Diagnosing postoperative lymph node metastasis in thyroid cancer with multimodal radiomics and clinical features.

Purpose: This study aims to evaluate the diagnostic value of texture analysis for lymph node metastasis after thyroid cancer surgery. Methods: We retrospectively analyzed patients who underwent positron emission tomography/computed tomography (PET/CT) examination before 131I treatment at Shanghai Tenth People's Hospital between 2017 and 2020. Clinical follow-up results were used as the criterion for determining the presence of lymph node metastasis. The study included 119 patients, who were then randomly divided into training and test groups in a 7:3 ratio. Regions of interest were identified, and radiomics features were extracted using LIFEx 7.3.0. Mann-Whitney U test and LASSO regression were employed to screen radiomics parameters for modeling. Subsequently, a nomogram model was built by combining radscore and clinical features. SPSS 26.0 software was utilized for statistical analysis, and p < 0.05 was considered statistically significant. Results: Follow-up confirmed 54 patients with thyroid cancer lymph node metastasis and 65 patients in the non-metastasis group. A total of 119 lymph nodes were delineated. For each lesion, 164 CT texture features and 164 PET texture features were extracted, and 107 significant parameters were identified, including 16 CT texture parameters and 91 PET texture parameters. After screening, 3 CT parameters, 4 PET parameters and 12 PET/CT parameters were selected to establish three radiomic models. The AUC values were as follows: AUC (CT) = 0.730, AUC (PET) = 0.759 and AUC (PET/CT) = 0.864. We then combined clinical features and radscore to construct a nomogram, resulting in a C-index of 0.915 in the training group. In the test group, the C-index was confirmed to be 0.868. Conclusions: Radiomics may enhance the diagnostic efficiency of lymph node metastases after thyroid cancer surgery and could potentially assist clinicians in future diagnoses. The developed nomogram, which combines radiomics and clinical features, offers relatively high accuracy in helping clinicians assess the risk of metastasis in thyroid patients after surgery.

Dipterocarpoidae genomics reveal their demography and adaptations to Asian rainforests.

Dipterocarpoideae species form the emergent layer of Asian rainforests. They are the indicator species for Asian rainforest distribution, but they are severely threatened. Here, to understand their adaptation and population decline, we assemble high-quality genomes of seven Dipterocarpoideae species including two autotetraploid species. We estimate the divergence time between Dipterocarpoideae and Malvaceae and within Dipterocarpoideae to be 108.2 (97.8‒118.2) and 88.4 (77.7‒102.9) million years ago, and we identify a whole genome duplication event preceding dipterocarp lineage diversification. We find several genes that showed a signature of selection, likely associated with the adaptation to Asian rainforests. By resequencing of two endangered species, we detect an expansion of effective population size after the last glacial period and a recent sharp decline coinciding with the history of local human activities. Our findings contribute to understanding the diversification and adaptation of dipterocarps and highlight anthropogenic disturbances as a major factor in their endangered status.

A Proposed Modified Staging System for Medullary Thyroid Cancer: A SEER Analysis With Multicenter Validation.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for medullary thyroid cancer (MTC) was implemented in 2018. However, its ability to predict prognosis remains controversial. PATIENTS AND METHODS: Patient data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database and multicenter datasets. Overall survival was the primary end-point of the present study. The concordance index (C-index) was used to assess the efficacy of various models to predict prognostic outcomes. RESULTS: A total of 1450 MTC patients were selected from the SEER databases and 349 in the multicenter dataset. According to the AJCC staging system, there were no significant survival differences between T4a and T4b categories (P = .299). The T4 category was thus redefined as T4a' category (≤3.5 cm) and T4b' category (>3.5 cm) based on the tumor size, which was more powerful for distinguishing the prognosis (P = .003). Further analysis showed that the T category was significantly associated with both lymph node (LN) location and count (P < .001). Therefore, the N category was modified by combining the LN location and count. Finally, the above-mentioned novel T and N categories were adopted to modify the 8th AJCC classification using the recursive partitioning analysis principle, and the modified staging system outperformed the current edition (C-index, 0.811 vs. 0.792). CONCLUSIONS: The 8th AJCC staging system was improved based on the intrinsic relationship among the T category, LN location, and LN count, which would have a positive impact on the clinical decision-making process and appropriate surveillance.

Molecular testing raises thyroid nodule fine needle aspiration diagnostic value.

Thyroid fine needle aspiration biopsy (FNAB) remains indeterminate in 16%-24% of the cases. Molecular testing could improve the diagnostic accuracy of FNAB. This study examined the gene mutation profile of patients with thyroid nodules and analyzed the diagnostic ability of molecular testing for thyroid nodules using a self-developed 18-gene test. Between January 2019 and August 2021, 513 samples (414 FNABs and 99 formalin-fixed paraffin-embedded (FFPE) specimens) underwent molecular testing at Ruijin Hospital. Sensitivity (Sen), specificity (Spe), positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. There were 457 mutations in 428 samples. The rates of BRAF, RAS, TERT promoter, RET/PTC, and NTRK3 fusion mutations were 73.3% (n=335), 9.6% (n=44), 2.8% (n=13), 4.8% (n=22), and 0.4% (n=2), respectively. The diagnostic ability of cytology and molecular testing were evaluated in Bethesda II and V-VI samples. For cytology alone, Sen, Spe, PPV, NPV, and accuracy were 100%, 25.0%, 97.4%, 100%, and 97.4%; these numbers were 87.5%, 50.0%, 98.0%, 12.5%, and 86.2% when considering positive mutation, and 87.5%, 75.0%, 99.0%, 17.6%, and 87.1% when considering positive cytology or and positive mutation. In Bethesda III-IV nodules, when relying solely on the presence of pathogenic mutations for diagnosis, Sen, Spe, PPV, NPV, and AC were 76.2%, 66.7%, 94.1%, 26.8%, and 75.0%, respectively. It might be necessary to analyze the molecular mechanisms of disease development at the genetic level to predict patients with malignant nodules more accurately in different risk strata and develop rational treatment strategies and definite management plans.

Inclusion of the Number of Metastatic Lymph Nodes in the Staging System for Medullary Thyroid Cancer: Validating a Modified American Joint Committee on Cancer Tumor-Node-Metastasis Staging System.

Background: The current American Joint Committee on Cancer (AJCC) staging system (8th edition) for medullary thyroid cancer (MTC) was originally extrapolated from the staging system for differentiated thyroid cancer. However, the current staging system does not accurately predict the prognosis of patients with MTC. Patients and Methods: The present study was based on data from the Surveillance, Epidemiology, and End Results (SEER) database and validated by multicenter data from the Shanghai Tenth People's Hospital, Tongji University School of Medicine, Xuzhou City Central Hospital, and Suzhou Ninth People's Hospital. Hazard ratio with its 95% confidence interval [CI] was estimated by Cox proportional hazards regression analysis. The concordance index (C-index) was used to evaluate the discrimination accuracy of the current AJCC tumor-node-metastasis (TNM) staging system and the modified AJCC (mAJCC) TNM staging system. Results: A total of 1175 MTC patients were selected from the SEER database and 312 from the three hospitals in China. We redefined the N category according to the number of metastatic lymph nodes (LNs) as follows: N'0 category (0 metastatic LNs), N'1 category (1-9 metastatic LNs), and N'2 category (≥10 metastatic LNs). The four distinct tumor stages were reclassified in the mAJCC staging system as follows: stage I (T1-4N'0M0, T1N'1M0), stage II (T2-3N'1M0, T1N'2M0), stage III (T4N'1M0, T2-4N'2M0), and stage IV (TanyN'anyM1). The C-index of the current AJCC staging system and the mAJCC staging system was 0.72 [CI, 0.67-0.78] and 0.78 [CI, 0.73-0.84], respectively. Similar results were observed in the survival analysis of the multicenter data set. Conclusions: The mAJCC staging system could discriminate the prognosis of MTC patients more effectively than the current AJCC staging system, indicating that it is feasible and appropriate to modify the current AJCC staging system by introducing the number of metastatic LNs instead of the location of LNs. These findings might be adopted in the next edition of the AJCC staging system and be used to guide clinical practice.

TUMOR SIZE IS AN INDEPENDENT PREDICTOR OF MORTALITY RISK IN DIFFERENTIATED THYROID CANCER PATIENTS WITH T4 DISEASE.

Objective: The eighth edition of the American Joint Committee on Cancer (AJCC) guideline on the tumor-node-metastasis staging system has been applied in clinical practice for thyroid cancer since 2018. However, using these criteria, a few studies have shown no significant difference between stage III and IV diseases amongst the differentiated thyroid cancer (DTC) patients. Thus, we aimed to study the underlying reason behind this observation. Methods: Patients were selected from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. The Cox proportional hazards regression model was used for the univariate and multivariate analyses to plot the Kaplan-Meier survival curves for overall survival (OS) and disease-specific survival (DSS). Results: A total of 1,431 patients had a median tumor size of 3.0 cm (range: 0.1 to 50 cm). When stratified by tumor size (≤2 cm, 2 to 4 cm, and >4 cm), lower survival rates were observed in patients with stage III (T4a) cancer and large tumor size than in those with stage IVA (T4b) cancer and small tumor size. Univariate and multivariate analyses showed that tumor size (≤4 cm versus >4 cm) is an independent prognostic factor for OS (P<.001) and DSS (P<.001) in DTC patients with T4a and T4b diseases. Conclusion: Tumor size is an independent prognostic factor for OS and DSS in DTC patients with T4 disease; tumor size-related modification of the T4 category can improve the AJCC staging system for DTC patient with stage III-IV diseases. Abbreviations: AJCC = American Joint Committee on Cancer; CI = confidence interval; DSS = disease-specific survival; DTC = differentiated thyroid cancer; FTC = follicular thyroid cancer; HR = hazard ratio; OS = overall survival; PTC = papillary thyroid cancer; SEER = Surveillance, Epidemiology, and End Results; TNM = tumor-node-metastasis.

Consideration of Age Is Necessary for Increasing the Accuracy of the AJCC TNM Staging System of Pancreatic Neuroendocrine Tumors.

Purpose: Currently, of the two most common staging systems of pancreatic neuroendocrine tumors (pNETs) one is from the European Neuroendocrine Tumor Society (ENETS) and the other is from the American Joint Committee on Cancer (AJCC). However, there are imperfections in both these staging systems. Patients and methods: Patients were selected retrospectively from the Surveillance Epidemiology and End Results (SEER) database (2004 to 2013). The effect of age on the hazard ratio (HR) was evaluated using restricted cubic splines. The discriminatory power of the staging systems was determined using the concordance index (C-index). Results: A total of 3,034 patients with pNETs were included in the final analyses. The risk of death increased slowly along with age for patients under 60 years of age, but the risk of death rose sharply for those over 60 years of age, forming a mirrored L-shaped survival curve. In the current AJCC tumor-node-metastasis (TNM) staging system, no statistical significance was observed between stages IA and IB (p = 0.105). Patients with stage IIB even had longer OS than patients with IIA, although there was no statistical significance (p = 0.574). The proportion of stage III patients was small (2.7%). In the proposed aTNM staging system, significant survival differences could be observed among stage I, IIA, and IIB (p < 0.001) and the proportion of stage III rose from 2.7 to 25.7%. Conclusion: Our findings suggest that age has a critical influence on the survival of patients with pNETs. Age should be considered as a factor in future staging systems of pNETs.

Simple Cholecystectomy Is Adequate for Patients With T1b Gallbladder Adenocarcinoma < 1 cm in Diameter.

Purpose: Consensus-based clinical guidelines recommend that simple cholecystectomy (SC) is adequate for T1a gallbladder adenocarcinoma (GBA), but extended cholecystectomy (EC), SC plus lymphatic dissection, should be considered for T1b and more advanced GBA. Whether lymphatic dissection is necessary for the treatment of T1b GBA remains controversial. This study attempts to better define the current criteria for local treatment of T1b GBA, by examining the relationship between lymph node (LN) metastasis and tumor size in such patients. Patients and methods: Clinical data from patients with T1b GBA receiving curative surgical treatment between 2004 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Baseline characteristics for the entire cohort were described, and overall survival (OS) and cancer-specific survival (CSS) were analyzed with the Kaplan-Meier method. Results: In total, 277 patients were enrolled for further analysis; 127 underwent lymphadenectomy. Among them, 23 patients had tumors <1 cm in diameter, none of which had LN metastasis; 104 patients had tumors ≥1 cm, 15 of which had positive LNs. In the group with tumor size <1 cm, there was no significant survival difference between treatment with SC or EC (P = 0.694). A clinical benefit was observed in T1b GBA patients with a tumor size ≥1 cm receiving EC vs. those receiving SC (P = 0.012). Conclusion: SC was adequate for treatment of T1b GBA < 1 cm in diameter. This evidence may be included as part of current guidelines.

Targeting EZH2 as a novel therapeutic strategy for sorafenib-resistant thyroid carcinoma.

Thyroid carcinoma is the most common endocrine malignancy. Surgery, post-operative selective iodine-131 and thyroid hormone suppression were the most common methods for the therapy of thyroid carcinoma. Although most patients with differentiated thyroid carcinoma (DTC) showed positive response for these therapeutic methods, some patients still have to face the radioactive iodine (RAI)-refractory problems. Sorafenib is an oral multikinase inhibitor for patients with advanced RAI refractory DTC. However, the side effects and drug resistance of sorafenib suggest us to develop novel drugs and strategies for the therapy of thyroid carcinoma. In this study, we firstly found that patients with sorafenib resistance showed no significant change in rapidly accelerated fibrosarcoma and VEGFR expression levels compared with sorafenib sensitive patients. Moreover, a further miRNAs screen by qRT-PCR indicated that miR-124-3p and miR-506-3p (miR-124/506) were remarkably reduced in sorafenib insensitive patients. With a bioinformatics prediction and functional assay validation, we revealed that enhancer of zeste homolog 2 (EZH2) was the direct target for miR-124/506. Interestingly, we finally proved that the sorafenib resistant cells regained sensitivity for sorafenib by EZH2 intervention with miR-124/506 overexpression or EZH2 inhibitor treatment in vitro and in vivo, which will lead to the decreased tri-methylation at lysine 27 of histone H3 (H3K27me3) and increased acetylated lysine 27 of histone H3 (H3K27ac) levels. Therefore, we conclude that the suppression of EZH2 represents a potential target for thyroid carcinoma therapy.

Anergic natural killer cells educated by tumor cells are associated with a poor prognosis in patients with advanced pancreatic ductal adenocarcinoma.

INTRODUCTION: Natural killer cells (NK) are often believed to play a positive role in the antitumor immune response. However, this is not the case for patients with advanced pancreatic cancer. This study was performed to determine the unique subtype of "educated" NK cells and their prognostic value in patients with advanced pancreatic cancer. METHODS: We divided 378 eligible patients into a derivation cohort (September 2010 to December 2014, n = 239) and a validation cohort (January 2015 to April 2016, n = 139). Flow cytometry was performed to analyze NK cells. Enzyme-linked immunosorbent assay was used to detect interleukin-2 (IL-2), interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. The Kaplan-Meier method and the Cox proportional hazards model were used. RESULTS: Survival analysis showed that a high density of NK cells accompanied by a high neutrophil-to-lymphocyte ratio was associated with reduced overall survival in both the derivation and validation cohorts. Multivariable analysis also showed that high NK infiltration (HR 1.45, 95% CI 1.17 to 1.79, p = 0.001) was an independent prognostic factor. In these patients, high NK infiltration was associated with reduced levels of IL-2, IFN-γ and TNF-α, although only IFN-γ reached statistical significance, which accounted for this unique phenomenon. DISCUSSION: Natural killer cells in patients with advanced pancreatic cancer are a unique subtype with anergic features. A high density of NKs predicts poor survival in these patients, possibly because an active inflammatory response and reduced secretion of IL-2, IFN-γ and TNF-α inhibit NK activation.

Application of the Eighth Edition of the American Joint Committee on Cancer Staging for Pancreatic Adenocarcinoma.

OBJECTIVES: Notable modifications have been made in the American Joint Committee on Cancer (AJCC) Staging eighth edition staging for pancreatic cancer for the consideration of the irreproducible and inapplicable of the AJCC seventh edition staging. However, the new staging classification has not been systemically verified. METHODS: A comparison was performed to evaluate the application of the AJCC seventh and eighth staging classifications using the Surveillance, Epidemiology, and End Results registry (18,450 patients) and an institutional series (2040 patients). RESULTS: For the eighth staging classification, patients with tumor diameter of greater than 4 cm (T3N0M0, IIA) had similar prognosis to patients with 1 to 3 positive nodes (T1-3N1M0, IIB). For patients who underwent tumor resection and without lymph node involvement, survival curves of T1 (≤2 cm), T2 (2-4 cm), and T3 (>4 cm) were well separated. Statistical difference in survival analyses was demonstrated in N0 (0 positive node), N1 (1-3 positive nodes), and N2 (≥4 positive nodes) patients underwent tumor resection. The AJCC eighth edition had better stage distribution than the AJCC seventh edition for pancreatic cancer. CONCLUSIONS: The eighth edition of AJCC staging is more applicable and accurate than the seventh edition for pancreatic adenocarcinoma.

Novel agents for pancreatic ductal adenocarcinoma: emerging therapeutics and future directions.

A poor prognosis of pancreatic ductal adenocarcinoma (PDAC) associated with chemoresistance has not changed for the past three decades. A multidisciplinary diagnosis followed by surgery and chemo(radiation)therapy is the main treatment approach. However, gemcitabine- and 5-fluorouracil-based therapies did not present satisfying outcomes. Novel regimens targeting pancreatic cancer cells, the tumor microenvironment, and immunosuppression are emerging. Biomarkers concerning the treatment outcome and patient selection are being discovered in preclinical or clinical studies. Combination therapies of classic chemotherapeutic drugs and novel agents or novel therapeutic combinations might bring hope to the dismal prognosis for PDAC patients.

MUC16 C terminal-induced secretion of tumor-derived IL-6 contributes to tumor-associated Treg enrichment in pancreatic cancer.

Pancreatic cancer is the most lethal tumor. CA125 (gene symbol MUC16) is an important serum marker for pancreatic cancer diagnosis and treatment. High serum CA125 is related to metabolic tumor burden and poor prognosis. The circulating Treg subset is another independent prognostic factor for pancreatic cancer. Our unpublished data indicated that the circulating Treg proportion might be related to the serum CA125 level. However, the potential relationship and underlying mechanism of MUC16 and Treg in pancreatic cancer tissues remain unclear. In this study, we found that pancreatic cancer tissues were positive for both MUC16 C terminal (MUC16c) and Foxp3 expression and that their expression was correlated. MUC16c released into the cytoplasm via EGF induction significantly increased IL-6 expression and secretion. The PI3K/AKT pathway may participate in the regulation of IL-6 expression and secretion. By treating CD4+ T cells with IL-6 or co-culturing the cells with pancreatic cancer cells, tumor-derived IL-6 was identified to promote Foxp3 expression and Treg differentiation, which was significantly inhibited by the JAK2 inhibitor AG-490. In sum, our study demonstrated that the relationship between the MUC16c level and Foxp3 expression in the local tumor environment was consistent with that of the serum CA125 level and circulating Treg proportion in the systemic environment. MUC16c promoted Foxp3 expression and tumor-associated Treg enrichment in tumor tissues through tumor-secreted IL-6 activation of the JAK2/STAT3 pathway. These findings may provide deeper insight into potential pancreatic cancer therapy approaches.

Distribution of Lewis and Secretor polymorphisms and corresponding CA19-9 antigen expression in a Chinese population.

The Lewis (FUT3) and Secretor (FUT2) genes, corresponding to secretion of Lewis ABO (H) histo-blood group antigen CA19-9, are highly polymorphic with differences between populations. In this study, the FUT3 and FUT2 genes in 316 Chinese participants were sequenced to detect polymorphisms, and the associated CA19-9 antigen secretion was also measured. In total, 14 genotypes of FUT3 and 10 genotypes of FUT2 were verified. Le/Le, Le/le59,508 and Le/le59 were the main genotypes of FUT3 with frequencies of 53.2%, 10.7% and 3.5%, respectively. Se/Se, Se/se385 and se385/se385 were the main genotypes of FUT2, with frequencies of 21.4%, 18.6% and 16.2%, respectively. The alleles le1067 and le508 were found extensively in the Chinese population, and the frequency of allele se385 was shown to be higher than previously reported. Phenotype analysis revealed that 9.8% of individuals were the Lewis-negative type and 22.5% were the secretor-negative type. Combined phenotypes showed that 3.2% of participants were of 'double-negative' phenotype (le, se) and 19.3% were of single dominant non-secretor phenotype (Le, se). Serum Lewis antigen CA19-9 levels were significantly different between subgroups and consistent with the defined phenotype. Our study revealed the unique distribution of Lewis and Secretor polymorphisms in a large Chinese population, and decoded the combined genotypes of the two CA19-9-related genes.

Revised nodal stage for pancreatic neuroendocrine tumors.

BACKGROUND: Previously we have proposed a modified European Neuroendocrine Tumor Society (mENETS) staging system for pNETs, which is more suitable than either the American Joint Committee on Cancer (AJCC) or the European Neuroendocrine Tumor Society (ENETS) systems. However, it is necessary to revise the nodal stage of the mENETS system for the under representation of stage III diseases. METHODS: Nodal substages of the upper gastrointestinal organs (N0: 0 node, N1: 1-2 nodes; N2: ≥3 nodes) or the lower gastrointestinal organs (0: 0 node, N1: 1-3 nodes, and N2:≥ 4 nodes) were incorporated into the mENETS system and evaluated using the Surveillance, Epidemiology, and End Results (SEER) registry series. RESULTS: The mENETS classification with the upper gastrointestinal N-stage revision (stage III, 17.1%) had better proportional distribution than the mENETS classification (stage III, 8.7%) or the lower gastrointestinal N-stage revision (stage III, 14.5%). N-stage revision (N0: 0 node, N1: 1-2 nodes; N2: ≥3 nodes) was incorporated in the mENETS staging definition for further analysis. Survival curves were well separated by nodal substages. HRs of stage IIA (T3N0M0) and IIB (T1-3N1M0) of the mENETS classification with N-stage revision were similar, indicating these two substages should be attributed to stage II. Survival curves were well separated by stage using the mENETS classification with N-stage revision. CONCLUSIONS: The mENETS classification with N-stage revision (N0: 0 node, N1: 1-2 nodes; N2: ≥3 nodes) had better prognostic value and proportional distribution than the mENETS classification for pNETs and can be used in clinical practice.

Somatic Genetic Variation in Solid Pseudopapillary Tumor of the Pancreas by Whole Exome Sequencing.

Solid pseudopapillary tumor of the pancreas (SPT) is a rare pancreatic disease with a unique clinical manifestation. Although CTNNB1 gene mutations had been universally reported, genetic variation profiles of SPT are largely unidentified. We conducted whole exome sequencing in nine SPT patients to probe the SPT-specific insertions and deletions (indels) and single nucleotide polymorphisms (SNPs). In total, 54 SNPs and 41 indels of prominent variations were demonstrated through parallel exome sequencing. We detected that CTNNB1 mutations presented throughout all patients studied (100%), and a higher count of SNPs was particularly detected in patients with older age, larger tumor, and metastatic disease. By aggregating 95 detected variation events and viewing the interconnections among each of the genes with variations, CTNNB1 was identified as the core portion in the network, which might collaborate with other events such as variations of USP9X, EP400, HTT, MED12, and PKD1 to regulate tumorigenesis. Pathway analysis showed that the events involved in other cancers had the potential to influence the progression of the SNPs count. Our study revealed an insight into the variation of the gene encoding region underlying solid-pseudopapillary neoplasm tumorigenesis. The detection of these variations might partly reflect the potential molecular mechanism.

MicroRNA-187 inhibits tumor growth and invasion by directly targeting CD276 in colorectal cancer.

Aberrantly expressed microRNAs contribute to the initiation and progression of human cancers. However, the underlying functions of microRNA-187 (miR-187) in colorectal cancer (CRC) remain largely unexplored. Here, we demonstrated that miR-187 was significantly down-regulated in CRC tissues and cell lines compared to their normal counterparts. By Kaplan-Meier analysis, we revealed that decreased miR-187 expression was closely associated with shorter overall survival and relapse-free survival of patients with CRC. By gain- and loss-of-function studies, we showed that miR-187 remarkably suppressed CRC cell proliferation, migration, invasion, and promoted cell apoptosis. Furthermore, bioinformatics analysis and luciferase reporter assay identified that CD276 was the direct functional target of miR-187 in CRC. Genetic silencing of CD276 recapitulated similar phenotype as observed in over-expression of miR-187, and restoration of CD276 completely rescued the inhibitory effect of miR-187 in CRC cells. Taken together, our study implied the essential roles of miR-187 in suppressing CRC progression, and a novel link between miR-187 and CD276 in CRC.

Prognostic value of regulator of G-protein signaling 6 in colorectal cancer.

Reprogrammed metabolism is a hallmark of cancer cells. Regulator of G-protein signaling 6 (RGS6), which is frequently down-regulated in multiple human malignancies, has been demonstrated to play a critical function in energy metabolism, cell apoptosis and tumorigenesis. However, limited knowledge is known about the expression pattern and prognostic value of RGS6 in colorectal cancer (CRC). In this study, we first observed that RGS6 mRNA and protein is commonly downregulated in 32 paired CRC tissues compared with their normal counterparts. Furthermore, by a large scale of immunohistochemical analysis in a tissue microarray containing 310 cases of CRC specimens, we demonstrated that the protein expression of RGS6 expression is downregulated in 40.97% (127/310) samples and detected that decreasing RGS6 expression is closely correlated with enhanced tumor size, CEA level, T classification, TNM stage, and easier lymphatic and distant metastasis. Meanwhile, Kaplan-Meier survival analysis showed that CRC patients with a lower RGS6 expression have a poorer clinical outcome than those with a higher RGS6 expression. Multivariate Cox regression analysis revealed that RGS6, lymphatic metastasis and distant metastasis are the independent prognostic factors for overall survival rate of CRC patients. Taken together, our studies reveal the prognostic value of RGS6 in CRC and support that RGS6 may act as a molecular target for CRC treatment.

Up-regulated CKS2 promotes tumor progression and predicts a poor prognosis in human colorectal cancer.

Cyclin-dependent kinases regulatory subunit 2 (CKS2) is a cyclin-dependent kinase-interacting protein, which is essential for cell cycle regulation. Elevated expression of CKS2 has been demonstrated in multiple types of human malignancies. However, the clinical significance, oncogenic functions and related mechanisms of CKS2 in colorectal cancer (CRC) remain largely unexplored. In this study, data from Oncomine database revealed that CKS2 is significantly up-regulated in CRC tissues compared with their normal counterparts. Immunohistochemical analysis of a CRC tissue microarray demonstrated that elevated CKS2 expression is closely associated with enhanced TNM stage, larger tumor size and a poor prognosis in patients with CRC. Multivariate Cox regression analysis revealed that CKS2 and TNM stage are two independent prognostic factors for CRC. Suppression of CKS2 expression resulted in decreased cell viability, increased cell apoptosis, cell cycle arrest and reduced expression of cyclins in Caco-2 and SW620 cells. Furthermore, gain and loss of function studies demonstrated that CKS2 promotes cell invasion in CRC cells through regulating claudin1. Taken together, our study reveal that CKS2 is promising prognostic indicator and contributes to tumor progression in CRC, and support that CKS2-related signaling may represent a novel target for CRC therapy.

Elevated expression of ECT2 predicts unfavorable prognosis in patients with colorectal cancer.

Epithelial cell transforming sequence 2 (ECT2) is a well-studied guanine nucleotide exchange factor for the Rho family GTPase, which has been demonstrated as an oncogene in many types of human cancers. However, little is known about the prognostic value of ECT2 in colorectal cancer (CRC). In current study, we investigated the expression pattern and underlying clinical significance of ECT2 in CRC. ECT2 expression was detected in 345 CRC specimens by immunohistochemistry, and its correlation with clinicopathologic parameters and prognosis of CRC patients were analyzed. Data from Oncomine database and real-time PCR demonstrated that ECT2 expression was elevated in CRC compared with normal tissues. Among the clinical parameters analyzed, high expression level of ECT2 significantly associated with tumor size (P=0.020), serum CEA levels (P = 0.000) and TNM stage (P=0.027). Kaplan-Meier survival analysis showed that patients with high ECT2 expression had a remarkably shorter overall survival. Cox regression analysis revealed that ECT2 expression level was a significant and independent prognostic factor for overall survival rate of CRC patients. These data suggested that ECT2 is an unfavorable biomarker of prognosis in CRC and that ECT2 may be a potential therapeutic candidate for CRC treatment.