Showing papers by "Chien-Feng Li published in 2017"

ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma.

Abstract: ALK oncogenic activation mechanisms were characterized in four conventional spindle-cell inflammatory myofibroblastic tumours (IMT) and five atypical IMT, each of which had ALK genomic perturbations. Constitutively activated ALK oncoproteins were purified by ALK immunoprecipitation and electrophoresis, and were characterized by mass spectrometry. The four conventional IMT had TPM3/4-ALK fusions (two cases) or DCTN1-ALK fusions (two cases), whereas two atypical spindle-cell IMT had TFG-ALK and TPM3-ALK fusion in one case each, and three epithelioid inflammatory myofibroblastic sarcomas had RANBP2-ALK fusions in two cases, and a novel RRBP1-ALK fusion in one case. The epithelioid inflammatory myofibroblastic sarcoma with RRBP1-ALK fusion had cytoplasmic ALK expression with perinuclear accentuation, different from the nuclear membranous ALK localization in epithelioid inflammatory myofibroblastic sarcomas with RANBP2-ALK fusions. Evaluation of three additional uncharacterized epithelioid inflammatory myofibroblastic sarcomas with ALK cytoplasmic/perinuclear- accentuation expression demonstrated RRBP1-ALK fusion in two cases. These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway

Abstract: // Hsin-Hwa Tsai 1, * , Hong-Yue Lai 2, * , Yueh-Chiu Chen 3, * , Chien-Feng Li 4 , Huei-Sheng Huang 5 , Hsiao-Sheng Liu 6 , Yau-Sheng Tsai 7 , Ju-Ming Wang 1, 8 1 Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan 2 Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan 3 Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan 4 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 5 Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan 6 Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan 7 Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan 8 Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan * The authors contributed equally to this work Correspondence to: Ju-Ming Wang, email: yumingw@mail.ncku.edu.tw Keywords: HCC, autophagy, apoptosis, CEBPD, metformin Received: May 30, 2016 Accepted: January 04, 2017 Published: January 13, 2017 ABSTRACT Metformin, as an AMP-activated protein kinase (AMPK) activator, can activate autophagy. A study showed that metformin decreased the risk of hepatocellular carcinoma (HCC) in diabetic patients. However, the detailed mechanism in the metformin-mediated anticancer effect remains an open question. Transcription factor CCAAT/enhancer-binding protein delta (CEBPD) has been suggested to serve as a tumor suppressor and is responsive to multiple anticancer drugs in HCC. In this study, we found that CEBPD and autophagy are involved in metformin-induced cell apoptosis in Huh7 cells. The underlying mechanisms in this process included a reduction in Src-mediated CEBPD protein degradation and an increase in CEBPD-regulated LC3B and ATG3 gene transcription under metformin treatment. We also found that AMPK is involved in metformin-induced CEBPD expression. Combined treatment with metformin and rapamycin can enhance autophagic cell death through the AMPK-dependent and AMPK-independent pathway, respectively. Taken together, we provide a new insight and therapeutic approach by targeting autophagy in the treatment of HCC.

Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist.

Abstract: Castration-resistant prostate cancer (CRPC) remains a major clinical challenge because of the lack of effective targeted therapy for its treatment. The mechanism underlying how CRPC gains resistance toward hormone depletion and other forms of chemotherapy is poorly understood. Research on understanding the factors that drive these processes is desperately needed to generate new therapies to cure the disease. Here, we discovered a fundamental role of S-phase protein kinase 2 (Skp2) in the formation and progression of CRPC. In transgenic adenocarcinoma mouse prostate model, Skp2 depletion leads to a profound repression of prostate tumor growth and distal metastasis and substantially prolonged overall survival. We revealed that Skp2 regulates CRPC through Twist-mediated oncogenic functions including epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) acquisitions. Mechanistically, Skp2 interacted with Twist and promoted the non-degradative ubiquitination of Twist. Consequently, Skp2 stabilized Twist protein expression by preventing proteasomal degradation of Twist by β-TrCP. We found that Twist overexpression augments CSC self-renewal and population and that Skp2 inhibition reverts Twist's effects on CSC regulation. Furthermore, genetically depleting or pharmacologically inactivating Skp2 synergistically re-sensitized CRPC cells toward chemotherapies such as paclitaxel or doxorubicin. Together, this study uncovering Skp2-mediated Twist stabilization and oncogenic functions in CRPC offers new knowledge on how CRPC progresses and acquires chemoresistance during tumor progression. It provides proof of principle that Skp2 targeting is a promising approach to combat metastatic CRPC by targeting Twist and CSCs.

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Abstract: Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy. Experimental Design: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity. Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel. Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201. Clin Cancer Res; 23(2); 503–13. ©2016 AACR.

Overexpressed Fatty Acid Synthase in Gastrointestinal Stromal Tumors: Targeting a Progression-Associated Metabolic Driver Enhances the Antitumor Effect of Imatinib.

Abstract: Purpose: In gastrointestinal stromal tumors (GIST), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN).Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNAi or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivoResults:FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (P < 0.0001). FASN overexpression was associated with a nongastric location (P = 0.05), unfavorable genotype (P = 0.005), and increased risk level (P < 0.001) and independently predicted shorter disease-free survival (P < 0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and resensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RPS6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT phosphorylation, Ki-67, and phosphorylated PI3K/AKT/mTOR levels and increased TUNEL labeling.Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs. Clin Cancer Res; 23(16); 4908-18. ©2017 AACR.

Sulfatase-1 overexpression indicates poor prognosis in urothelial carcinoma of the urinary bladder and upper tract

Abstract: // Hsiang-Ying Lee 1, 3, 4, 8 , Bi-Wen Yeh 3, 4 , Ti-Chun Chan 5, 6 , Kei-Fu Yang 2, 3 , Wei-Ming Li 2, 3, 4, 7 , Chun-Nung Huang 3, 4 , Hung-Lung Ke 3, 4 , Ching-Chia Li 3, 4, 8 , Hsin-Chih Yeh 2, 3, 4, 7 , Peir-In Liang 9 , Yow-Ling Shiue 6 , Wen-Jeng Wu 2, 3, 4, 8, 10, 11, 12 and Chien-Feng Li 5, 9, 11, 13, 14, 15 1 Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 4 Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 6 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 7 Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan 8 Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan 9 Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 10 Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan 11 Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan 12 Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan 13 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan 14 National Cancer Research Institute, National Health Research Institutes, Tainan, Taiwan 15 Department of Internal Medicine and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Correspondence to: Chien-Feng Li, email: angelo.p@yahoo.com.tw Wen-Jeng Wu, email: wejewu@kmu.edu.tw Keywords: urothelial carcinoma, transcriptome, SULF1, prognosis Received: November 25, 2016 Accepted: April 17, 2017 Published: May 03, 2017 ABSTRACT Urothelial carcinoma (UC), arising from the urothelium of the urinary tract, can occur in the upper (UTUC) and the urinary bladder (UBUC). A representative molecular aberration for UC characteristics and prognosis remains unclear. Data mining of Gene Expression Omnibus focusing on UBUC, we identified sulfatase-1 ( SULF1 ) upregulation is associated with UC progression. SULF1 controls the sulfation status of heparan sulfate proteoglycans and plays a role in tumor growth and metastasis, while its role is unexplored in UC. To first elucidate the clinical significance of SULF1 transcript expression, real-time quantitative RT-PCR was performed in a pilot study of 24 UTUC and 24 UBUC fresh samples. We identified that increased SULF1 transcript abundance was associated with higher primary tumor (pT) status. By testing SULF1 immunoexpression in independent UTUC and UBUC cohorts consisted of 340 and 295 cases, respectively, high SULF1 expression was significantly associated with advanced pT and nodal status, higher histological grade and presence of vascular invasion in both UTUC and UBUC. In multivariate survival analyses, high SULF1 expression was independently associated with worse DSS (UTUC hazard ratio [HR] = 3.574, P < 0.001; UBUC HR = 2.523, P = 0.011) and MeFS (UTUC HR = 3.233, P < 0.001; UBUC HR = 1.851, P = 0.021). Furthermore, depletion of SULF1 expression by using RNA interference leaded to impaired cell proliferative, migratory, and invasive abilities in vitro . In addition, we further confirmed oncogenic role of SULF1 with gain-of function experiments. In conclusion, our findings implicate the oncogenic role of SULF1 expression in UC, suggesting SULF1 as a prognostic and therapeutic target of UC.

DPP4/CD26 overexpression in urothelial carcinoma confers an independent prognostic impact and correlates with intrinsic biological aggressiveness.

Abstract: Urothelial carcinoma (UC) is common cancer worldwide. The molecular aberrations regarding tumor progression remain unclear. Pericellular proteolysis is crucial in tumorigenesis, but its significance is unexplored in UC. By data mining the datasets in Gene Expression Omnibus, specifically focus on the proteolysis pathway, and followed by a preliminary validation in a pilot batch of tumor samples, we identified that the upregulation of dipeptidyl peptidase 4 (DPP4) was most significantly associated with clinical aggressiveness of UCs. Quantitative RT-PCR confirmed upregulation of DPP4 mRNA in advanced stage UCs. The clinical significance of DPP4 expression was validated in our large cohort consists of 635 UCs from upper urinary tract and urinary bladder. Univariate and multivariate analyses show that DPP4 is an independent prognosticatory biomarker for disease-specific survival and metastasis-free survival. Comparing the DPP4 expression level of three urothelial cell lines with normal urothelial cells, J82 and RTCC-1 showed a significantly increased in transcript and protein expression. DPP4 knockdown as conducted by using short-hairpin RNA resulted in a significantly decreased cell viability, proliferation, migration, and invasion in J82 and RTCC-1 cells. These findings implicate that DPP4 plays a role in the aggressiveness of UCs, and can serve as a novel prognostic marker and therapeutic target.

PLCB4 copy gain and PLCß4 overexpression in primary gastrointestinal stromal tumors: Integrative characterization of a lipid-catabolizing enzyme associated with worse disease-free survival

Abstract: // Chien-Feng Li 1, 2, 3, 8 , Ting-Ting Liu 4 , I-Chieh Chuang 4, 8 , Yen-Yang Chen 5 , Fu-Min Fang 6 , Ti-Chun Chan 1 , Wan-Shan Li 7, 8 , Hsuan-Ying Huang 4, 8 1 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 2 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan 3 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan 4 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 6 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 7 Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 8 Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan Correspondence to: Hsuan-Ying Huang, email: cfli.hyhuang@gmail.com Keywords: metabolism, lipid catabolism, PLCB4, transcriptome, GIST Abbreviations: GIST, gastrointestinal stromal tumor; NIH, National Institute of Health; NCCN, National Comprehensive Cancer Network; PLCB4, phospholipase C-s4. Received: October 09, 2016 Accepted: December 08, 2016 Published: February 13, 2017 ABSTRACT To explore the implications of lipid catabolism-associated genes in gastrointestinal stromal tumors, we reappraised transcriptomic and genomic datasets and identified copy-gained and differentially upregulated PLCB4 gene associated with tumor progression. On full sections, PLCB4 mRNA abundance and PLCs4 immunoexpression were validated in 70 cases. On tissue microarrays, PLCB4 gene copies and PLCs4 immunoexpression were both informative in 350 cases with KIT/PDGFRA/BRAF genotypes noted in 213. In GIST48 cell line, we stably silenced PLCB4 and YAP1 to characterize their functional effects and regulatory link. Compared with normal tissue, PLCB4 mRNA abundance significantly increased across tumors of various risk levels (p<0.001), and was strongly correlated with immunoexpression level (p<0.001, r=0.468). Including polysomy (12.6%) and amplification (17.4%), PLCB4 copy gain was detected in 105 (30%) cases and significantly more frequent (p<0.001) in cases exhibiting higher PLCs4 immunoexpression (82/175). Copy gain and protein overexpression were modestly associated with unfavorable genotypes (both p<0.05), strongly associated with increased size, mitosis, and risk levels defined by both the NIH and NCCN schemes (all p<0.001), and univariately predictive of shorter disease-free survival (both p<0.0001). In PLCs4-overexpressing cases, PLCB4 copy gain still predicted worse prognosis (p<0.0001). In a multivariate comparison, both overexpression (p=0.007, hazard ratio: 2.454) and copy gain (p=0.031, hazard ratio: 1.892) exhibited independent impact. In vitro , YAP1 increased PLCB4 mRNA and protein expression, and both molecules significantly promoted cell proliferation. Being driven by copy gain or YAP1, PLCs4 is a novel overexpressed enzyme regulating lipid catabolism that promotes cell proliferation and independently confers a worse prognosis.

Transmembrane and Coiled-Coil Domain 1 Impairs the AKT Signaling Pathway in Urinary Bladder Urothelial Carcinoma: A Characterization of a Tumor Suppressor.

Abstract: Purpose: Urinary bladder urothelial carcinoma (UBUC) is a common malignant disease in developed countries. Cell-cycle dysregulation resulting in uncontrolled cell proliferation has been associated with UBUC development. This study aimed to explore the roles of TMCO1 in UBUCs.Experimental Design: Data mining, branched DNA assay, immunohistochemistry, xenograft, cell culture, quantitative RT-PCR, immunoblotting, stable and transient transfection, lentivirus production and stable knockdown, cell-cycle, cell viability and proliferation, soft-agar, wound-healing, transwell migration and invasion, coimmunoprecipitation, immunocytochemistry, and AKT serine/threonine kinase (AKT) activity assays and site-directed mutagenesis were used to study TMCO1 involvement in vivo and in vitroResults: Data mining identified that the TMCO1 transcript was downregulated during the progression of UBUCs. In distinct UBUC-derived cell lines, changes in TMCO1 levels altered the cell-cycle distribution, cell viability, cell proliferation, and colony formation and modulated the AKT pathway. TMCO1 recruited the PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) to dephosphorylate pAKT1(serine 473) (S473). Mutagenesis at S60 of the TMCO1 protein released TMCO1-induced cell-cycle arrest and restored the AKT pathway in BFTC905 cells. Stable TMCO1 (wild-type) overexpression suppressed, whereas T33A and S60A mutants recovered, tumor size in xenograft mice.Conclusions: Clinical associations, xenograft mice, and in vitro indications provide solid evidence that the TMCO1 gene is a novel tumor suppressor in UBUCs. TMCO1 dysregulates cell-cycle progression via suppression of the AKT pathway, and S60 of the TMCO1 protein is crucial for its tumor-suppressor roles. Clin Cancer Res; 23(24); 7650-63. ©2017 AACR.

Overexpression of Transcobalamin 1 is an Independent Negative Prognosticator in Rectal Cancers Receiving Concurrent Chemoradiotherapy.

Abstract: Objective: Neoadjuvant concurrent chemoradiotherapy (CCRT) is an increasingly common therapeutic strategy for locally advanced rectal cancer, but stratification of risk and final outcomes remain a major challenge Transcobalamin 1 (TCN1), a vitamin B12 (cobalamin)-binding protein, regulates cobalamin homeostasis High expression of TCN1 have been reported in neoplasms such as breast cancer and hepatocellular carcinoma However, little is known about the relevance of TCN1 to rectal cancer receiving CCRT This study examined the predictive and prognostic impact of TCN1 expression in patients with rectal cancer following neoadjuvant CCRT Methods: Through data mining from a published transcriptome of rectal cancers (GSE35452), we identified upregulation of TCN1 gene as the most significantly predicted poor response to CCRT among ion transport-related genes (GO:0006811) We evaluated TCN1 immunohistochemistry and performed an H-score analysis on endoscopic biopsy specimens from 172 rectal cancer patients receiving neoadjuvant CCRT followed by curative surgery Expression levels of TCN1 were further correlated with clinicopathologic features, therapeutic response, tumor regression grade (TRG) and survivals including metastasis-free survival (MeFS), disease-specific survival (DSS) and recurrent-free survival (LRFS) Results: TCN1 overexpression was significantly related to advanced post-treatment tumor (T3, T4; p<0001) and nodal status (N1, N2; p<0001), vascular invasion (p=0003) and inferior tumor regression grade (p < 0001) In survival analyses, TCN1 overexpression was significantly associated with shorter DSS (p<00001), MeFS (p=00002) and LRFS (p=00001) Furthermore, it remained an independent prognosticator of worse DSS (p=0002, hazard ratio=3344), MeFS (p=0021, hazard ratio=3015) and LRFS (p=0037, hazard ratio=3037) in the multivariate comparison Conclusion: Overexpression of TCN1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT, justifying the potential prognostic value of TCN1 in rectal cancer receiving CCRT

Hypoxia-regulated MicroRNA-210 Overexpression is Associated with Tumor Development and Progression in Upper Tract Urothelial Carcinoma.

Abstract: BACKGROUND Hypoxia has been shown to facilitate tumor progression Hypoxia-regulated microRNA-210 (miR-210) may play an important role in carcinogenesis and tumor progression In this study, we evaluated the clinical significance of miR-210 expression in upper tract urothelial carcinoma (UTUC) METHODS Eighty-three UTUC patients participated in this study All of them provided cancer tissue samples and 50 of them provided non-cancerous urothelium samples Clinicopathologic data were collected by reviewing medical records The expression of miR-210 and hypoxia-inducible factor-1α (HIF-1α) was determined by quantitative real-time polymerase chain reaction The relationship between clinicopathologic variables and the expression of miR-210 and HIF-1α was analyzed statistically RESULTS MiR-210 is overexpressed in UTUC compared to non-cancerous urothelium (p < 0001); it is also upregulated in high-stage and high-grade tumors (p = 0020 and 0049, respectively) HIF-1α is overexpressed in UTUC and correlates positively with miR-210 expression (r = 0442, p = 0001) CONCLUSION Both miR-210 and HIF-1α are involved in promoting UTUC carcinogenesis MiR-210 is also correlated with tumor progression Further studies are needed to clarify the underlying mechanism

High Expression of Aldolase B Confers a Poor Prognosis for Rectal Cancer Patients Receiving Neoadjuvant Chemoradiotherapy.

Abstract: Background : Colorectal cancer is the third most common cancer in both sex worldwide and it is also the fourth most common cause of cancer mortality. For rectal cancer, neoadjuvant concurrent chemoradiotherapy (CCRT) followed by radical proctectomy is gold standard treatment for patients with stage II/III rectal cancer. By data mining a documented database of rectal cancer transcriptome (GSE35452) from Gene Expression Omnibus, National Center of Biotechnology Information, we recognized that ALDOB was the most significantly up-regulated transcript among those related to glycolysis (GO: 0006096). Hence, we analyzed the clinicopathological correlation and prognostic effect of ALDOB protein (Aldolase B), which encoded by ALDOB gene. Methods : ALDOB immunostain was performed in 172 rectal adenocarcinomas treated with preoperative chemoradiotherapy followed by radical surgery, which were divided into high- and low-expression groups. Furthermore, statistical analyses were examined to correlate the relationship between ALDOB immunoreactivity and important clinical and pathological characteristics, as well as three survival indices: disease-specific survival (DSS), local recurrence-free survival (LRFS) and metastasis-free survival (MeFS). Results : ALDOB (Aldolase B) over-expression was significantly associated with pre-CCRT and post-CCRT tumor advancement, lymphovascular invasion, perineural invasion and poor response to CCRT (all P ≤ .023). In addition, ALDOB high expression was linked to adverse DSS, LRFS and MeFS in univariate analysis (P ≤ .0075) and also served as an independent prognosticator indicating dismal DSS and MeFS in multivariate analysis (hazard ratio (HR) = 3.462, 95% confidence interval (CI): 1.263-9.495; HR = 2.846, 95% CI: 1.190-6.808, respectively). Conclusion : ALDOB (Aldolase B) may play an imperative role in rectal cancer progression and responsiveness to neoadjuvant CCRT, and serve as a novel prognostic biomarker. Additional researches to clarify the molecular and biochemical pathways are essential for developing promising ALDOB-targeted therapies for patients with rectal cancers.

High Expression of EphA4 Predicted Lesser Degree of Tumor Regression after Neoadjuvant Chemoradiotherapy in Rectal Cancer.

Abstract: Background: Numerous transmembrane receptor tyrosine kinase pathways have been found to play an important role in tumor progression in some cancers. This study was aimed to evaluate the clinical impact of Eph receptor A4 (EphA4) in patients with rectal cancer treated with neoadjuvant concurrent chemoradiotherapy (CCRT) combined with mesorectal excision, with special emphasis on tumor regression. Methods: Analysis of the publicly available expression profiling dataset of rectal cancer disclosed that EphA4 was the top-ranking, significantly upregulated, transmembrane receptor tyrosine kinase pathway-associated gene in the non-responders to CCRT, compared with the responders. Immunohistochemical study was conducted to assess the EphA4 expression in pre-treatment biopsy specimens from 172 rectal cancer patients without distant metastasis. The relationships between EphA4 expression and various clinicopathological factors or survival were statistically analyzed. Results: EphA4 expression was significantly associated with vascular invasion (P=0.015), post-treatment depth of tumor invasion (P=0.006), pre-treatment and post-treatment lymph node metastasis (P=0.004 and P=0.011, respectively). More importantly, high EphA4 expression was significantly predictive for lesser degree of tumor regression after CCRT (P=0.031). At univariate analysis, high EphA4 expression was a negative prognosticator for disease-specific survival (P=0.0009) and metastasis-free survival (P=0.0001). At multivariate analysis, high expression of EphA4 still served as an independent adverse prognostic factor for disease-specific survival (HR, 2.528; 95% CI, 1.131-5.651; P=0.024) and metastasis-free survival (HR, 3.908; 95% CI, 1.590-9.601; P=0.003). Conclusion: High expression of EphA4 predicted lesser degree of tumor regression after CCRT and served as an independent negative prognostic factor in patients with rectal cancer.