Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway.

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1WT) as a potential diagnostic and prognostic biomarker for non-small cell lung cancer (NSCLC), but how IDH1WT modulates NSCLC progression remains elusive. Here, we report that IDH1WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1WT interacts with and stabilizes PHGDH and fragile X-related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1WT-PHGDH and IDH1WT-FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine-depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1WT in serine metabolism, highlighting IDH1WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.

Nomogram for predicting the overall survival of the patients with oesophageal signet ring cell carcinoma.

BACKGROUND: The purpose of this study was to explore the prognostic factors of oesophageal signet ring cell (SRC) carcinoma and to construct a nomogram for predicting the outcome of SRC carcinoma of oesophagus. METHODS: A total of 968 cases of oesophageal SRC carcinoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016. Cases were divided into training cohort and validation cohort. Univariate and multivariable Cox analyses was performed to select the predictors of overall survival (OS for the nomogram. The performance of nomogram was validated with Harrell's concordance index (C-index), calibration curves and decision curve analysis (DCA). RESULTS: The 1- and 5-year OS in the training cohort were 0.446 and 0.146, respectively, and the 1- and 5-year OS in the validation cohort were 0.459 and 0.138. The independent prognostic factors for establishing the nomogram were marital status, invasion of the surrounding tissue, lymph node metastasis, distant metastasis, surgery and chemotherapy. The Harrell's c-index value of the training cohort and validation cohort were 0.723 and 0.708. In the calibration curves, the predicted survival probability and the actual survival probability have a considerable consistency. DCA indicated the favourable potential clinical utility of the nomogram. CONCLUSIONS: A nomogram to predict the OS of patients with oesophageal SRC carcinoma was established. The validation of the nomogram fully demonstrates its great performance.

Clinical recommendations for perioperative immunotherapy-induced adverse events in patients with non-small cell lung cancer.

Perioperative adjuvant treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). In particular, the success of immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, in patients with lung cancer has increased our expectations for the success of these therapeutics as neoadjuvant immunotherapy. Neoadjuvant therapy is widely used in patients with resectable stage IIIA NSCLC and can reduce primary tumor and lymph node stage, improve the complete resection rate, and eliminate microsatellite foci; however, complete pathological response is rare. Moreover, because the clinical benefit of neoadjuvant therapy is not obvious and may complicate surgery, it has not yet entered the mainstream of clinical treatment. Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancellation of surgery, additional illness, and even death, and have therefore attracted much attention. In this article, we draw on several sources of information, including (i) guidelines on adverse reactions related to immune checkpoint inhibitors, (ii) published data from large-scale clinical studies in thoracic surgery, and (iii) practical experience and published cases, to provide clinical recommendations on adverse events in NSCLC patients induced by perioperative immunotherapy.

Log odds of positive lymph nodes is a better prognostic factor for oesophageal signet ring cell carcinoma than N stage.

BACKGROUND: Signet ring cell carcinoma is a rare type of oesophageal cancer, and we hypothesized that log odds of positive lymph nodes (LODDS) is a better prognostic factor for oesophageal signet ring cell carcinoma. AIM: To explore a novel prognostic factor for oesophageal signet ring cell carcinoma by comparing two lymph node-related prognostic factors, log odds of positive LODDS and N stage. METHODS: A total of 259 cases of oesophageal signet ring cell carcinoma after oesopha-gectomy were obtained from the Surveillance, Epidemiology, and End Results database between 2006 and 2016. The prognostic value of LODDS and N stage for oesophageal signet ring cell carcinoma was evaluated by univariate and multivariate analyses. The Akaike information criterion and Harrell's C-index were used to assess the value of two prediction models based on lymph nodes. External validation was performed to further confirm the conclusion. RESULTS: The 5-year cancer-specific survival (CSS) and 5-year overall survival (OS) rates of all the cases were 41.3% and 27.0%, respectively. The Kaplan-Meier method showed that LODDS had a higher score of log rank chi-squared (OS: 46.162, CSS: 41.178) than N stage (OS: 36.215, CSS: 31.583). Univariate analyses showed that insurance, race, T stage, M stage, TNM stage, radiation therapy, N stage, and LODDS were potential prognostic factors for OS (P < 0.1). The multivariate Cox regression model showed that LODDS was an significant independent prognostic factor for oesophageal signet ring carcinoma patients after surgical resection (P < 0.05), while N stage was not considered to be a significant prognostic factor (P = 0.122). Model 2 (LODDS) had a higher degree of discrimination and fit than Model 1 (N stage) (LODDS vs N stage, Harell's C-index 0.673 vs 0.656, P < 0.001; Akaike information criterion 1688.824 vs 1697.519, P < 0.001). The results of external validation were consistent with those in the study cohort. CONCLUSION: LODDS is a superior prognostic factor to N stage for patients with oesophageal signet ring cell carcinoma after oesophagectomy.

TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target.

High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.

Disruption of the EGFR-SQSTM1 interaction by a stapled peptide suppresses lung cancer via activating autophagy and inhibiting EGFR signaling.

Despite the success of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations, intrinsic or acquired resistance remains the major obstacle to long-term disease remission. Defective autophagy has been reported as an EGFR-TKI resistance mechanism. However, how EGFR regulate autophagic flux are still not fully understood. Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking. SAH-EJ2, a staple optimized EGFR-derived peptide, showed enhanced in vitro and in vivo antitumor activity against NSCLC than the prototype regardless of EGFR mutation status. Mechanistically, SAH-EJ2 disrupts the EGFR-SQSTM1 interaction and protects against EGFR-induced SQSTM1 phosphorylation, which hinders the dimerization of the SQSTM1 UBA domains and restores SQSTM1 cargo function. Moreover, SAH-EJ2 suppresses EGFR activity by blocking its dimerization and reducing its protein stability, which reciprocally activates the core autophagy machinery. Our observations reveal that disturbing the EGFR-SQSTM1 interaction by SAH-EJ2 confers a potential strategy in the treatment of NSCLC through suppressing EGFR signalling and activating autophagy simultaneously.

Genetic landscape of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

[Nationwide speaking tour of standardized diagnosis and treatment for esophageal cancer].

For a long time, the diagnosis and treatment protocol for esophageal cancer has been made either entirely based on the experience of Western countries or on our own experience alone. A suitable standardized guideline for diagnosis and treatment of esophageal cancer in our country has not been established until 2010. Due to lack of opportunities for mutual exchange and learning, the overall level of standardized diagnosis and treatment was relatively low in China. In addition, less advanced technologies were applied and varying treatment protocols were implemented in different districts, the treatment results has been unsatisfactory, and the overall 5-year survival rate after surgical treatment has been maintained from 30% to 40%. Therefore, it is imperative that China needs to conduct its own clinical studies and establish its own suitable standardized treatment and diagnosis guideline for esophageal cancer. This article reviews and also made comments on the process of academic speaking tour and development of standardized diagnosis and treatment guidelines as well as the problems resolved by these activities for esophageal cancer since the beginning of this century.

[Preliminary experience of clinical applications of the 7th UICC-AJCC TNM staging system of esophageal carcinoma].

OBJECTIVE: To compare the instructive value of the 6th and 7th editions of the UICC-AJCC staging system in prognosis of esophageal cancer (EC) patients. METHODS: The staging and prognosis of 1397 esophageal carcinoma patients undergoing curative resection from Jan. 2003 to Dec. 2006 in our hospital were retrospectively reviewed and analyzed according to the 6th AJCC staging system and the 7th UICC-AJCC staging system. RESULTS: The 5-year overall survival (OS) of EC patients with curative resection was 38.5% (481/1250 cases), with a follow-up rate of 89.5% (1250/1397 case). In overall terms, both the editions were statistically significant discriminators of OS (P < 0.05). The 5-year OS of stages I, II and III patients were 64.9%, 43.5%, 25.2% according to the 6th edition, and 63.5%, 44.5%, 23.5% according to the 7th edition, respectively. Distinct differences in survival were present among patients categorized as stage Ia and Ib according to the 7th edition (P < 0.05), with a 5-year OS of 80.0% and 58.3%, respectively. Similarly, according to the 7th edition, the 5-year overall survivals (OS) of the stages IIIa, IIIb and IIIc patients were 28.2%, 18.4% and 16.7%, respectively, showing that the prognoses were significantly different (P < 0.05). In addition, according to the 7th edition, the prognoses of patients in stages N0, N1, N2 and N3 were also significantly different (P < 0.01), and the 5-year OS were 50.0%, 31.5%, 18.7% and 16.7%, respectively. CONCLUSIONS: Both the 6th and 7th editions of UICC-AJCC staging system are significant discriminators for survival of esophageal cancer patients. The 7th edition is proved to be more accurate in prognosis. The number of lymph node metastases is an important predictor of prognosis.

[Diagnosis and surgical treatment of pulmonary sclerosing hemangioma].

OBJECTIVE: As a rare benign lung tumor, pulmonary sclerosing hemangioma (PSH) occurs predominantly in Asian women in their fifth and sixth decades of life. PSH is considered to be evolved from primitive undifferentiated respiratory epithelium. In this study, we summarized our experience in 89 cases of PSH. METHOD: There were a total of 89 patients who received surgical resection and were histopathologically diagnosed as PSH during the period January 2001 to December 2010 in department of thoracic surgery, Cancer Institute and Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences. The clinical data of these patients including symptoms, disease courses, image characteristics and surgical procedures were collected and reviewed retrospectively. RESULTS: The PSHs were most frequently (50.6%) found in the patients aged 41 to 60 years with a median age of 51 years (range: 24 - 71), and the sex ratio (male/female) was approximately 1:7 in this series. In the 89 patients, 53 (59.6%) were asymptomatic while the other 36 (40.4%) had some non-special symptoms such as cough (30.3%), hemoptysis (24.7%). There were only 3 cases (3.4%) with multiple PSHs, 4 cases (4.5%) combined with synchronous primary lung cancer, and 13 cases (14.6%) with lesions located in the hilar region. The median diameter of the 92 lesions was 2.3 cm (range: 0.3 - 6.0 cm), of which 38% located in the right lower lobe and 26.1% in the right middle lobe, and only about 1/3 were assumed as PSHs preoperatively based on CT imaging. One of the five patients who underwent PET-CT scan had been misdiagnosed as malignant. Of the 92 lesions, 47 were resected by enucleation, 29 by wedge resection, 14 by lobectomy, and 2 by pneumonectomy. CONCLUSION: PSH frequently occurs in the middle-aged women. Most individuals with PSH are asymptomatic or have some non-specific symptoms. Their lesions are usually found accidentally by chest imaging. Although PSH often shows typical imaging characteristics of benign neoplasm of the lung, it is difficult to establish a defined pathological diagnosis preoperatively. The significant error or deferred rate of intraoperative frozen-section evaluation for PSH may result in some unnecessarily extensive surgical procedures. The complete surgical resection is considered the only effective treatment for PSH, and the normal pulmonary tissue should be reserved as possible.

[Relationship between ROCK2 expression and clinicopathologic characteristics of esophageal squamous cell carcinoma].

OBJECTIVE: To investigate the expression and relationship of Rho-associated protein kinase 2 (ROCK2) and clinical characteristics in esophageal squamous cell carcinoma (ESCC). METHODS: Immunohistochemistry was performed to assay the expression of ROCK2 in tumor tissues and adjacent normal epithelium from 118 ESCC patients in tissue microarray. The relationship between ROCK2 level and clinicopathologic profiles such as age, gender, location, smoking, differentiation degree, T stage, lymph node metastasis and TNM stage were analyzed. RESULTS: The ROCK2 expression was up-regulated in 54 of 118 (45.76%) ESCC tissues. The up-regulated expression of ROCK2 was observed in 55.74% (34/61) ESCC tissues of patients under 61 years old. And it was significantly higher than that in 35.09% (20/57) of patients over 61 years old (χ(2) = 5.062, P = 0.024). In addition, the rate of up-regulation of ROCK2 was significantly higher in high-grade differentiation group (58.70%, 27/46) than that in moderate-grade and low-grade differentiation group (37.50%, 27/72) (χ(2) = 5.080, P = 0.024). CONCLUSION: The up-regulated expression of ROCK2 is correlated with patient age and differentiation grade of ESCC.

miR-29c induces cell cycle arrest in esophageal squamous cell carcinoma by modulating cyclin E expression.

Cyclin E is reported to be an important cell cycle regulator, and its dysregulation is implicated in tumorigenesis including esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) regulate gene expression at the posttranscriptional level and play important roles in tumor initiation and progression. However, the regulation of cyclin E by miRNAs is still unclear in ESCC. In the present study, we found that overexpression of miR-29c inhibited cyclin E expression by targeting 3' untranslated region of cyclin E messenger RNA in ESCC cells. Moreover, overexpression of miR-29c induced cell cycle G(1)/G(0) arrest through suppression of cyclin E expression, without affecting other G(1) phase-related proteins level, such as cyclin D1, cyclin D2, cyclin dependent kinase (CDK) 2 and CDK6. Furthermore, we demonstrated that overexpression of miR-29c inhibited proliferation of ESCC cells in vitro and in vivo. In addition, we detected miR-29c expression in 26 pairs of esophageal tumor-in-site-tissues and 60 pairs of ESCC tissues. The result showed that miR-29c level significantly decreased in ESCC tumor tissues and cell lines compared with normal esophageal epithelia. Taken together, our findings indicated that miR-29c was frequently downregulated in ESCC tissues and cells and suppressed tumor growth by inducing cell cycle G(1)/G(0) arrest mainly through modulating cyclin E expression.

microRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin.

microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play important roles in tumor initiation and progression. Recently, we examined the global miRNA expression profile of esophageal squamous cell carcinoma (ESCC) and demonstrated that miR-92a was highly expressed in tumor tissues. In this study, we found that the up-regulation of miR-92a was significantly correlated with the status of lymph node metastasis and TNM stage in 107 ESCC patients. Moreover, the up-regulation of miR-92a was associated with poor survival of ESCC patients and might be used as an independent prognostic factor. Next, we investigated the role and mechanism of miR-92a in ESCC cells, and found that miR-92a modulated the migration and invasion but not apoptosis and proliferation of ESCC cells in vitro. We further demonstrated that miR-92a directly targeted the CDH1 3'-UTR and repressed the expression of CDH1, a tumor metastasis suppressor. In addition, restoring of miR-92a-resistant CDH1 expression in miR-92a-overexpression cells recovered the pro-metastasis activity of miR-92a. Taken together, we demonstrated that miR-92a promotes ESCC cell migration and invasion at least partially via suppression of CDH1 expression, and patients with up-regulated miR-92a are prone to lymph node metastasis and thus have poor prognosis.

[Correlations between 14-3-3ε expression and clinicopathological factors and prognosis in patients with esophageal squamous cell carcinoma].

OBJECTIVE: To investigate the expression of 14-3-3ε in esophageal squamous cell carcinoma (ESCC) and relationship of 14-3-3ε and clinicopathological factors of ECSS patients. METHODS: The 14-3-3ε expression in tumors and adjacent normal epithelia from 72 ESCC patients was detected by immunohistochemical staining. Correlations of 14-3-3ε expression or their subcellular localization and clinicopathological factors were analyzed using Chi-squared test. Survival curves were generated according to the Kaplan-Meier method, and the statistical analysis was performed by Log-rank test. RESULTS: The expression of 14-3-3ε protein was significantly up-regulated in tumors with 77.8% positive and 27.8% strong positive staining, compared with paired adjacent normal epithelia with 43.1% positive and only 2.8% strong positive staining (P < 0.01). In a total of 56 positive staining tumors, 14-3-3ε was detected in cytoplasm of 37 (66.1%), in nucleus of 4 (7.1%), in both cytoplasm and nucleus of 15 (26.8%) cases. Whereas, in a total of 31 positive staining normal epithelia, 14-3-3ε was detected in cytoplasm of 0, in nucleus of 13 (41.9%), in both cytoplasm and nucleus of 18 (58.1%) cases (P < 0.01). Statistical analysis revealed that strong 14-3-3ε expression was correlated with lymph node metastasis (P = 0.028) and lower 5-year survival (P = 0.018). The survival curves calculated by Kaplan-Meier method further showed that the patients with strong 14-3-3ε expression had a shorter survival than patients with negative or weak 14-3-3ε expression (Log-rank, P = 0.031). No correlation was found between subcellular localization of 14-3-3ε in tumor cells and clinicopathologic factors and prognosis of ESCC patients. CONCLUSION: The 14-3-3ε expression is significantly up-regulated in ESCCs. It was usually located in cytoplasm of tumor cells, but nucleus of normal epithelia. Strong expression of 14-3-3ε in tumors is associated with lymph node metastasis and considered as an poor prognostic factor for ESCC.