Sensory perception, including thermosensation, shapes longevity in diverse organisms, but longevity-modulating signals from the sensory neurons are largely obscure. Here we show that CRH-1/CREB activation by CMK-1/CaMKI in the AFD thermosensory neuron is a key mechanism that maintains lifespan at warm temperatures in C. elegans. In response to temperature rise and crh-1 activation, the AFD neurons produce and secrete the FMRFamide neuropeptide FLP-6. Both CRH-1 and FLP-6 are necessary and sufficient for longevity at warm temperatures. Our data suggest that FLP-6 targets the AIY interneurons and engages DAF-9 sterol hormone signaling. Moreover, we show that FLP-6 signaling downregulates ins-7/insulin-like peptide and several insulin pathway genes, whose activity compromises lifespan. Our work illustrates how temperature experience is integrated by the thermosensory circuit to generate neuropeptide signals that remodel insulin and sterol hormone signaling and reveals a neuronal-endocrine circuit driven by thermosensation to promote temperature-specific longevity.

Gastric carcinoma is one of the most common malignancies and the second most lethal cancer worldwide. The mechanisms underlying aggressiveness of gastric cancer still remain obscure. c-Myc promoter binding protein 1 (MBP-1) is a negative regulator of c-myc expression and ubiquitously expressed in normal human tissues. It is produced by alternative translation initiation of α-enolase gene. Both MBP-1 and α-enolase are involved in the control of tumorigenesis including gastric cancer. MicroRNAs (miRNAs) are involved in tumorigenesis and could have diagnostic, prognostic and therapeutic potential. In this study, whether miRNAs modulate tumorigenesis of gastric cancer cells through targeting MBP-1 was evaluated. We found that miR-363 targets 3'-untranslated region of human MBP-1/α-enolase messenger RNA. The exogenous miR-363 promotes growth, viability, progression, epithelial-mesenchymal transition and tumorsphere formation of SC-M1 gastric cancer cells through downregulation of MBP-1, whereas the knockdown of endogenous miR-363 suppresses tumorigenesis and progression of SC-M1 cells via upregulation of MBP-1. The miR-363/MBP-1 axis is also involved in the control of carcinogenesis in KATO III and SNU-16 gastric cancer cells. Furthermore, miR-363 induces the xenografted tumor growth and lung metastasis of SC-M1 cells through MBP-1 in vivo. Taken together, these results suggest that miR-363 plays an important role in the increment of gastric carcinogenesis via targeting MBP-1.

We validated an 18-gene classifier (GC) initially developed to predict local/regional recurrence after mastectomy in estimating distant metastasis risk. The 18-gene scoring algorithm defines scores as: <21, low risk; ≥21, high risk. Six hundred eighty-three patients with primary operable breast cancer and fresh frozen tumor tissues available were included. The primary outcome was the 5-year probability of freedom from distant metastasis (DMFP). Two external datasets were used to test the predictive accuracy of 18-GC. The 5-year rates of DMFP for patients classified as low-risk (n = 146, 21.7%) and high-risk (n = 537, 78.6%) were 96.2% (95% CI, 91.1%–98.8%) and 80.9% (74.6%–81.9%), respectively (median follow-up interval, 71.8 months). The 5-year rates of DMFP of the low-risk group in stage I (n = 62, 35.6%), stage II (n = 66, 20.1%), and stage III (n = 18, 10.3%) were 100%, 94.2% (78.5%–98.5%), and 90.9% (50.8%–98.7%), respectively. Multivariate analysis revealed that 18-GC is an independent prognostic factor of distant metastasis (adjusted hazard ratio, 5.1; 95% CI, 1.8–14.1; p = 0.0017) for scores of ≥21. External validation showed that the 5-year rate of DMFP in the low- and high-risk patients was 94.1% (82.9%–100%) and 80.3% (70.7%–89.9%, p = 0.06) in a Singapore dataset, and 89.5% (81.9%–94.1%) and 73.6% (67.2%–79.0%, p = 0.0039) in the GEO-GSE20685 dataset, respectively. In conclusion, 18-GC is a viable prognostic biomarker for breast cancer to estimate distant metastasis risk.

Recurrent triple‐negative breast cancer (TNBC) needs new therapeutic targets. Src homology region 2 domain‐containing phosphatase‐1 (SHP‐1) can act as a tumor suppressor by dephosphorylating oncogenic kinases. One major target of SHP‐1 is STAT3, which is highly activated in TNBC. In this study, we tested a sorafenib analogue SC‐60, which lacks angiokinase inhibition activity, but acts as a SHP‐1 agonist, in TNBC cells. SC‐60 inhibited proliferation and induced apoptosis by dephosphorylating STAT3 in both a dose‐ and time‐dependent manner in TNBC cells (MDA‐MB‐231, MDA‐MB‐468, and HCC1937). By contrast, ectopic expression of STAT3 rescued the anticancer effect induced by SC‐60. SC‐60 also increased the SHP‐1 activity, but this effect was inhibited when the N‐SH2 domain (DN1) was deleted or with SHP‐1 point mutation (D61A), implying that SHP‐1 is the major target of SC‐60 in TNBC. The use of SC‐60 in combination with docetaxel synergized the anticancer effect induced by SC‐60 through the SHP‐1/STAT3 pathway in TNBC cells. Importantly, SC‐60 also displayed a significant antitumor effect in an MDA‐MB‐468 xenograft model by modulating the SHP‐1/STAT3 axis, indicating the anticancer potential of SC‐60 in TNBC treatment. Targeting SHP‐1/p‐STAT3 and the potential combination of SHP‐1 agonist with chemotherapeutic docetaxel is a feasible therapeutic strategy for TNBC.

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We previously identified 34 genes of interest (GOI) in 2006 to aid the oncologists to determine whether post-mastectomy radiotherapy (PMRT) is indicated for certain patients with breast cancer. At this time, an independent cohort of 135 patients having DNA microarray study available from the primary tumor tissue samples was chosen. Inclusion criteria were 1) mastectomy as the first treatment, 2) pathology stages I-III, 3) any locoregional recurrence (LRR) and 4) no PMRT. After inter-platform data integration of Affymetrix U95 and U133 Plus 2.0 arrays and quantile normalization, in this paper we used 18 of 34 GOI to divide the mastectomy patients into high and low risk groups. The 5-year rate of freedom from LRR in the high-risk group was 30%. In contrast, in the low-risk group it was 99% (p < 0.0001). Multivariate analysis revealed that the 18-gene classifier independently predicts rates of LRR regardless of nodal status or cancer subtype.

The 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a potential regulatory node in the mevalonate pathway that is frequently dysregulated in tumors. This study found that HMGCS1 expression is upregulated in stomach adenocarcinoma samples of patients and tumorspheres of gastric cancer cells. HMGCS1 elevates the expression levels of the pluripotency genes Oct4 and SOX-2 and contributes to tumorsphere formation ability in gastric cancer cells. HMGCS1 also promotes in vitro cell growth and progression and the in vivo tumor growth and lung metastasis of gastric cancer cells. After blocking the mevalonate pathway by statin and dipyridamole, HMGCS1 exerts nonmetabolic functions in enhancing gastric cancer progression. Furthermore, the level and nuclear translocation of HMGCS1 in gastric cancer cells are induced by serum deprivation. HMGCS1 binds to and activates Oct4 and SOX-2 promoters. HMGCS1 also enhances the integrated stress response (ISR) and interacts with the endoplasmic reticulum (ER) stress transducer protein kinase RNA-like endoplasmic reticulum kinase (PERK). Our results reveal that HMGCS1 contributes to gastric cancer progression in both metabolic and nonmetabolic manners.

Background: Triple-negative breast cancer (TNBC) is aggressive and has a poor prognosis. Kynurenine 3-monooxygenase (KMO), a crucial kynurenine metabolic enzyme, is involved in inflammation, immune response and tumorigenesis. We aimed to study the role of KMO in TNBC. Methods: KMO alteration and expression data from public databases were analyzed. KMO expression levels in TNBC samples were analyzed using immunohistochemistry. Knockdown of KMO in TNBC cells was achieved by RNAi and CRISPR/Cas9. KMO functions were examined by MTT, colony-forming, transwell migration/invasion, and mammosphere assays. The molecular events were analyzed by cDNA microarrays, Western blot, quantitative real-time PCR and luciferase reporter assays. Tumor growth and metastasis were detected by orthotopic xenograft and tail vein metastasis mouse models, respectively. Findings: KMO was amplified and associated with worse survival in breast cancer patients. KMO expression levels were higher in TNBC tumors compared to adjacent normal mammary tissues. In vitro ectopic KMO expression increased cell growth, colony and mammosphere formation, migration, invasion as well as mesenchymal marker expression levels in TNBC cells. In addition, KMO increased pluripotent gene expression levels and promoter activities in vitro. Mechanistically, KMO was associated with b-catenin and prevented b-catenin degradation, thereby enhancing the transcription of pluripotent genes. KMO knockdown suppressed tumor growth and the expression levels of b-catenin, CD44 and Nanog. Furthermore, mutant KMO (known with suppressed enzymatic activity) could still promote TNBC cell migration/invasion. Importantly, mice bearing CRISPR KMO-knockdown TNBC tumors showed decreased lung metastasis and prolonged survival. Interpretation: KMO regulates pluripotent genes via b-catenin and plays an oncogenic role in TNBC progression.