The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism.

Lymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer.

Adipocyte-Derived Exosomal MTTP Suppresses Ferroptosis and Promotes Chemoresistance in Colorectal Cancer.

Obesity is closely related to a poor prognosis in patients with advanced colorectal cancer (CRC), but the mechanisms remain unclear. Ferroptosis is a form of nonapoptotic cell death characterized by lipid reactive oxygen species (ROS) accumulation and iron dependency and is associated with the chemoresistance of tumors. Here, it is shown that adipose-derived exosomes reduce ferroptosis susceptibility in CRC, thus promoting chemoresistance to oxaliplatin. It is found that microsomal triglyceride transfer protein (MTTP) expression is increased in the plasma exosomes of CRC patients with a high body fat ratio, serving as an inhibitor of ferroptosis and reducing sensitivity to chemotherapy. Mechanistically, the MTTP/proline-rich acidic protein 1 (PRAP1) complex inhibited zinc finger E-box binding homeobox 1 expression and upregulated glutathione peroxidase 4 and xCT, leading to a decreased polyunsaturated fatty acids ratio and lipid ROS levels. Moreover, experiments are carried out in organoids, and a tumor implantation model is established in obese mice, demonstrating that the inhibition of MTTP increases the sensitivity to chemotherapy. The results reveal a novel intracellular signaling pathway mediated by adipose-derived exosomes and suggest that treatments targeting secreted MTTP might reverse oxaliplatin resistance in CRC.

Maximum allele frequency observed in plasma: A potential indicator of liquid biopsy sensitivity.

Personalized medicine is revolutionizing the diagnosis and treatment of cancer; however, for personalized medicine to be used accurately, patient information is essential to determine the appropriate diagnosis, prognosis and treatment. The detection of genomic mutations in liquid biopsy samples is a non-invasive method of characterizing the genotype of a tumor. However, next generation sequencing-based plasma genotyping only has a sensitivity of ~70%. Identifying potential indicators that may reflect the sensitivity of a liquid biopsy analysis could offer important information for its clinical application. In the present study, 47 pairs of patient-matched plasma and tumor tissue samples obtained from patients with advanced lung cancer were sequenced using a panel of 56 cancer-associated genes. The plasma maximum allele frequency (Max AF) was identified as a novel biomarker to indicate the sensitivity of plasma genotyping. Using the identified somatic mutations in patient tissue biopsy samples as a reference, the sensitivity of the corresponding patient plasma test was investigated. The by-variant sensitivity of the plasma test was 68.1%, with 79 matched and 37 missed genetic aberrances. The by-patient sensitivity was calculated as 83%. Patients with a high plasma Max AF value (>2.2%) demonstrated a higher concordance with the range of mutations identified in the patient-matched tissue samples. The Max AF observed in patient plasma samples was positively correlated with liquid biopsy sensitivity and could be used as a potential indicator of liquid biopsy sensitivity. Therefore, patients with a low plasma Max AF (≤2.2%) may need to undergo further tissue biopsy to allow personalized oncology treatment. In summary, the present study may offer a non-invasive testing method for a sub-group of patients with advanced lung cancer.

The ideal methods for the management of rib fractures.

The clinical treatment choices for multiple rib fractures and flail chest are controversial. For example, among conservative treatment and surgical treatment, different studies have different conclusions and recommendations. Furthermore, early clinical research was mainly focused on the treatment of flail chest due to its severity. Nowadays, the treatment for multiple rib fractures patients without a flail chest is drawing an increased clinical interest. However, we are facing many challenges for the treatment of rib fractures, such as insufficient understanding of the available treatment options, lack of clinical research, lack of the internationally recognized clinical indication for the surgical stabilization of rib fractures (SSRF), and the constant controversies and debates in terms of treatment options, surgery timing, and surgical techniques. All these challenges make it difficult to select the most appropriated clinical decisions for the proper treatment of a rib fracture, resulting in a seriously hindered development of novel rib fractures treatment choices. The concepts and ideas for traditional rib fractures treatment are relatively old, and even have some misunderstandings or errors. With the emergence of more and more research, the understandings of the rib fractures treatment has gradually improved; for example, the benefits provided to patients under the open reductions and internal fixation of fractures treatment. In this article, we outlined the new concepts in rib fractures treatment, which mainly included four parts, damage control, pain management, fixation selection, and quality of life. We hope these concepts help practitioners better manage rib fracture patients.

MDM2 promotes epithelial-mesenchymal transition through activation of Smad2/3 signaling pathway in lung adenocarcinoma.

BACKGROUND: Mouse double minute 2 (MDM2) contributes to cancer metastasis and epithelial-mesenchymal transition (EMT). This study aimed to investigate small mothers against decapentaplegic (Smad) signaling in MDM2-mediated EMT in lung adenocarcinoma (LAC). MATERIALS AND METHODS: Expression patterns of MDM2 in LAC tissues, adjacent tissues, and cell lines (BEAS-2B, PC9, H1975, and A549) were detected. We then overexpressed MDM2 in PC9 cells and knocked it down in H1975 cells. To explore whether MDM2 activates EMT through the Smad2/3 signaling pathway, Smad2 and Smad3 were also silenced by siRNA in H1975 cells. Male BALB/c nude mice were used in in vivo model to validate the effects of MDM2 on LAC cells. RESULTS: MDM2 was significantly upregulated in LAC tissues compared with adjacent tissues. The expression of MDM2 was relatively higher in PC9 cells and relatively lower in H1975 cells compared with A549 cells. Overexpression of MDM2 significantly increased cell proliferation, migration, and invasion in LAC cells, while inhibiting apoptosis in PC9 cells. On the contrary, silencing of MDM2 significantly inhibited the expression of EMT-related genes N-cadherin and vimentin, while promoting the expression of E-cadherin and ß-catenin. In vivo, MDM2 knockdown inhibited tumor growth. In addition, the expression of Smad2/3 was correlated with MDM2 in H1975 cells transfected with Smad2 and Smad3 siRNAs, which inhibited EMT progress. CONCLUSION: MDM2 can activate the Smad2/3 signaling pathway, which promotes the proliferation and EMT progress of LAC cells.

Long non-coding RNA MALAT1 interaction with miR-429 regulates the proliferation and EMT of lung adenocarcinoma cells through RhoA.

Homo sapiens metastasis associated lung adenocarcinoma transcript 1 (LncRNA MALAT1) plays an important role in many types of cancer, but its role in human lung adenocarcinoma (LAC) is still unclear. In this paper, we found that LncRNA MALAT1 had high expression in human LAC tissues (vs. paracancerous normal tissue) and human lung adenocarcinoma cells (vs. human normal lung tissue cells). The expression of lncRNA MALAT1 was significantly associated with human lung adenocarcinoma tumor size, lymph node metastasis, and TNM staging, and was negatively correlated with miR-429 expression in lung adenocarcinoma tissues. In vitro, LncRNA MALAT1 could block human LAC cells in the G1 phase to inhibit proliferation by reducing the expression of cyclin D1 protein. LncRNA MALAT1 could inhibit the invasion and migration of human LAC cells by decreasing the expression of MMP-9 and vimentin and increasing the expression of E-cadherin. We also found that Malat1 functions as a competing endogenous RNA (ceRNA) for miR-429 and directly suppressed the expression of RhoA protein. RhoA knockout and transfection of miR-429-mimic could play the same function which is to decrease the expression of cyclin D1, MMP-9, and vimentin proteins and increased E-cadherin protein expression. These results suggested that LncRNA Malat1 could promote the proliferation and EMT of human lung adenocarcinoma cells by competing with RhoA for binding to miR-429.

MiR-7 inhibited peripheral nerve injury repair by affecting neural stem cells migration and proliferation through cdc42.

Objective Neural stem cells play an important role in the recovery and regeneration of peripheral nerve injury, and the microRNA-7 (miR-7) regulates differentiation of neural stem cells. This study aimed to explore the role of miR-7 in neural stem cells homing and proliferation and its influence on peripheral nerve injury repair. Methods The mice model of peripheral nerve injury was created by segmental sciatic nerve defect (sciatic nerve injury), and neural stem cells treatment was performed with a gelatin hydrogel conduit containing neural stem cells inserted into the sciatic nerve injury mice. The Sciatic Function Index was used to quantify sciatic nerve functional recovery in the mice. The messenger RNA and protein expression were detected by reverse transcription polymerase chain reaction and Western blot, respectively. Luciferase reporter assay was used to confirm the binding between miR-7 and the 3'UTR of cell division cycle protein 42 (cdc42). The neural stem cells migration and proliferation were analyzed by transwell assay and a Cell-LightTM EdU DNA Cell Proliferation kit, respectively. Results Neural stem cells treatment significantly promoted nerve repair in sciatic nerve injury mice. MiR-7 expression was decreased in sciatic nerve injury mice with neural stem cells treatment, and miR-7 mimic transfected into neural stem cells suppressed migration and proliferation, while miR-7 inhibitor promoted migration and proliferation. The expression level and effect of cdc42 on neural stem cells migration and proliferation were opposite to miR-7, and the luciferase reporter assay proved that cdc42 was a target of miR-7. Using co-transfection into neural stem cells, we found pcDNA3.1-cdc42 and si-cdc42 could reverse respectively the role of miR-7 mimic and miR-7 inhibitor on neural stem cells migration and proliferation. In addition, miR-7 mimic-transfected neural stem cells could abolish the protective role of neural stem cells on peripheral nerve injury. Conclusion MiR-7 inhibited peripheral nerve injury repair by affecting neural stem cells migration and proliferation through cdc42.

Functional role of lncRNA DB327252 in lung cancer.

BACKGROUND: Lung cancer becomes a concerning health issue and is considered one of the most deadly cancers in the worldwide. Most recently, long non-coding RNAs (lncRNAs) are newfound non-coding RNAs that are thought as one of the major players in a range of biological processes of human diseases. Although lncRNAs are involved in numerous cancer types, the precise understandings of lncRNAs' functional roles and mechanisms in lung cancer are limited. In this study, we looked for lung cancer related lncRNAs. METHODS: The quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) technique was utilized to investigate the lncRNA DB327252 expression in 91 paired clinical lung cancer tissues and related cell lines. Moreover, its biological functions were also evaluated in the development of lung cancer. RESULTS: The results indicated that the expression of DB327252 was up-regulated in lung cancer tissues compared to the cancer-adjacent normal tissues (P<0.05); and the up-regulated expression is likely to relate to those with bigger tumor size, adenocarcinoma and advanced TNM stage (P<0.05). In addition, the knockdown of DB327252 inhibited the growth and proliferation of tumor cell in vitro and in vivo. According to the observation from our study, we found that the knockdown of the DB327252 expression, led to G0/G1 phase cell-cycle arrested, colony formation suppressed in vitro, and tumor growth inhibited in a nude mouse xenograft model. Our experimental results also suggest that lncRNA DB327252 may be a lncRNA related to lung cancer and acts an important role in A549 and 16HBE-T cancer cells, which provides evidence that DB327252 has an oncogene-like function in lung cancer. CONCLUSIONS: The lncRNA DB327252 is up-regulated in lung cancer, and its expression implies that it was probable related to biologic functions of lung cancer.

The 2011 IASLC/ATS/ERS pulmonary adenocarcinoma classification: a landmark in personalized medicine for lung cancer management.

In 2011, three authoritative academic communities, International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society (IASLC/ATS/ERS), published a novel lung adenocarcinoma histologic classification. The major modifications of this classification include the abolishment of the term "bronchioloalveolar carcinoma (BAC)", the establishment of new classification systems for resection and small biopsy or cytology specimens, the emphasis of molecular test and comprehensive histologic evaluation for tumor specimens, etc. This new lung adenocarcinoma classification signifies the era of personalized medicine comes to real-world practice in lung cancer field. Here, we introduce the background why the lung adenocarcinoma classification needs to be revised, and what we should consider in clinical practice according to this new classification.