TOPK promotes the development of psoriasis and worenine alleviates psoriasiform dermatitis by inhibiting TOPK activity.

BACKGROUND: Psoriasis is an inflammatory skin disease. The pathogenesis of psoriasis has not been fully elucidated. T-lymphokine-activated killer cell-originated protein kinase (TOPK) activity increases in a proinflammatory environment, and inhibiting TOPK blocks inflammation. However, whether TOPK is involved in the pathogenesis of psoriasis remains to be identified. OBJECTIVES: We aimed to study the role of TOPK in psoriasis and attempted to find a drug targeting TOPK for the prevention and treatment of psoriasis. METHOD: Firstly, the expressions of TOPK in psoriatic patients, psoriatic cell and animal model were analysed by Gene Expression Omnibus database, immunohistochemistry (IHC) staining and western blot (WB). After inhibiting TOPK by chemical or gene knockout, the effect of TOPK on the development of psoriasis was verified in cell and animal model by WB, qRT-PCR, ELISA, haematoxylin-eosin (H&E) and IHC staining. Moreover, phosphoproteomic analysis was performed to explore the signalling pathways regulated by TOPK in the occurrence and development of psoriasis. Then, an in vitro kinase assay was performed to prove TOPK kinase activity was inhibited by worenine. Ultimately, WB, qRT-PCR, ELISA, H&E and IHC staining were used to verify the anti-psoriasis effect of worenine by inhibiting TOPK was in cell and animal model. RESULTS: In this study, we found that TOPK was highly expressed in psoriasis patients, psoriatic cell and animal model, which suggests that TOPK might be associated with psoriasis pathogenesis. Interestingly, chemical or genetic inhibition of TOPK alleviated M5- and imiquimod (IMQ)-induced psoriasis-like dermatitis, which further confirmed the role of TOPK in promoting the development of psoriasis. Moreover, we determined that worenine inhibited TOPK kinase activity. In addition, worenine relieved M5- and IMQ-induced psoriasiform dermatitis by inhibiting TOPK activity. CONCLUSIONS: T-lymphokine-activated killer cell-originated protein kinase promotes the development of psoriasis. Therefore, TOPK might be a promising drug target for the prevention and treatment of psoriasis. Worenine alleviates psoriasiform dermatitis by inhibiting TOPK activity, providing new strategies for clinical intervention.

Nitrogen addition accelerates litter decomposition and arsenic release of Pteris vittata in arsenic-contaminated soil from mine.

The arsenic (As) release from litter decomposition of As-hyperaccumulator (Pteris vittata L.) in mine areas poses an ecological risk for metal dispersion into the soil. However, the effect of atmospheric nitrogen (N) deposition on the litter decomposition of As-hyperaccumulator in the tailing mine area remains poorly understood. In this study, we conducted a microcosm experiment to investigate the As release during the decomposition of P. vittata litter under four gradients of N addition (0, 5, 10, and 20 mg N g-1). The N10 treatment (10 mg N g-1) enhanced As release from P. vittata litter by 1.2-2.6 folds compared to control. Furthermore, Streptomyces, Pantoea, and Curtobacterium were found to primarily affect the As release during the litter decomposition process. Additionally, N addition decreased the soil pH, subsequently increased the microbial biomass, as well as hydrolase activities (NAG) which regulated N release. Thereby, N addition increased the As release from P. vittata litter and then transferred to the soil. Moreover, this process caused a transformation of non-labile As fractions into labile forms, resulting in an increase of available As concentration by 13.02-20.16% within the soil after a 90-day incubation period. Our findings provide valuable insights into assessing the ecological risk associated with As release from the decomposition of P. vittata litter towards the soil, particularly under elevated atmospheric N deposition.

The role of T-LAK cell-originated protein kinase in targeted cancer therapy.

Targeted therapy has gradually become the first-line clinical tumor therapy due to its high specificity and low rate of side effects. TOPK (T-LAK cell-originated protein kinase), a MAP kinase, is highly expressed in various tumor tissues, while it is rarely expressed in normal tissues, with the exceptions of testicular germ cells and some fetal tissues. It can promote cancer cell proliferation and migration and is also related to drug resistance. Therefore, TOPK is considered a good therapeutic target. Moreover, a number of studies have shown that targeting TOPK can inhibit the proliferation of cancer cells and promote their apoptosis. Here, we discussed the biological functions of TOPK in cancer and summarized its tumor-related signaling network and known TOPK inhibitors. Finally, the role of TOPK in targeted cancer therapy was concluded, and future research directions for TOPK were assessed.

Polymorphism in PHD1 gene and risk of non-small cell lung cancer in a Chinese population.

Hypoxia is a common phenomenon in the development of solid tumors, and hypoxia inducible factor 1 (HIF-1) plays a central role in coordinating the cellular response to hypoxia and in oxygen homeostasis. The prolyl hydrolase 1 (PHD1) is a key adjustment factor that mediates the HIF-1 degradation and relates with the process of tumorigenesis. Thus, polymorphism in PHD1 may affect cellular response to hypoxic conditions and associate with cancer susceptibility. We conducted a case-control study with 406 non-small cell lung cancer cases and 812 healthy controls matched on age and sex to examine the effect of rs10680577 polymorphism within the PHD1 promoter on non-small cell lung cancer (NSCLC) risk in a Chinese population. The genotype of rs10680577 polymorphism was detected by non-denaturing polyacrylamide gel electrophoresis. The ins/del genotype of rs10680577 was associated with significantly increased non-small cell lung cancer risk (ins/del vs. ins/ins: OR = 1.35, 95 % confidence interval (CI) 1.05-1.74, P = 0.020; ins/del vs. ins/ins + del/del: OR = 1.34, 95 % CI = 1.04-1.72, P = 0.022). In addition, the association was more pronounced in the group of >60 years of age. rs10680577 polymorphism is associated with the risk of non-small cell lung cancer in a Chinese population. This is the first time to show that PHD1 rs10680577 is associated NSCLC risk.

Response patterns of the microbiome during hexavalent chromium remediation by Tagetes erecta L.

Chromium pollution, particularly hexavalent chromium [Cr(VI)], may threaten the environment and human health. This study investigated the potential of Tagetes erecta L. (Aztec marigold) for phytoremediation of soil contaminated with Cr(VI), and focused on the effects of varying concentrations of Cr(VI) on both the physicochemical properties of soil and microbiome of Tagetes erecta L. We observed that Tagetes erecta L. showed tolerance to Cr(VI) stress and maintained normal growth under these conditions, as indicated by bioconcentration factors of 0.33-0.53 in shoots and 0.39-0.70 in roots. Meanwhile, the structure and diversity of bacterial communities were significantly affected by Cr(VI) pollution. Specifically, Cr(VI) had a more significant effect on the microbial community structure in the endophytic of Tagetes erecta L. than in the rhizosphere (p < 0.05). The genera Devosia and Methylobacillus were positively correlated with Cr(VI) concentrations. Biomarkers such as Bacilli and Pseudonocardia were identified under the different Cr(VI)-contaminated treatments using LEfSe. In addition, the interaction and stability of the endophytic microbiome were enhanced under Cr(VI) stress. This study explored the interactions between heavy metals, microorganisms, and plants, providing valuable insights for developing in situ bioremediation of Cr(VI)-contaminated soils.

TOPK Inhibition Enhances the Sensitivity of Colorectal Cancer Cells to Radiotherapy by Reducing the DNA Damage Response.

OBJECTIVE: Abnormal expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) was reported to be closely related to the resistance of prostate cancer to radiotherapy and to targeted drug resistance in lung cancer. However, the role of TOPK inhibition in enhancing radiosensitivity of colorectal cancer (CRC) cells is unclear. This study aimed to evaluate the radiosensitization of TOPK knockdown in CRC cells. METHODS: The expression of TOPK was detected in CRC tissues by immunohistochemistry, and the effect of TOPK knockdown was detected in CRC cells by Western blotting. CCK-8 and clonogenic assays were used to detect the growth and clonogenic ability of CRC cells after TOPK knockdown combined with radiotherapy in CRC cells. Furthermore, proteomic analysis showed that the phosphorylation of TOPK downstream proteins changed after radiotherapy. DNA damage was detected by the comet assay. Changes in the DNA damage response signaling pathway were analyzed by Western blotting, and apoptosis was detected by flow cytometry. RESULTS: The expression of TOPK was significantly greater in CRC tissues at grades 2-4 than in those at grade 1. After irradiation, CRC cells with genetically silenced TOPK had shorter comet tails and reduced expression levels of DNA damage response-associated proteins, including phospho-cyclin-dependent kinase 1 (p-CDK1), phospho-ataxia telangiectasia-mutated (p-ATM), poly ADP-ribose polymerase (PARP), and meiotic recombination 11 homolog 1 (MRE11). CONCLUSIONS: TOPK was overexpressed in patients with moderately to poorly differentiated CRC. Moreover, TOPK knockdown significantly enhanced the radiosensitivity of CRC cells by reducing the DNA damage response.

MARK3 kinase: Regulation and physiologic roles.

Microtubule affinity-regulating kinase 3 (MARK3), a member of the MARK family, regulates several essential pathways, including the cell cycle, ciliated cell differentiation, and osteoclast differentiation. It is important to understand the control of their activities as MARK3 contains an N-terminal serine/threonine kinase domain, ubiquitin-associated domain, and C-terminal kinase-associated domain, which perform multiple regulatory functions. These functions include post-translational modification (e.g., phosphorylation) and interaction with scaffolding and other proteins. Differences in the amino acid sequence and domain position result in different three-dimensional protein structures and affect the function of MARK3, which distinguish it from the other MARK family members. Recent data indicate a potential role of MARK3 in several pathological conditions, including congenital blepharophimosis syndrome, osteoporosis, and tumorigenesis. The present review focuses on the physiological and pathological role of MARK3, its regulation, and recent developments in the small molecule inhibitors of the MARK3 signalling cascade.

TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC.

TOPK/PBK (T-LAK Cell-Originated Protein Kinase) is a serine/threonine kinase that is highly expressed in a variety of human tumors and is associated with poor prognosis in many types of human malignancies. Its activation mechanism is not yet fully understood. A bidirectional signal transduced between TOPK and ERK2 (extracellular signal-regulated kinase 2) has been reported, with ERK2 able to phosphorylate TOPK at the Thr9 residue. However, mutated TOPK at Thr9 cannot repress cellular transformation. In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2. Phospho-TOPK (S32) was found to be involved in the resistance of renal cell carcinoma (RCC) to sorafenib. Herein, combined a TOPK inhibitor with sorafenib could promoted the apoptosis of sorafenib-resistant RCC. High expression of HGF/c-met contributes to activation of p-TOPK (S32) during the development of sorafenib resistance in RCC. The current research presents a possible mechanism of sorafenib resistance in RCC and identifies a potential diagnostic marker for predicting sorafenib resistance in RCC, providing a valuable supplement for the clinically targeted treatment of advanced RCC.

BCKDK Promotes Ovarian Cancer Proliferation and Migration by Activating the MEK/ERK Signaling Pathway.

Background: Ovarian cancer (OC) is the most fatal gynecologic cancer. The branched-chain α-keto acid dehydrogenase kinase (BCKDK) plays an important role in many serious human diseases, including cancers. Its function in promoting cell proliferation and migration has been reported in various cancers. However, the biological role of BCKDK and its molecular mechanisms underlying OC initiation and progression are unclear. Methods: First, the expression level of BCKDK in OC cell lines or tissues was determined using tissue microarray- (TMA-) based immunohistochemistry or western blotting. Then, growth curve analysis, anchorage-independent cell transformation assays, wound healing assays, cell migration assays, and tumor xenografts were used to test whether BCKDK could promote cell transformation or metastasis. Finally, the signaling pathways involved in this process were investigated by western blotting or immunoprecipitation. Results: We found that the expression of BCKDK was upregulated in OC tissues and the high expression of BCKDK was correlated with an advanced pathological grade in patients. The ectopic overexpression of BCKDK promoted the proliferation and migration of OC cells, and the knockdown of BCKDK with shRNAs inhibited the proliferation and migration of OC ex vivo and in vivo. Moreover, BCKDK promoted OC proliferation and migration by activating MEK. Conclusions: Our results demonstrate that BCKDK promotes OC proliferation and migration by activating the MEK/ERK signaling pathway. Targeting the BCKDK-MEK axis may provide a new therapeutic strategy for treating patients with OC.

Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC.

T-LAK cell-oriented protein kinase (TOPK) is a potential therapeutic target in tumors. However, its role in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) has not been reported. Here, we found that TOPK was highly expressed in ALK-positive NSCLC. Additionally, ALK was identified as another upstream kinase of TOPK by in vitro kinase assay screening. Then, it was proven that ALK phosphorylated TOPK at Y74 in vitro and ex vivo, and the pathways downstream of ALK-TOPK were explored by phosphoproteomic analysis. Subsequently, we demonstrated that inhibiting TOPK enhanced tumor sensitivity to alectinib (an ALK inhibitor). The combination of alectinib and HI-032 (a TOPK inhibitor) suppressed the growth and promoted the apoptosis of ALK-positive NSCLC cells ex vivo and in vivo. Our findings reveal a novel ALK-TOPK signaling pathway in ALK-positive NSCLC. The combination of alectinib and HI-032 might be a promising therapeutic strategy for improving the sensitivity of ALK-positive NSCLC to targeted therapy.

Worenine Prevents Solar Ultraviolet-Induced Sunburn by Inhibiting JNK2.

Excessive solar ultraviolet (SUV) radiation often causes dermatitis, photoaging, and even skin cancer. In the pathological processes of SUV-induced sunburn, JNK is activated by phosphorylation, and it in turn phosphorylates its downstream transcription factors, such as ATF2 and c-jun. The transcription factors further regulate the expression of pro-inflammatory genes, such as IL-6 and TNF-α, which ultimately leads to dermatitis. Therefore, inhibiting JNK may be a strategy to prevent dermatitis. In this study, we screened for worenine as a potential drug candidate for inhibiting sunburn. We determined that worenine inhibited the JNK-ATF2/c-jun signaling pathway and the secretion of IL-6 and TNF-α in cell culture and in vivo, confirming the role of worenine in inhibiting sunburn. Furthermore, we determined that worenine bound and inhibited JNK2 activity in vitro through the MST, kinase, and in vitro kinase assays. Therefore, worenine might be a promising drug candidate for the prevention and treatment of SUV-induced sunburn.

Phosphorylation of BCKDK of BCAA catabolism at Y246 by Src promotes metastasis of colorectal cancer.

Branched-chain α-keto acid dehydrogenase kinase (BCKDK), the key enzyme of branched-chain amino acids (BCAAs) metabolism, has been reported to promote colorectal cancer (CRC) tumorigenesis by upregulating the MEK-ERK signaling pathway. However, the profile of BCKDK in metastatic colorectal cancer (mCRC) remains unknown. Here, we report a novel role of BCKDK in mCRC. BCKDK is upregulated in CRC tissues. Increased BCKDK expression was associated with metastasis and poor clinical prognosis in CRC patients. Knockdown of BCKDK decreased CRC cell migration and invasion ex vivo, and lung metastasis in vivo. BCKDK promoted the epithelial mesenchymal transition (EMT) program, by decreasing the expression of E-cadherin, epithelial marker, and increasing the expression of N-cadherin and Vimentin, which are mesenchymal markers. Moreover, BCKDK-knockdown experiments in combination with phosphoproteomics analysis revealed the potent role of BCKDK in modulating multiple signal transduction pathways, including EMT and metastasis. Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. In summary, the identification of BCKDK as a novel prometastatic factor in human CRC will be beneficial for further diagnostic biomarker studies and suggests novel targeting opportunities.

Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in patients with ESCC. RSK4 was found to be a direct downstream transcriptional target of ΔNp63α, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the ß-catenin signaling pathway through direct phosphorylation of GSK-3ß at Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improved radiosensitivity in both nude mouse and patient-derived xenograft models. Collectively, our results strongly suggest that the ΔNp63α/RSK4/GSK-3ß axis plays a key role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.

Sulfasalazine suppresses thyroid cancer cell proliferation and metastasis through T-cell originated protein kinase.

Thyroid cancer patients with radioactive iodine-refractory or rapidly progressing presentation require effective treatment. T-cell originated protein kinase (TOPK) is highly expressed in a number of different tumor types, where it promotes proliferation and metastasis. However, the expression of TOPK in thyroid cancer is poorly documented. Therefore, immunohistochemistry was used to detect the expression of TOPK in thyroid cancer tissues, and its clinical significance in this disease was investigated. Sulfasalazine, a targeted inhibitor of TOPK that directly binds the protein with a dissociation constant (Kd) of 228 µM, was also investigated using microscale thermophoresis. Sulfasalazine inhibited TOPK activity, as determined by an in vitro pull-down assay. Furthermore, sulfasalazine inhibited the proliferation and metastasis of thyroid cancer cells. The results indicated that TOPK may be a potential therapeutic target and diagnostic biomarker for thyroid cancer and may be used as an index to evaluate malignant thyroid nodules. Therefore, sulfasalazine is a potential novel compound for the targeted treatment of thyroid cancer.

TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ.

ULK1, the upper-most protein of the ULK1 complex, is emerging as a crucial node in autophagy induction. However, the regulation of ULK1 is not fully understood. In this study, we identified TOPK (T-LAK cell-originated protein kinase), an oncokinase, as a novel upstream kinase to phosphorylate ULK1. We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1. In addition, we want to examine the initiation of autophagy because the reduction activity of ULK1 reduces the occurrence of autophagy. We demonstrated that TOPK could inhibit the initiation and progression of autophagy in glioma cells. Furthermore, TOPK inhibition increased the sensitivity of glioma cells to temozolomide (TMZ). This discovery provides insight into the problem of TMZ-resistance in GBM treatment.

Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells.

MET overactivation is one of the crucial reasons for tyrosine kinase inhibitor (TKI) resistance, but the mechanisms are not wholly clear. Here, COX2, TOPK, and MET expression were examined in EGFR-activating mutated NSCLC by immunohistochemical (IHC) analysis. The relationship between COX2, TOPK, and MET was explored in vitro and ex vivo. In addition, the inhibition of HCC827GR cell growth by combining COX2 inhibitor (celecoxib), TOPK inhibitor (pantoprazole), and gefitinib was verified ex vivo and in vivo. We found that COX2 and TOPK were highly expressed in EGFR-activating mutated NSCLC and the progression-free survival (PFS) of triple-positive (COX2, MET, and TOPK) patients was shorter than that of triple-negative patients. Then, we observed that the COX2-TXA2 signaling pathway modulated MET through AP-1, resulting in an inhibition of apoptosis in gefitinib-resistant cells. Moreover, we demonstrated that MET could phosphorylate TOPK at Tyr74 and then prevent apoptosis in gefitinib-resistant cells. In line with these findings, the combination of celecoxib, pantoprazole, and gefitinib could induce apoptosis in gefitinib-resistant cells and inhibit tumor growth ex vivo and in vivo. Our work reveals a novel COX2/MET/TOPK signaling axis that can prevent apoptosis in gefitinib-resistant cells and suggests that a triple combination of FDA-approved drugs would provide a low-cost and practical strategy to overcome gefitinib resistance.

T-lymphokine-activated killer cell-originated protein kinase (TOPK) as a prognostic factor and a potential therapeutic target in glioma.

TOPK is overexpressed in various types of cancer and associated with poor outcomes in different types of cancer. In this study, we first found that the expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) was significantly higher in Grade III or Grade IV than that in Grade II in glioma (P = 0.007 and P < 0.001, respectively). Expression of TOPK was positively correlated with Ki67 (P < 0.001). Knockdown of TOPK significantly inhibited cell growth, colony formation and increased sensitivities to temozolomide (TMZ) in U-87 MG or U-251 cells, while TOPK overexpression promoted cell growth and colony formation in Hs 683 or A-172 cells. Glioma patients expressing high levels of TOPK have poor survival compared with those expressing low levels of TOPK in high-grade or low-grade gliomas (hazard ratio = 0.2995; 95% CI, 0.1262 to 0.7108; P = 0.0063 and hazard ratio = 0.1509; 95% CI, 0.05928 to 0.3842; P < 0.0001, respectively). The level of TOPK was low in TMZ-sensitive patients compared with TMZ-resistant patients (P = 0.0056). In TMZ-resistant population, patients expressing high TOPK have two months' shorter survival time than those expressing low TOPK. Our findings demonstrated that TOPK might represent as a promising prognostic and predictive factor and potential therapeutic target for glioma.

Protein Kinases as Tumor Biomarkers and Therapeutic Targets.

Over the last three decades, neoplasms have become the largest cause of human mortality due to both high tumor incidence and mortality. Chemotherapy is one of the main therapies employed to treat neoplasms. Although classical genotoxic drugs, such as cyclophosphamide, 5-FU, cisplatin and doxorubicin have been applied in clinical settings and have achieved very good treatment efficacy, many cancer patients died of tumor metastasis, drug toxicity or drug resistance due to tumor heterogeneity. Targeted molecular treatments based on the genes, receptors, and kinases expressed by a tumor make individualized treatment possible. Protein kinases catalyze the phosphorylation of proteins and are involved in multiple cellular processes. In many cancers, mutation or abnormal expression of protein kinases is correlated with tumorigenesis, metastasis and resistance to chemotherapy. Tumor-related protein kinases have become important molecular targets and biomarkers. The use of protein kinases as tumor biomarkers primarily focuses on tyrosine and serine/threonine kinases. Many tumor drugs targeting protein kinases, such as monoclonal antibody and tyrosine kinase inhibitors (TKIs), are widely utilized in clinic. Additional drugs aimed at combating drug resistance and metastasis should be developed targeting protein kinases. In this review, we summarize several important protein kinases involved in cancer and analyze why these kinases can be used as biomarkers or targets for cancer diagnosis and/or treatment. Furthermore, numerous drugs targeting protein kinases as well as their development and activity are discussed.

The Prediction of Clinical Outcome in Hepatocellular Carcinoma Based on a Six-Gene Metastasis Signature.

PURPOSE: The dismal outcome of hepatocellular carcinoma (HCC) is largely attributed to its early recurrence and venous metastases. We aimed to develop a metastasis-related model to predict hepatocellular carcinoma prognosis. EXPERIMENTAL DESIGN: Using microarrays, sequencing, and RT-PCR, we measured the expression of mRNAs and lncRNAs in a training set of 94 well-defined low-risk (LRM) and high-risk metastatic (HRM) HCC patients from a Shanghai cohort. We refined a metastasis signature and established a corresponding model using logistic regression analysis. The validation set consisted of 567 HCC patients from four-center cohorts. Survival analysis was performed according to the metastasis model. RESULTS: Using relative expression of tumor to para-tumor tissues, we refined the metastasis signature of five mRNAs and one lncRNA. A generalized linear model was further established to predict the probability of metastasis (MP). Using MP cutoff of 0.7 to separate LRM and HRM in Shanghai cohort, the specificity and sensitivity of the model were 96% [95% confidence interval (CI), 85%-99%] and 74% (95% CI, 58%-86%), respectively. Furthermore, HRM patients showed a significantly shorter overall and recurrence-free survival in validation cohorts (P < 0.05 for each cohort). Early HCC patients also have a poorer outcome for multicenter HRM patients. Finally, Cox regression analysis indicated that continuous MP was an independent risk factor and associated with the recurrence and survival of HCC patients after resection (HR 2.98-16.6, P < 0.05). CONCLUSIONS: We developed an applicable six-gene metastasis signature, which is robust and reproducible in multicenter cohorts for HCC prognosis. Clin Cancer Res; 23(1); 289-97. ©2016 AACR.

BCKDK of BCAA Catabolism Cross-talking With the MAPK Pathway Promotes Tumorigenesis of Colorectal Cancer.

Branched-chain amino acids catabolism plays an important role in human cancers. Colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, and the new global incidence is over 1.2 million cases. The branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a rate-limiting enzyme in branched-chain amino acids catabolism, which plays an important role in many serious human diseases. Here we investigated that abnormal branched-chain amino acids catabolism in colorectal cancer is a result of the disease process, with no role in disease initiation; BCKDK is widely expressed in colorectal cancer patients, and those patients that express higher levels of BCKDK have shorter survival times than those with lower levels; BCKDK promotes cell transformation or colorectal cancer ex vivo or in vivo. Mechanistically, BCKDK promotes colorectal cancer by enhancing the MAPK signaling pathway through direct MEK phosphorylation, rather than by branched-chain amino acids catabolism. And the process above could be inhibited by a BCKDK inhibitor, phenyl butyrate.