Golgi dispersal in cancer stem cells promotes chemoresistance of colorectal cancer via the Golgi stress response.

Chemotherapy is a crucial treatment for colorectal tumors. However, its efficacy is restricted by chemoresistance. Recently, Golgi dispersal has been suggested to be a potential response to chemotherapy, particularly to drugs that induce DNA damage. However, the underlying mechanisms by which Golgi dispersal enhances the capacity to resist DNA-damaging agents remain unclear. Here, we demonstrated that DNA-damaging agents triggered Golgi dispersal in colorectal cancer (CRC), and cancer stem cells (CSCs) possessed a greater degree of Golgi dispersal compared with differentiated cancer cells (non-CSCs). We further revealed that Golgi dispersal conferred resistance against the lethal effects of DNA-damaging agents. Momentously, Golgi dispersal activated the Golgi stress response via the PKCα/GSK3α/TFE3 axis, resulting in enhanced protein and vesicle trafficking, which facilitated drug efflux through ABCG2. Identification of Golgi dispersal indicated an unexpected pathway regulating chemoresistance in CRC.

Nuclear Softness Promotes the Metastatic Potential of Large-Nucleated Colorectal Cancer Cells via the ErbB4-Akt1-Lamin A/C Signaling Pathway.

Abnormal nuclear enlargement is a diagnostic and physical hallmark of malignant tumors. Large nuclei are positively associated with an increased risk of developing metastasis; however, a large nucleus is inevitably more resistant to cell migration due to its size. The present study demonstrated that the nuclear size of primary colorectal cancer (CRC) cells at an advanced stage was larger than cells at an early stage. In addition, the nuclei of CRC liver metastases were larger than those of the corresponding primary CRC tissues. CRC cells were sorted into large-nucleated cells (LNCs) and small-nucleated cells (SNCs). Purified LNCs exhibited greater constricted migratory and metastatic capacity than SNCs in vitro and in vivo. Mechanistically, ErbB4 was highly expressed in LNCs, which phosphorylated lamin A/C at serine 22 via the ErbB4-Akt1 signaling pathway. Furthermore, the level of phosphorylated lamin A/C was a negative determinant of nuclear stiffness. Taken together, CRC LNCs possessed greater constricted migratory and metastatic potential than SNCs due to ErbB4-Akt1-mediated lamin A/C phosphorylation and nuclear softening. These results may provide a potential treatment strategy for tumor metastasis by targeting nuclear stiffness in patients with cancer, particularly CRC.

An Unusual Cause of Intestinal Ulcers Masquerading as Inflammatory Bowel Disease: A Case Report of Allied Disorders of Hirschsprung's Disease.

Background: Allied disorders of Hirschsprung's disease (ADHD) exhibit symptoms akin to those of Hirschsprung's disease, primarily characterized by intestinal obstruction, bowel dilatation, and chronic constipation. The occurrence of amyloid complications in patients with ADHD is infrequent. In this report, we present a case of ADHD with intestinal ulcers as the initial gastrointestinal manifestation, and subsequent pathological examination revealed the presence of amyloid deposits in the colonic mucosa. Case Report: A male patient, aged 20, exhibited recurring abdominal distension and intestinal obstruction for a duration of three years. Multiple colonoscopies revealed the presence of recurrent colonic ulcers, with pathological examination indicating the existence of amyloid deposits within the mucosal layer of the colon. Abdominal CT scans suggested colonic dilatation. Following a multidisciplinary consultation, a subtotal resection of the colon was performed, and subsequent postoperative pathology confirmed a decrease and absence of myenteric plexus ganglion cells. Considering the patient's symptoms and the findings from the postoperative pathology, a diagnosis of ADHD was made. The patient's symptoms resolved postoperatively and he was discharged from the hospital and followed up for 1 year in stable condition. Conclusion: Our study highlights the potential association between ADHD and the initial presentation of recurrent colonic ulcers, accompanied by amyloid deposition in the intestinal mucosa. This finding suggests a possible pathogenic mechanism for ADHD and offers a novel perspective on its diagnosis.

Knowledge, attitude, and practice of monitoring early gastric cancer after endoscopic submucosal dissection.

BACKGROUND: Early gastric cancer (EGC) is typically treated with endoscopic submucosal dissection (ESD). However, recurrence may occur after ESD, requiring surveillance. AIM: To examine the knowledge, attitude, and practice (KAP) of EGC survivors following ESD regarding gastric cancer recurrence. METHODS: This cross-sectional study was conducted between June 1, 2022 and October 1, 2022 in Zhejiang, China. A total of 400 EGC survivors who underwent ESD at the Affiliated Jinhua Hospital, Zhejiang University School of Medicine participated in this study. A self-administered questionnaire was developed to assess KAP monitoring gastric cancer after ESD. RESULTS: The average scores for KAP were 3.34, 23.76, and 5.75 out of 5, 30, and 11, respectively. Pearson correlation analysis revealed positive and significant correlations between knowledge and attitude, knowledge and practice, and attitude and practice (r = 0.405, 0.511, and 0.458, respectively; all P < 0.001). Multivariate logistic regression analysis showed that knowledge, attitude, 13-24 mo since the last ESD (vs ≤ 12 mo since the last ESD), and ≥ 25 mo since the last ESD (vs ≤ 12 mo since the last ESD) were independent predictors of proactive practice (odds ratio = 1.916, 1.253, 3.296, and 5.768, respectively, all P < 0.0001). CONCLUSION: EGC survivors showed inadequate knowledge, positive attitude, and poor practices in monitoring recurrences after ESD. Adequate knowledge, positive attitude, and a longer time since the last ESD were associated with practice.

A novel hepatocellular carcinoma-specific mTORC1-related signature for anticipating prognosis and immunotherapy.

Tumor oncogenesis, cancer metastasis, and immune evasion were substantially impacted by the mammalian target of the rapamycin complex 1 (mTORC1) pathway. However, in hepatocellular carcinoma (HCC), no mTORC1 signaling-based gene signature has ever been published. mTORC1 scores were computed employing a single sample gene set enrichment analysis based on databases including the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). The PAG1, LHFPL2, and FABP5 expression levels were obtained to construct a mTORC1 pathway-related model. In two databases, the overall survival (OS) rate was shorter for high-mTORC1 score patients compared to those with low scores. The activation of TFs in the group with high risk was enhanced, such as the HIF-1 pathway. Additionally, it was discovered that a high mTORC1 score was linked to an immune exclusion phenotype and enhanced immunosuppressive cell infiltration. Notably, it was discovered that high-mTORC1 scores patients had poorer immunotherapeutic results and might not gain benefit from immunotherapy. When compared to the low HCC metastatic cell lines, the high HCC metastatic cell lines have overexpressed levels of PAG1, LHFPL2, and FABP5 expression. The expression of PAG1, LHFPL2, and FABP5 was inhibited by the MAPK and mTORC1 pathway inhibitors. Our study identified mTORC1 score signature can aid in the development of individualized immunotherapy protocols and predict the HCC patients' prognoses.

An unusual cause of gastrointestinal bleeding: adult mixed-type Henoch-Schönlein purpura.

A 25-year-old man presented with 3-day history of abdominal pain, vomiting, diarrhea, and bloody stools. The contrast-enhanced CT examination of the abdomen detected thickening and edema of intestinal canal wall. The complete colonoscopy showed hyperemia, dropsy and erosion in the sigmoid colon and rectum. The biopsies revealed obvious bleeding points in mucosa. Then, wireless capsule endoscopy (OMOM ® JS-ME-I) was carried out and showed multiple lesions in the entire small intestine with diffused hyperemia, dropsy and erosion, even multiple and large ulcers. Subsequently, symmetrical scattered purpura distributed over the extensor surfaces of the lower limbs. Hence, a firm diagnosis of adult mixed-type Henoch-Schönlein purpura (HSP) was made. With the use of methylprednisolone, the patient was recovered. The patient remained well during our follow-up.

Lactate promotes metastasis of normoxic colorectal cancer stem cells through PGC-1α-mediated oxidative phosphorylation.

Uneven oxygen supply in solid tumors leads to hypoxic and normoxic regions. Hypoxic cells exhibit increased secretion of lactate, which creates an acidic tumor microenvironment (TME). This acidic TME is positively associated with tumor metastasis. Despite the increased metastatic capacity of hypoxic cells, they are located relatively further away from the blood vessels and have limited access to the circulatory system. Studies have shown that cancer stem cells (CSCs) are enriched for tumor metastasis-initiating cells and generally undergo aerobic respiration, which could be enhanced by lactate. We therefore hypothesized that TME-derived lactate may promote the metastasis of normoxic CSCs. In the present study, the abundance of hypoxic and normoxic CSCs was analyzed in primary CRC tumors. It was found that the proportion of normoxic CSCs was positively associated with tumor stage. Using two human CRC cell lines, LoVo and SW480, and a patient-derived xenograft (XhCRC), it was found that treatment with lactate promoted normoxic CSC metastasis. Metabolism analysis indicated that, upon treatment with lactate, oxidative phosphorylation (OXPHOS) activity in normoxic CSCs was enhanced, whereas hypoxic CSCs were rarely altered. At the molecular level, the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of lactate oxidation, was found to be elevated in normoxic CSCs. Furthermore, PGC-1α knockdown markedly reduced the metastatic potential of normoxic CSCs. Notably, both the PGC-1α-mediated OXPHOS activity and metastatic potential were impaired when hypoxia-inducible factor-1α (HIF-1α) was activated in normoxic CSCs. Together, these findings provide a therapeutic strategy against tumor metastasis through the targeting of PGC-1α and, thus, the suppression of lactate-feeding OXPHOS in normoxic CSCs may improve the therapeutic benefit of patients with cancer, particularly CRC.

Transcriptome analysis of grass carp (Ctenopharyngodon idella) and Holland's spinibarbel (Spinibarbus hollandi) infected with Ichthyophthirius multifiliis.

Ichthyophthirius multifiliis is a protozoan ciliate that causes white spot disease (also known as ichthyophthiriasis) in freshwater fish. Holland's spinibarbel (Spinibarbus hollandi) was less susceptible to white spot disease than grass carp (Ctenopharyngodon Idella). In this study, grass carp and Holland's spinibarbel are infected by I. multifiliis and the amount of infection is 10,000 theronts per fish. All grass carp died within 12 days after infection, and the survival rate of Holland's spinibarbel was more than 80%. In order to study the difference in sensitivity of these two fish species to I. multifiliis, transcriptome analysis was conducted using gill, skin, liver, spleen and head kidney of Holland's spinibarbel and grass carp at 48 h post-infection with I. multifiliis. A total of 489,296,696 clean reads were obtained by sequencing. A total of 105 significantly up-regulated immune-related genes were obtained by Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis in grass carp. Cluster of differentiation 40 (CD40), cluster of differentiation 80 (CD 80), tumor necrosis factor-alpha (TNF-α), toll-like receptor 4 (TLR-4), interleukin 1 beta (IL-1ß) and other inflammatory-related genes in grass carp were enriched in the cytokine-cytokine receptor interaction pathway and toll-like receptor pathway. In Holland's spinibarbel, a total of 46 significantly up-regulated immune-related genes were obtained by GO classification and KEGG pathway enrichment analysis. Immune-related genes, such as Immunoglobin heavy chain (IgH), cathepsin S (CTSS), complement C1q A chain (C1qA), complement component 3 (C3) and complement component (C9) were enriched in phagosome pathway, lysosome pathway and complement and coagulation concatenation pathway. C3 was significantly up-regulated in gill and head kidney. Fluorescence in situ hybridization (FISH) showed that the C3 gene was highly expressed in gill tissue of Holland's spinibarbel infected with I. multifiliis. A small amount of C3 gene was expressed in the gill arch of grass carp after infected with I. multifiliis. In conclusion, the severe inflammatory response in vivo after infecting grass carp with I. multifiliis might be the main cause of the death of grass carp. The extrahepatic expression of the gene of Holland's spinibarbel might play an important role in the immune defense against I. multifiliis.

Cyclin D1b induces changes in the macrophage phenotype resulting in promotion of tumor metastasis.

In breast cancer, tumor-associated macrophages with activated phenotypes promote tumor invasion and metastasis. The more aggressive mesenchymal-like breast cancer cells have a selective advantage, skewing macrophages toward the more immunosuppressive subtype. However, the mechanism underlying this shift is poorly understood. Cyclin D1b is a highly oncogenic variant of cyclin D1. Our previous study showed that non-metastatic epithelial-like breast cancer cells were highly metastatic in vivo when cyclin D1b was overexpressed. The present study determined whether cyclin D1b contributed to the interaction between breast cancer cells and macrophages. The results showed that cyclin D1b promoted the invasion of breast cancer cells in vitro. Specifically, through overexpression of cyclin D1b, breast cancer cells regulated the differentiation of macrophages into a more immunosuppressive M2 phenotype. Notably, tumor cells overexpressing cyclin D1b activated macrophages and induced migration of breast cancer cells. Further investigations indicated that SDF-1 mediated macrophage activation through breast cancer cells overexpressing cyclin D1b. These results revealed a previously unknown link between aggressive breast cancer cells and Tumor-associated macrophages, and highlighted the importance of cyclin D1b activity in the breast cancer microenvironment.

Effects of adjuvant chemotherapy on recurrence rate in T1abN0M0 triple-negative breast cancer: A meta-analysis.

PURPOSE: Triple-negative breast cancer (TNBC) is known for its higher recurrence rate in short-term (3-5 years) follow-up and limited systemic therapeutic methods (chemotherapy). Current literature debates over whether chemotherapy should be given to TNBC with a very early disease stage (T1a/bN0). This meta-analysis aimed to compare short-term recurrence rate between patients receiving adjuvant chemotherapy or not for this population. METHODS: We performed a comprehensive search in databases including PubMed, Web of Science, Embase, and Cochrane library from January 2008 to December 2019. Raw data on local or distance recurrence events was extracted, odds ratio (OR) values, 95% confidence interval (CI) values, and P values were then calculated. RESULTS: 9 studies out of 426 were included in the meta-analysis. Our main results showed that breast cancer recurrence rate in T1a/bN0 TNBC patients receiving chemotherapy was significantly lower than those without chemotherapy (OR 0.54, 95% CI 0.37-0.78, P = 0.001). Similar results were detected in the T1b group (OR 0.45, 95% CI 0.26-0.78). The main result remained stable after sensitivity analysis. No significant publication bias was found. CONCLUSIONS: Our results revealed that adjuvant chemotherapy reduced recurrence rate for T1mi/a/bN0 TNBC, especially for T1bN0. The benefit of chemotherapy for T1mi/aN0 disease is still debated.

Differentiated cancer cell-originated lactate promotes the self-renewal of cancer stem cells in patient-derived colorectal cancer organoids.

Tumors harbor diverse compartments of cells with distinct metabolic properties and phenotypes, but the mechanism by which metabolic commensalism among distinct subsets of cancer cells affects tumor progression remains unclear. Colorectal cancer (CRC) has been reported to consist of cancer stem cells (CSCs) and differentiated cancer cells (non-CSCs). In the present study, organoid models were employed to show that CSCs and non-CSCs in CRC were characterized by distinct metabolic phenotypes. Treatment with either non-CSC-derived conditioned medium or exogenous lactate enhanced organoid-forming and tumor-initiating capacity of CSCs. In tumor regeneration assays with co-implanted CSCs and non-CSCs, the tumor-initiating activity was reduced when either monocarboxylate transporter (MCT)4 in non-CSCs or MCT1 in CSCs was silenced or inhibited. Mechanistically, oxiadative phosphorylation-derived reactive oxygen species in CSCs activated AKT-Wnt/ß-catenin signaling, which could be induced by lactate from non-CSCs. Overall, these results suggest that CSCs and non-CSCs possess distinct metabolic profiles and, unexpectedly, non-CSC-originated lactate promotes self-renewal of CSCs and thus contributes to CRC progression. Our findings establish a rationale for developing novel therapies targeting the metabolic commensalism between different cell populations in CRC.

Hypoxic colorectal cancer cells promote metastasis of normoxic cancer cells depending on IL-8/p65 signaling pathway.

Tumor heterogeneity is an important feature of malignant tumors, and cell subpopulations may positively interact to facilitate tumor progression. Studies have shown that hypoxic cancer cells possess enhanced metastatic capacity. However, it is still unclear whether hypoxic cancer cells may promote the metastasis of normoxic cells, which have greater access to the blood circulation. When cocultured with hypoxic CRC cells or treated with hypoxic CRC cell-derived CM, normoxic CRC cells possessed increased metastatic capacity. Furthermore, hypoxic CRC cell-derived CM was enriched in interleukin 8. Hypoxic CRC cell-derived CM and recombinant human IL-8 both enhanced the metastatic capacity of normoxic cells by increasing the phosphorylation of p65 and then by inducing epithelial-mesenchymal transition. Knockdown of IL-8 in hypoxic CRC cells or the use of an anti-IL-8 antibody attenuated the CM- or rhIL-8-induced prometastatic capacity of normoxic CRC cells. Inhibition or knockdown of p65 abrogated IL-8-induced prometastatic effects. Most importantly, hypoxia-treated xenograft tumors enhanced the metastasis of normoxic CRC cells. Hypoxic CRC cell-derived IL-8 promotes the metastatic capacity of normoxic cells, and novel therapies targeting the positive interactions between hypoxic and normoxic cells should be developed.

A new method of cryopreserving colorectal carcinoma cells for patient derived xenograft model generation.

Patient derived xenograft (PDX) models provide an efficient way to study anti-tumor drug efficacy. In this respect, it is essential to study the optimal method needed to cryopreserve the starting cells obtained from tumor samples for PDX model generation. Cryopreservation of cells prior to xenografting is necessary for cross-verification of results obtained by xenografting and also for practical planning of experiments. In the present work, we studied the cryopreservation of colorectal carcinoma (CRC) cells isolated from patient tumor samples for generating their patient derived xenograft models. CRC therapeutics study is essential for early stage intervention and treatment of the disease. CRC cell lines do not ideally depict the molecular characteristics of patient CRC tumor samples. This necessitates the generation of CRC PDX models for drug discovery. We show that CRC cells isolated from patient tumor samples have comparable recovery, viability and growth with both conventional cryopreservation methods as well as Fibulas BioFlash Drive™. However, xenograft tumor formation was much more effective with Fibulas BioFlash Drive™ cryopreserved cells than with cells cryopreserved with conventional methods. Therefore, we put forward an effective way to cryopreserve primary cells obtained from patient tumor samples for PDX model generation in this study.

Mesenteric phlebosclerosis with amyloidosis in association with the long-term use of medicinal liquor: A case report.

BACKGROUND: Mesenteric phlebosclerosis (MP) is a rare disease of the colon. The clinical manifestations of this disease are nonspecific and it may easily be misdiagnosed. We report a case of MP with amyloidosis in the colonic vessel walls in a patient with hypertension who had been consuming Chinese medicinal liquor for 10 years. We also review the relevant literature and summarize the characteristics of MP in patients in mainland China. CASE SUMMARY: A 64-year-old man was referred to our department from his primary hospital because of abdominal pain, diarrhea, and fever for almost 10 d. Computed tomography showed colon wall thickening, with threadlike calcifications in the mesenteric vein in the transverse colon. Colonoscopy revealed purple-blue mucosa with multiple ulcers in the ascending and transverse colon. Biopsy showed thickening and calcification of the vein walls, perivascular and mucosal collagen degeneration, and amyloidosis. The patient had been consuming Chinese medicinal liquor, mainly that made from gardenia fruit, for 10 years. Based on these results, a diagnosis of MP with amyloidosis was made. After conservative treatment, the patient's discomfort subsided and he was followed closely. The use of Chinese herbal medicine was suspected to play a role in the pathogenesis of MP. CONCLUSION: The clinical manifestations of MP are nonspecific. Recognition of its typical imaging findings, including multiple calcifications on computed tomography and purple-blue mucosal discoloration on colonoscopy, is vital.

Strategies to optimize stereotactic radiosurgery plans for brain tumors with volumetric-modulated arc therapy.

PURPOSE: Prescription practice in SRS plans for brain tumors differs significantly for different modalities. In this retrospective study, the strategies to optimize SRS plans for brain tumors with volumetric arc therapy (VMAT) were presented. METHODS: Fifty clinically treated cases were stratified by the maximum target size into two groups (≥ 2 cm in 25 cases and <2 cm but ≥1 cm in 25 cases), which were optimized using traditional LINAC MLC-based approaches with the average prescription isodose line (P-IDL) of (91.4 ± 0.6)%. Four to five plans have been created for each case with variation of the P-IDL from 65% to 90%. The optimization strategies to select an optimal P-IDL, to use tuning structures within the target and beyond as well as to use NTO (normal tissue objectives), were applied to all new plans. RESULTS: The optimal P-IDL was found to be around 75%. After applying the new optimization strategies with an average P-IDL of 74.8%, the mean modified gradient index (mGI) and V12 were reduced by 25% and 35%, respectively for both groups. The Paddick conformity index (PCI) was averagely improved by 8%. The average homogeneity index (HI) and focal index (FI) were increased by 22% and 50%, respectively. The mGI was inversely proportional to the PTV volumes. The shape of the dose distribution in target was also changed from concave to convex. The comparison of PCI with historical data from other institutes and modalities shows that the plans in this study have the best conformity near the target. CONCLUSIONS: With the new optimization strategies for VMAT SRS plan of brain tumor more conformal plans in both high and intermediate dose region (~50% of the PD) were created, in which the dose in the core of the target was notably increased while V12 and mGI were significantly decreased, and PCI was improved. The mGI was inversely proportional to the PTV volumes. The optimal P-IDL is around 75%. The average PCI is the best in this study compared with the published historical data. These strategies are applicable to treatment planning for multiple brain and liver tumors where sparing the tissue peripheral to the target is critical.

Sphere­forming assay vs. organoid culture: Determining long­term stemness and the chemoresistant capacity of primary colorectal cancer cells.

Three­dimensional (3D) cultures are indispensable for capturing tumor heterogeneity in colorectal cancer (CRC) in vitro. Although 3D cultures (such as sphere­forming assay and organoid culture) can partially preserve the morphological and molecular characteristics of primary CRC, whether these 3D cultures maintain the long­term stemness of cancer stem cells (CSCs) remains largely unknown. In the present study, spheres and organoids were generated side by side using individual primary CRC specimens, then respectively processed as serial passages. The results revealed that during serial passages, the percentage of CSCs (such as cluster of differentiation­133+ and Wnt+ cells) in organoids and the tumor­initiating capacity of organoid­derived cells were constant, while they gradually increased in the sphere­derived cells. Furthermore, during serial passages, resistance to chemotherapeutic agents (including 5­fluorouracil and oxaliplatin) in sphere­ and organoid­derived cells was evaluated. The results indicated that the percentage of chemoresistant cells was constant in serial organoid cultures; however, it gradually increased in the serial sphere­forming assays. Taken together, the results of the present study comprehensively demonstrate that, with regard to long­term culture in vitro, organoid culture may be useful in maintaining tumor heterogeneity and the levels of chemoresistant cells, while the sphere formation assay enriches for CSCs and chemoresistant cells.

Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism.

BACKGROUND/AIMS: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. METHODS: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-ß (TGF-ß) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. RESULTS: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. CONCLUSION: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway.

Statin Use and Cancer Incidence in Patients with Type 2 Diabetes Mellitus: A Network Meta-Analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) patients are involved closely with cancer. This work aims to conduct a systematic review and network meta-analysis (NMA) to examine the effect of different types of statins on cancer incidence in patients with T2DM. METHODS: We systematically searched the Cochrane Library, PubMed, Embase, and Wanfang databases from January 1999 to March 2017. We performed a pairwise meta-analysis to estimate the pooled ratios (ORs) and 95% confidence intervals (CIs). A NMA was performed to compare different types of statins. RESULTS: Seven publications were included. In pairwise meta-analysis, the incidence of cancer in T2DM patients was reduced when simvastatin, atorvastatin, pravastatin, fluvastatin, lovastatin, rosuvastatin, and pitavastatin were used. In the result of NMA, the usage of simvastatin (RR 0.30 and 95% CI 0.16-0.56), atorvastatin (RR 0.29 and 95% CI 0.09-0.88), pravastatin (RR 0.34 and 95% CI 0.12-0.93), fluvastatin (RR 0.27 and 95% CI 0.09-0.83), rosuvastatin (RR 0.22 and 95% CI 0.10-0.49), and pitavastatin (RR 0.33 and 95% CI 0.20-0.57) was superior to the nonstatin groups. When compared with six other statins, rosuvastatin appeared to be the best one. CONCLUSIONS: Different statins can reduce the risk of cancer in patients with T2DM. Our analyses suggest that rosuvastatin may be more effective than others.

Cyclin D1b Splice Variant Promotes αvß3-mediated EMT Induced by LPS in Breast Cancer Cells.

Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer metastasis, and is relevant to the inflammatory microenvironment. Lipopolysaccharide (LPS), a cell wall constituent of gram-negative bacteria, has been reported to induce EMT of cancer cells through TLR4 signal. We previously reported that LPS promoted metastasis of mesenchymallike breast cancer cells with high expression of cyclin D1b. However, the role of cyclin D1b in LPS-induced EMT has not been fully elucidated. In the present study, we described that cyclin D1b augmented EMT induced by LPS in MCF-7 breast cancer cells. Cyclin D1b markedly amplified integrin αvß3 expression, which was further up-regulated under LPS stimulation. Our results showed ectopic expression of cyclin D1b promoted invasiveness of epithelial-like MCF-7 cells under LPS stimulation. Additionally, LPS-induced metastasis and EMT in MCF-7-D1b cells might depend on αvß3 expression. Further exploration indicated that cyclin D1b cooperated with HoxD3, a transcription factor promoting αvß3 expression, to promote LPSinduced EMT. Knockout of HoxD3 repressed LPS-induced EMT and αvß3 over-expression in MCF-7 cells with high expression of cyclin D1b. Specifically, all these effects were in a cyclin Dla independent manner. Taken all together, LPS up-regulated integrin αvß3 expression in MCF-7 cells with high expression of cyclin D1b and induced EMT in breast cancer cells, which highlights that cyclin D1b may act as an endogenous pathway participating in exogenous signal inducing EMT in breast cancer cells.