Defect of SLC38A3 promotes epithelial-mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma

Objective: Solute carrier family 38(SLC38 s) transporters play important roles in amino acid transportation and signaling transduction. However, their genetic alterations and biological roles in tumors are still largely unclear.This study aimed to elucidate the genetic signatures of SLC38 s transporters and their implications in esophageal squamous cell carcinoma(ESCC).Methods: Analyses on somatic mutation and copy number alterations(CNAs) of SLC38 A3 were performed as described. Immunohistochemistry(IHC) assay and Western blot assay were used to detect the protein expression level. MTS assay, colony formation assay, transwell assay and wound healing assay were used to explore the malignant phenotypes of ESCC cells. Immunofluorescence assay was used to verify the colocalization of two indicated proteins and immunopreciptation assay was performed to confirm the interaction of proteins.Results: Our findings revealed that SLC38 s family was significantly disrupted in ESCC, with high frequent CNAs and few somatic mutations. SLC38 A3 was the most frequent loss gene among them and was linked to poor survival and lymph node metastasis. The expression of SLC38 A3 was lower in tumor tissues compared to that in normal tissues, which was also significantly associated with worse clinical outcome. Further experiments revealed that depletion of SLC38 A3 could promote EMT in ESCC cell lines, and the interaction of SLC38 A3 and SETDB1 might lead to the reduced transcription of Snail. Pharmacogenomic analyses demonstrated that fifteen inhibitors were showed significantly correlated with SLC38 A3 expression.Conclusions: Our investigations have provided insights that SLC38 A3 could act as a suppressor in EMT pathway and serve as a prognostic factor and predictor of differential drug sensitivities in ESCC.

达芬奇机器人手术系统在肥胖或高龄合并子宫内膜癌患者治疗中的应用

子宫内膜癌是常见的女性生殖系统恶性肿瘤,肥胖和年龄是子宫内膜癌的危险因素。肥胖对患者的生理尤其是呼吸循环系统产生影响,腹壁较厚的脂肪层也给手术带来挑战。高龄患者的器官功能衰弱、代偿能力差、常常不可耐受创伤较大的手术。近年来,达芬奇机器人手术系统(Da Vinci surgical system,DVSS)在肥胖或高龄合并子宫内膜癌患者的微创治疗中得到广泛地应用,并获得良好的临床疗效。与传统腹腔镜相比,DVSS显示出较明显的优势。本文就DVSS在肥胖或高龄合并子宫内膜癌患者治疗中的应用进行综述。

CDK7-YAP-LDHD axis promotes D-lactate elimination and ferroptosis defense to support cancer stem cell-like properties

Reprogrammed cellular metabolism is essential for maintaining cancer stem cells(CSCs)state.Here,we report that mitochondrial D-lactate catabolism is a necessary initiating oncogenic event during tumorigenesis of esophageal squamous cell carcinoma(ESCC).We discover that cyclin-dependent kinase 7(CDK7)phosphorylates nuclear Yes-associated protein 1(YAP)at S127 and S397 sites and enhances its transcription function,which promotes D-lactate dehydrogenase(LDHD)protein expression.Moreover,LDHD is enriched significantly in ESCC-CSCs rather than differentiated tumor cells and high LDHD status is connected with poor prognosis in ESCC patients.Mechanistically,the CDK7-YAP-LDHD axis helps ESCC-CSCs escape from ferroptosis induced by D-lactate and generates pyruvate to satisfy energetic demands for their elevated self-renewal potential.Hence,we conclude that esophageal CSCs adopt a D-lactate elimination and pyruvate accumulation mode dependent on CDK7-YAP-LDHD axis,which drives stemness-associated hallmarks of ESCC-CSCs.Reasonably,targeting metabolic checkpoints may serve as an effective strategy for ESCC therapy.

Chrysin serves as a novel inhibitor of DGKα/FAK interaction to suppress the malignancy of esophageal squamous cell carcinoma(ESCC)

Among current novel druggable targets,proteineprotein interactions(PPIs)are of considerable and growing interest.Diacylglycerol kinase a(DGKα)interacts with focal adhesion kinase(FAK)band 4.1-ezrin-radixin-moesin(FERM)domain to induce the phosphorylation of FAK Tyr397 site and promotes the malignant progression of esophageal squamous cell carcinoma(ESCC)cells.Chrysin is a multi-functional bioactive flavonoid,and possesses potential anticancer activity,whereas little is known about the anticancer activity and exact molecular mechanisms of chrysin in ESCC treatment.In this study,we found that chrysin significantly disrupted the DGKα/FAK signalosome to inhibit FAKcontrolled signaling pathways and the malignant progression of ESCC cells both in vitro and in vivo,whereas produced no toxicity to the normal cells.Molecular validation specifically demonstrated that Asp435 site in the catalytic domain of DGKαcontributed to chrysin-mediated inhibition of the assembly of DGKα/FAK complex.This study has illustrated DGKα/FAK complex as a target of chrysin for the first time,and provided a direction for the development of natural products-derived PPIs inhibitors in tumor treatment.

Membranous NOX5-derived ROS oxidizes and activates local Src to promote malignancy of tumor cells

Reactive oxygen species(ROS)localized at the precise subcellular compartments are essential for regulating the activity of signaling proteins.Furthermore,ROS are master regulators of tumor malignant progression that respond to a diverse set of environmental stress,especially hypoxia.NADPH oxidases(NOXs)appear to be activated within discrete subcellular compartments to facilitate local ROS production.However,the subcellular function of NOXs in hypoxic tumor is still unclear.In this study,we demonstrated that NOX5 was greatly upregulated in clinical esophageal squamous cell carcinoma(ESCC)tumors,ESCC cell lines or primary ESCC cells,and elevated NOX5 was correlated to malignancy of ESCC tumors and poor prognosis.NOX5 induced the malignant progression of ESCC by activating Src,especially under hypoxic condition.Mechanistically,we showed that hypoxia promoted the interaction between NOX5 and Pyk2 on cell membrane via facilitating Ca^(2+)-mediated Pyk2 Tyr^(402)site phosphorylation.Subsequently,Pyk2 acted as a scaffold for c-Abl phosphorylating the catalytic domain of NOX5 Tyr^(476/478)sites,which in turn upregulated hydrogen peroxide(H_(2)O_(2))inside the Pyk2/NOX5 complex to oxidize and activate local Src.These findings provide insights into the biological significance of NOX5 in the development of ESCC.

Accumulation and Dynamic Trends of Triterpenoid Saponin in Vegetative Organs of Achyranthus bidentata

The relationship between structural features of various vegetative organs and triterpenoid saponin accumulation in Achyranthus bidentata Blume was investigated using anatomy, histochemistry and phytochemistry. The results showed that the primary and secondary structures of roots, and the structures of stems and leaves of A. bidentata, were similar to those of ordinary dicotyledonous plants. The enlargement of its roots, however, was primarily associated with growth and differentiation of tertiary structures. There were collateral medullary vascular bundles in addition to the normal vascular bundles in the stem. The tertiary structure was not only main parts in the roots of A. bidentata, but also important storage region of triterpenoid saponin in its growth and development. The stem may be the essential transport organ of triterpenoid saponin, while palisade parenchyma may be the primary synthesis location. In November, the total quantity of triterpenoid saponin and overall biomass in the roots reach a maximum level. This was the best time, therefore, to harvest the roots and corresponded to the traditional harvest period. Despite the withered appearance of leaves, stems also contained substantial amounts of triterpenoid saponin, and it was recommended that the stems of A. bidentata should be used.