Identify the Clinicopathological Characteristics of Lung Carcinoma Patients Being False Negative in Folate Receptor Based Circulating Tumor Cell Detection.

In lung cancer diagnosis, folate receptor (FR)-based circulating tumor cell (CTC) has shown its ability to distinguish malignancy from benign disease to some extent. However, there are still some patients that cannot be identified by FR-based CTC detection. And studies comparing the characteristics between true positive (TP) and false negative (FN) patients are few. Thus, the study comprehensively analyzes the clinicopathological characteristics of FN and TP patients in the current study. According to inclusion and exclusion criteria, 3420 patients are enrolled. Combining the pathological diagnosis with CTC results, patients are divided into FN and TP groups, and clinicopathological characteristics are compared between two groups. Compared with TP patients, FN patients have smaller tumor, early T stage, early pathological stage, and without lymph node metastasis. Epidermal growth factor receptor (EGFR) mutation status is different between FN and TP group. And this result is also demonstrated in lung adenocarcinoma subgroup but not in lung squamous cell carcinoma subgroup. Tumor size, T stage, pathological stage, lymph node metastasis, and EGFR mutation status may influence the accuracy of FR-based CTC detection in lung cancer. However, further prospective studies are needed to confirm the findings.

The role of GPR110 in lung cancer progression.

BACKGROUND: G protein-coupled receptors (GPCRs) are involved in several signaling pathways. However, the roles of many GPCRs in tumor oncogenesis and progression are not fully understood. In our previous study, we concluded that the absence of Gpr110 decelerates the development of liver brosis/cirrhosis into tumorigenesis. In our current study, the role of GPR110 in the oncogenesis and progression of lung cancer was observed. METHODS: After collecting tumor tissues from lung cancer patients, the expression of GPR110 was analyzed by both Western blotting and real-time PCR. Immunofluorescence was used to observe GPR110 expression in human lung cancer cells. A CCK8 kit was used to analyze the proliferation of human lung cancer cells transfected with Gpr110. Changes in cell migration were evaluated with wound healing and Transwell assays. A nude mouse xenograft model was constructed. Lung cancer model was induced in Gpr110-/- mice with urethane. RESULTS: GPR110 mRNA and protein expression was significantly higher in lung cancer tissue. GPR110 was barely expressed in H460, A549, H1299, and SPC-A1 cells, but its expression in PC-9 and QG56 cells was significantly higher. Overexpression of GPR110 promoted the proliferation and cell aggregation of H1299 cells and H1299 cell migration was also enhanced. Overexpression of GPR110 in H1299 cells significantly promoted tumor development in the nude mice tumor xenograft model. There was no statistical significance between the Gpr110+/+ and Gpr110-/- mice despite the lesions in the Gpr110-/- mice group decreasing at 35 and 40 weeks after the initial injection of urethane. CONCLUSIONS: Our findings indicate that GPR110 promotes the progression of lung cancer through accelerating cell proliferation and migration.

Overcoming Obstacles in Pathological Diagnosis of Pulmonary Nodules through Circulating Tumor Cell Enrichment.

With the popularity of low-dose computed tomography (LDCT) in clinical examination of the lung, the prevalence of pulmonary nodules has significantly increased, thus significantly improving the early diagnosis of lung cancer, but also potentially contributing to overtreatment. This study aims to develop a noninvasive method to assist in diagnosing the pulmonary nodules. To do so, 3798 patients are recruited from the Department of Thoracic Surgery at Shanghai Pulmonary Hospital and peripheral blood samples are collected from them before surgery. From these samples, circulating tumor cells (CTC) are isolated using folate receptor (FR) positivity, and then enriched and analyzed in relation to cancer gene expression, stage, and level of invasion. The average CTC concentration of patients with lung disease is 11.97 functional unit (FU) in a 3 mL sample of blood. FR-positive CTC levels correlate with the expression of lung cancer driver genes tumor-node-matastasis (TNM) stage, and pleura invasion. The sensitivity of CTC levels to lung cancer diagnosis is 87.05%. Results from this study demonstrate that the determination of FR-positive CTC concentration is a convenient and time-saving strategy to improve the pathological diagnosis of pulmonary nodules.

Druggable driver gene alterations in redefined large cell carcinoma in Chinese patients: an observational study.

BACKGROUND: Few reports have investigated the genetic status of large cell carcinoma (LCC) in Chinese patients under the 2015 World Health Organization (WHO) classification. We aimed to analyze the distribution of druggable driver gene alterations, including mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), proto-oncogene B-Raf (BRAF), and phosphatidylinositol-4,5 biphosphate 3-kinase catalytic subunit alpha (PIK3CA) and translocations in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and ROS proto-oncogene 1 (ROS1), in a large population of patients with LCC under the 2015 WHO classification, and to assess the clinical outcomes of patients with LCC harboring these genetic alterations. METHODS: A cohort of 322 patients with LCC resected between June 2015 and December 2018 was included in this study. The clinical characteristics of the patients and data on the distribution of EGFR, KRAS, BRAF, PIK3CA, EML4-ALK, and ROS1 alterations were retrospectively collected. The disease-free survival (DFS) of patients with LCC was analyzed using the log-rank test. RESULTS: Among the patients with redefined LCC, the proportion of males was much higher than that of females. Detection of LCC was more frequent in patients >60 years of age (71.4%). Mutations of EGFR were found in 3.6% of the LCC participants, predominantly in non-smokers. Mutations in KRAS were observed in 7.8% of the LCC patients, mainly in males and smokers. Mutations in PIK3CA and EML4-ALK translocations comprised 2.1% and 0.52% of the identified alterations, respectively. No alterations were identified in ROS1 and BRAF. After molecular stratification, no significant difference in DFS was identified between wild-type (WT) and mutation groups (29.91±3.83 vs. 25.33±6.04 months, P=0.48). CONCLUSIONS: Under the 2015 WHO criteria, LCC was more frequently detected in elderly male patients with inferior prognoses. The frequency of EGFR and KRAS mutations was found to be the highest. Mutations in EGFR occurred more frequently in non-smokers, whereas KRAS mutations occurred predominantly in males and smokers. The PIK3CA mutations and EML4-ALK translocations were rare in patients with LCC. Our data revealed that the identification of clinically actionable molecular alterations in LCC may help guide personalized cancer treatment decisions in the future.

Rdh13 deficiency weakens carbon tetrachloride-induced liver injury by regulating Spot14 and Cyp2e1 expression levels.

Mitochondrion-localized retinol dehydrogenase 13 (Rdh13) is a short-chain dehydrogenase/reductase involved in vitamin A metabolism in both humans and mice. We previously generated Rdh13 knockout mice and showed that Rdh13 deficiency causes severe acute retinal light damage. In this study, considering that Rdh13 is highly expressed in mouse liver, we further evaluated the potential effect of Rdh13 on liver injury induced by carbon tetrachloride (CCl4). Although Rdh13 deficiency showed no significant effect on liver histology and physiological functions under regular culture, the Rdh13-/- mice displayed an attenuated response to CCl4-induced liver injury. Their livers also exhibited less histological changes and contained lower levels of liver-related metabolism enzymes compared with the livers of wild-type (WT) mice. Furthermore, the Rdh13-/- mice had Rdh13 deficiency and thus their liver cells were protected from apoptosis, and the quantity of their proliferative cells became lower than that in WTafter CCl4 exposure. The ablation of Rdh13 gene decreased the expression levels of thyroid hormone-inducible nuclear protein 14 (Spot14) and cytochrome P450 (Cyp2e1) in the liver, especially after CCl4 treatment for 48 h. These data suggested that the alleviated liver damage induced by CCl4 in Rdh13-/- mice was caused by Cyp2e1 enzymes, which promoted reductive CCl4 metabolism by altering the status of thyroxine metabolism. This result further implicated Rdh13 as a potential drug target in preventing chemically induced liver injury.

Gpr110 deficiency decelerates carcinogen-induced hepatocarcinogenesis via activation of the IL-6/STAT3 pathway.

Hepatocarcinogenesis is a complex process that includes pronounced necroinflammation, unregulated hepatocyte damage, subsequent extensive fibrosis, and carcinogenesis. GPR110 was an adhesion G protein-coupled receptor. Analysis of the expression pattern of Gpr110 in mice displayed that Gpr110 was expressed highly in liver, implicating the tissue compartments where Gpr110 could execute its functions, the role of Gpr110 in the physiological and pathological state of liver remains unclear. Based on a Gpr110 knockout mouse model, we evaluated the role of Gpr110 in hepatocarcinogenesis by using a carbon tetrachloride (CCl4)-induced liver injury and fibrosis model, as well as diethylnitrosamine (DEN) plus CCl4-induced liver cancer model. In this study, we found subdued chronic liver injury, reduced compensatory proliferation, lower liver fibrosis, but enhanced inflammation occurred in Gpr110-/- mice during CCl4 challenge. In addition, Gpr110-/- mice were resistant to liver tumorigenesis induced by DEN plus CCl4 injection. Molecular mechanisms underlying these differences correlated with augmented activation of the IL-6/STAT3 pathway, which exerted hepatoprotective effects during liver damage, fibrosis, and oncogenesis in Gpr110-/- mice. Furthermore, pharmacological inhibition of the activation of the IL-6/STAT3 pathway enhanced hepatic fibrosis and promoted DEN plus CCl4-induced carcinogenesis in Gpr110-/- mice. In summary, absence of Gpr110 decelerates liver fibrosis/cirrhosis progressing into tumorigenesis, due to strengthening activation of the IL-6/STAT3 pathway, leading to a weaker liver injury and fibrosis microenvironment. It is indicated that targeting Gpr110 and activating the IL-6/STAT3 pathway may be considered to be preventive methods for some cirrhosis transition.

MicroRNA Let-7b inhibits keratinocyte migration in cutaneous wound healing by targeting IGF2BP2.

Wound healing is a complex process which involves proliferation and migration of keratinocyte for closure of epidermal injuries. A member of microRNA family, let-7b, has been expressed in mammalian skin, but its exact role in keratinocyte migration is still not in knowledge. Here, we showed that let-7b regulates keratinocyte migration by targeting the insulin-like growth factor IGF2BP2. Overexpression of let-7b led to reduced HaCaT cell migration, while knockdown of let-7b resulted in enhanced migration. Furthermore, let-7b was decreased during wound healing in wild-type mice, which led us to construct the transgenic mice with overexpression of let-7b in skin. The re-epithelialization of epidermis of let-7b transgenic mice was reduced during wound healing. Using bioinformatics prediction software and a reporter gene assay, we found that IGF2BP2 was a target of let-7b, which contributes to keratinocyte migration. Introduction of an expression vector of IGF2BP2 also rescued let-7b-induced migration deficiency, which confirms that IGF2BP2 is an important target for let-7b regulation. Our findings suggest that let-7b significantly delayed the re-epithelialization possibly due to reduction of keratinocyte migration and restraints IGF2BP2 during skin wound healing.