < 0.001); and the American Joint Committee on Cancer stage 3, 4 (p < 0.001). Multivariate analysis suggested high CDK4 expression was an independent prognostic indicator of worse DMeFS (p = 0.001, hazard ratio (HR) = 3.226) and DSS (p = 0.037, HR = 1.838). Although CDK4 is frequently upregulated, its gene locus is very uncommonly amplified in NPC. CDK4 overexpression is mostly independent with gene amplification and represents a potential prognostic biomarker in NPC and may indicate tumor aggressiveness through cell cycle dysregulation.
TL;DR: In GBC, BCL6 overexpression correlated with adverse phenotypes and decreased p19ARF expression and independently predicts worse DSS and DFS, suggesting it has a role in tumorigenesis or carcinogenesis and could be a potential prognostic indicator in GBC.
Abstract: B cell lymphoma 6 (BCL6) is a protein that is vital for lymphogenesis. Its expression has been well established in lymphoma, especially in diffuse large B-cell lymphoma. Its role in carcinogenesis is less well understood. Previous study shows that BCL6 expression may regulate p19 functions, an important regulator for the p53 pathway. No prior study has attempted to evaluate the significance of BCL6 and p19(ARF) expression in a large cohort of patients with gallbladder carcinomas (GBCs). We selected 164 patients with GBC and performed immunostains for BCL6 and p19(ARF). BCL6 expression and p19(ARF) expression were evaluated using a histochemical score (H-score). We then correlated the results with various clinicopathological factors, disease-specific survival (DSS), and disease-free survival (DFS). BCL6 overexpression was significantly associated with high pT status, high TNM stage, higher histological grade (p = 0.029), vascular invasion, perineurial invasion, high Ki-67 labeling index, and low p19 expression. Importantly, BCL6 overexpression in GBC was strongly associated with worse DSS (p < 0.0001) and DFS (p < 0.0001) in the univariate analysis, and remained independently predictive of adverse outcomes (p = 0.001, hazard ratio (H.R.) = 3.098 for DSS; p = 0.002, H.R. = 2.255 for DFS). Low p19(ARF) expression was correlated with a poor DSS (p = 0.0144) and DFS (p = 0.0032) in the univariate analysis but was not prognosticatory in the multivariate analysis. In GBC, BCL6 overexpression correlated with adverse phenotypes and decreased p19(ARF) expression. BCL6 overexpression also independently predicts worse DSS and DFS, suggesting it has a role in tumorigenesis or carcinogenesis and could be a potential prognostic indicator in GBC.
TL;DR: AMACR overexpression was identified as an important prognosticator and a potential therapeutic target in the future and correlated with the clinicopathological variables, disease-specific survival (DSS), distant metastasis-free survival (DMFS), and local recurrence- free survival (LRFS).
Abstract: The molecular prognostic adjunct in patients with nasopharyngeal carcinomas (NPCs) still remains obscured. Through data mining from published transcriptomic database, alpha-methylacyl-CoA racemase (AMACR) was first identified as a differentially upregulated gene in NPC tissues, which is a key enzyme for isometric conversion of fatty acids entering the β-oxidation. Given the roles of AMACR in prognostication and frontline therapeutic regimen of common carcinomas, such as prostate cancer, we explored AMACR immunoexpression status and its clinical significance in NPC patients. AMACR immunohistochemistry was retrospectively performed and analyzed using H-score for biopsy specimens from 124 NPC patients who received standard treatment without distant metastasis at initial diagnosis. Those cases with H-score larger than the median value were construed as featuring AMACR overexpression. The findings were correlated with the clinicopathological variables, disease-specific survival (DSS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Endogenous AMACR protein expressions were assessed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting in NPC cells and non-neoplastic mucosal cells. AMACR overexpression was significantly associated with increment of primary tumor status (P = 0.009) and univariately predictive of adverse outcomes for DSS, DMFS, and LRFS. In the multivariate comparison, AMACR overexpression still remained prognostically independent to portend worse DSS (P = 0.006, hazard ratio = 2.129), DMFS (P = 0.001, hazard ratio = 2.795), and LRFS (P = 0.041, hazard ratio = 2.009), together with advanced American Joint of Cancer Committee (AJCC) stages III–IV. Compared with non-neoplastic cells, both HONE1 and TW01 NPC cells demonstrated markedly increased AMACR expression. AMACR overexpression was identified as an important prognosticator and a potential therapeutic target in the future.
TL;DR: High expression of CKS1B is common and associated with adverse prognostic factors and might confer tumor aggressiveness through dysregulation of the cyclin‐dependent protein kinase (intrinsic regulatory activity) during cell cycle progression.
Abstract: Data mining on public domain identified that CDC28 protein kinase regulatory subunit 1B (CKS1B) transcript was highly expressed in nasopharyngeal carcinoma (NPC). The expression of CKS1B protein and its clinicopathological associations in patients with NPC were further evaluated. Immunoexpression of CKS1B was retrospectively assessed in biopsies of 124 consecutive NPC patients without initial distant metastasis and treated with consistent guidelines. The correlations between CKS1B immunoexpression levels and clinicopathological features, as well as patient survivals, were analyzed. High CKS1B expression (49.2%) was correlated with the 7th American Joint Committee on Cancer (AJCC) stage (p = 0.014). In multivariate analyses, high CKS1B expression emerged as an independent prognostic factor for worse disease-specific survival (p < 0.001), metastasis-free survival (p < 0.001), and local recurrence-free survival (p = 0.001). High expression of CKS1B is common and associated with adverse prognostic factors and might confer tumor aggressiveness through dysregulation of the cyclin-dependent protein kinase (intrinsic regulatory activity) during cell cycle progression.
TL;DR: Patients with NPC who overexpressed galectin-1 in cytoplasm showed more aggressive tumor growth and significantly shorter disease-specific survival (DSS) and distant metastasis-free survival (DMFS) than patients with NPCs who did not overexpress galectIn-1.
Abstract: Conclusions: Galectin-1 overexpression is significantly correlated with the survival rate of patients with nasopharyngeal carcinoma (NPC). Immunohistochemical analysis of galectin-1 expression might be useful for identifying patients with a high risk of distant metastasis and for prompting timely adjuvant systemic therapy for patients with aggressive NPC. Objectives: We examined the effect of galectin-1 on the survival rate of patients with NPC. Methods: A total of 124 patients diagnosed between 1998 and 2002 with NPC without distant metastasis were enrolled in this single-center historical prospective cohort study. Immunohistochemical analysis was used to correlate the galectin-1 expression score in the cytoplasm and the survival rate of patients with NPC. Results: Patients with NPC who overexpressed galectin-1 in cytoplasm showed more aggressive tumor growth and significantly shorter disease-specific survival (DSS) (p = 0.0037) and distant metastasis-free survival (DMFS) (p = 0.0006) than patie...
TL;DR: Through down-regulation of CDK2, high p12CDK2AP1 level induced cell cycle arrest and the mitochondrial-dependent apoptotic pathway and represents a poor prognostic factor in patients with myxofibrosarcoma.
Abstract: Attenuated endogenous protein levels of cyclin-dependent kinase 2 associated protein 1 (p12CDK2AP1) and its active homodimer p25CDK2AP1 were found in myxofibrosarcoma-derived cell lines. Clinical and biological significances of this putative tumor suppressor in myxofibrosarcoma were studied. Plasmids carrying the CDK2AP1 gene and small hairpin RNA interference (shRNAi) targeting CDK2AP1 were transfected into NMFH-1 and/or OH931 cells to evaluate the effects on the CDK2, active caspase 3 (CASP3), cleaved-CASP8 and -CASP9 levels, cell cycle regulation, and/or apoptotic responses. Immunostaining of p12CDK2AP1 was interpretable in 102 primary myxofibrosarcomas and correlated with clinicopathological variables, CDK2, Ki-67 and active CASP3 protein levels, and disease-specific survival.
Exogenous expression of p12CDK2AP1 in NMFH-1 and OH931 cells significantly induced G0/G1 cell cycle arrest and down-regulated CDK2 protein level. In NMFH-1 cells, these aspects were reversed by shRNAi targeting CDK2AP1 gene. Increased active CASP3 and cleaved-CASP9, but not -CASP8, were detected after CDK2AP1 overexpression, suggesting the cellular apoptosis were induced through the mitochondrial pathway. Immunostains of p12CDK2AP1 were aberrantly decreased in 56.9 % of cases; positively and negatively correlated with protein levels of CDK2 (p = 0.023), Ki-67 (p = 0.001) and active CASP3 (p < 0.001), respectively. Following by high histological grades, p12CDK2AP1 down-regulation was predictive of worse disease-specific survival in univariate (p = 0.003) and multivariate (p = 0.004) analyses. Through down-regulation of CDK2, high p12CDK2AP1 level induced cell cycle arrest and the mitochondrial-dependent apoptotic pathway. Low p12CDK2AP1 level represents a poor prognostic factor in patients with myxofibrosarcoma.
TL;DR: A case of rapid-growing DFSP of the breast with abscess formation mimicking breast cancer is reported, and a review of related literature is made.