LncRNA H19 Participates in Leukemia Inhibitory Factor Mediated Stemness Promotion in Colorectal Cancer Cells.

Colorectal cancer (CRC) is a common human malignancy and the third leading cause of cancer-related death worldwide. Cancer stem cells (CSCs) were considered to play important roles in the genesis and development of many tumors. In recent years, it has been observed that leukemia inhibitory factor (LIF) might be involved in the regulation of stemness in cancer cells. In this study, we observed that LIF could increase the spheroid formation and stemness marker expression (inculding Nanog and SOX2) in CRC cell lines, such as HCT116 and Caco2 cells. Meanwhile, we also observed that LIF could upregulate LncRNA H19 expression via PI3K/AKT pathway. Knockdown of the expression of LncRNA H19 could decrease the spheroid formation and SOX2 expression in LIF-treated HCT116 and Caco2 cells, and thereby LncRNA H19 knockdown could compensate for the stemness enhancement effects induced by LIF. Our results indicated that LncRNA H19 might participate in the stemness promotion of LIF in CRC cells.

Emodin is a Potential Drug Targeting CD44-positive Hepatocellular Cancer.

BACKGROUND: Liver cancer is one of the most prevalent forms of cancer of the digestive system in our country. The most common subtype of this disease is hepatocellular carcinoma (HCC). Currently, treatment options for HCC patients include surgical resection, liver transplantation, radiofrequency ablation, chemoembolization, and biologic-targeted therapy. However, the efficacy of these treatments is suboptimal, as they are prone to drug resistance, metastasis, spread, and recurrence. These attributes are closely related to cancer stem cells (CSCs). Therefore, the utilization of drugs targeting CSCs may effectively inhibit the development and recurrence of HCC. METHODS: HepG2 and Huh7 cells were used to analyze the antitumor activity of emodin by quantifying cell growth and metastasis, as well as to study its effect on stemness. RESULTS: Emodin effectively suppressed the growth and movement of HCC cells. Emodin also significantly inhibited the proliferation of CD44-positive hepatoma cells. CONCLUSION: Emodin shows promise as a potential therapeutic agent for HCC by targeting CD44-- positive hepatoma cells.

Leukemia Inhibitory Factor Impairs the Function of Peripheral γδT Cells in Patients with Colorectal Cancer.

Immunotherapeutic strategies are recognized as promising treatment methods for colorectal cancer (CRC). αßT cell-mediated cytotoxicity is tolerated by cancer cells with low MHC class I expression; therefore, γδT cell-based cancer immunotherapy has generated increasing interest as a potential treatment option. To enhance the potency of γδT cell-based immunotherapy, the key factors involved in the regulation of γδT cells in CRC need to be identified along with devising ways to overcome potential hurdles. In this study, we observed that leukemia inhibitory factor (LIF), the serum level of which was highly increased in those with solid tumors, could specifically attenuate the cytotoxic function of peripheral γδT cells in patients with CRC. We observed that in patients with CRC, the expression levels of perforin and granzyme were significantly decreased in the recombinant human LIF (rhLIF)-treated peripheral γδT cells, whereas that of the LIF receptor (LIFR) was higher. The regulation of the cytotoxic function of the γδT cells by rhLIF was effected mainly through the STAT3 signaling pathway, which caused an increase in the expression levels of interleukin (IL)-17, COX-2, and prostaglandin E2 (PGE2). Our results revealed that rhLIF could impair the function of γδT cells in CRC patients by reducing the cytotoxic function and increasing the expression of tumor-promoting molecules, such as IL-17, COX-2, and PGE2.

miRNAs in anti-cancer drug resistance of non-small cell lung cancer: Recent advances and future potential.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors worldwide. Clinical success is suboptimal owing to late diagnosis, limited treatment options, high recurrence rates, and the development of drug resistance. MicroRNAs (miRNAs), a range of small endogenous non-coding RNAs that are 22 nucleotides in length, have emerged as one of the most important players in cancer initiation and progression in recent decades. Current evidence has revealed the pivotal roles of miRNAs in regulating cell proliferation, migration, invasion, and metastasis in NSCLC. Recently, several studies have demonstrated that miRNAs are strongly associated with resistance to anti-cancer drugs, ranging from traditional chemotherapeutic and immunotherapy drugs to anti-vascular drugs, and even during radiotherapy. In this review, we briefly introduce the mechanism of miRNA dysregulation and resistance to anti-tumor therapy in NSCLC, and summarize the role of miRNAs in the malignant process of NSCLC. We then discuss studies of resistance-related miRNAs in chemotherapy, radiotherapy, targeted therapy, immunotherapy, and anti-vascular therapy in NSCLC. Finally, we will explore the application prospects of miRNA, an emerging small molecule, for future anti-tumor therapy. This review is the first to summarize the latest research progress on miRNAs in anti-cancer drug resistance based on drug classification, and to discuss their potential clinical applications.

Polyphyllin VII is a Potential Drug Targeting CD44 Positive Colon Cancer Cells.

BACKGROUND: Current therapies for colon cancer are hindered by treatment failure and recurrence, mainly due to colon cancer stem cells (CSCs). Thus, treatment using drugs targeting CSCs should be effective in eliminating colon cancer cells and impeding cancer recurrence. OBJECTIVE: This study aimed to test if PPVII can be a potent drug candidate for the treatment of colon cancer by targeting CD44 positive colon cancer cells. METHODS: In this study, we first demonstrated that CD44 is highly expressed in colon cancer tissues by TCGA/GTEX database analysis and immunohistochemical staining. RESULTS: In this study, we first demonstrated that CD44 is highly expressed in colon cancer tissues by TCGA/GTEX database analysis. CD44 had high accuracy as a diagnostic and predictive index for colorectal cancer through receiver operating characteristic curve (ROC) analysis. At the same time, survival curve analysis also showed that the high expression of CD44 was associated with poor prognosis in patients with colon cancer. CD44's higher expression in colon cancer tissues was further confirmed by immunohistochemical staining; the positive rate of CD44 expression was 87.95%. Then, one of the constituents that derives from the root of Paris polyphylla, Polyphyllin VII (PPVII), has been confirmed to inhibit the migration of colon cancer cells. Our results also demonstrated that PPVII could inhibit the sphere-forming ability of colon cancer cells. Further experiment results showed that PPVII could downregulate the expression of CD44 in colon cancer cells. In addition, PPVII was proved to have inhibitory effects against CD44 positive colon cancer cells. CONCLUSION: Therefore, PPVII might be a potent candidate reagent for the treatment of colon cancer by targeting CD44 positive colon cancer cells.

Detection of circulating genetically abnormal cells using 4-color fluorescence in situ hybridization for the early detection of lung cancer.

PURPOSE: Available biomarkers lack sensitivity for an early lung cancer. Circulating genetically abnormal cells (CACs) occur early in tumorigenesis. To determine the diagnostic value of CACs in blood detected by 4-color fluorescence in situ hybridization (FISH) for lung cancer. METHODS: This was a prospective study of patients with pulmonary nodules ≤ 30 mm detected between 10/2019 and 01/2020 at four tertiary hospitals in China. All patients underwent a pathological examination of lung nodules found by imaging and were grouped as malignant and benign. CACs were detected by 4-color FISH. Patients were divided into the training and validation cohorts. Receiver operating characteristics analysis was used to analyze the diagnosis value of CACs. RESULTS: A total of 205 participants were enrolled. Using a cut-off value of ≥ 3, blood CACs achieved areas under the curve (AUCs) of 0.887, 0.823, and 0.823 for lung cancer in the training and validation cohorts, and all patients, respectively. CACs had high diagnostic values across all tumor sizes and imaging lesion types. CACs were decreased after surgery (median, 4 vs. 1, P < 0.001) in the validation set. The CAC status between blood and tissues was highly consistent (kappa = 0.909, P < 0.001). The AUC of CAC (0.823) was higher than that of CEA (0.478), SCC (0.516), NSE (0.506), ProGRP (0.519), and CYFRA21-1 (0.535) (all P < 0.001). CONCLUSION: CACs might have a high value for the early diagnosis of lung cancer. These findings might need to be validated in future studies. Evidence suggested homology in genetic aberrations between the CACs and the tumor cells.

MicroRNAs: Emerging oncogenic and tumor-suppressive regulators, biomarkers and therapeutic targets in lung cancer.

Lung cancer is one of the most common solid tumors worldwide and the leading cause of cancer-related deaths, causing a devastating impact on human health. The clinical prognosis of lung cancer is usually restricted by delayed diagnosis and resistance to anticancer therapies. MicroRNAs, a range of small endogenous noncoding RNAs 22 nucleotides in length, have emerged as one of the most important players in cancer initiation and progression in recent decades. Current evidence reveals pivotal roles of microRNAs in regulating cell proliferation, migration, invasion and metastasis in lung cancer. An increasing number of preclinical and clinical studies have also explored the potential of microRNAs as promising biomarkers and new therapeutic targets for lung cancer. The current review summarizes the most recent progress on the functional mechanisms of microRNAs involved in lung cancer development and progression and further discusses the clinical application of miRNAs as putative therapeutic targets for molecular diagnosis and prognostic prediction in lung cancer.

PTEN-Induced Putative Kinase 1 (PINK1)/Parkin-Mediated Mitophagy Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity.

BACKGROUND The pathogenesis of chemotherapy-induced neuropathy, a dose-dependent adverse effect of cisplatin, involves mitochondrial dysfunction. PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy removes damaged mitochondria under various pathological conditions. The objective of this study was to determine mitophagy status and its effects on mitochondrial function and neuronal cell damage after cisplatin treatment using an in vitro model of cisplatin-induced neurotoxicity. MATERIAL AND METHODS PC12 cells were transfected with Parkin or Parkin siRNA using lentiviral particles and Lipofectamine 3000™, respectively, and then were exposed to 10 µM cisplatin. The expression of autophagic proteins was measured by Western blot analysis. Mitophagy in PC12 cells was detected by confocal microscopy analysis of mitochondria-lysosomes colocalization and autophagic flux. The effects of PINK1/Parkin-mediated mitophagy on cisplatin-induced neurotoxicity were assessed via mitochondrial function, neuritic length, nuclear diameter, and apoptosis. RESULTS Cisplatin activated PINK1/Parkin-mediated mitophagy in PC12 cells. Autophagic flux analysis revealed that cisplatin inhibits the late stage of the autophagic process. The knockdown of Parkin suppressed cisplatin-induced mitophagy, aggravating cisplatin-induced depolarization of mitochondria, cellular ATP deficits, reactive oxygen species outburst, neuritic shortening, nuclear diameter reduction, and apoptosis, while Parkin overexpression enhanced mitophagy and reversed these effects. CONCLUSIONS PINK1/Parkin-regulated mitophagy can protect against cisplatin-related neurotoxicity, suggesting therapeutic enhancement of mitophagy as a potential intervention for cisplatin-induced peripheral neuropathies. The interference of cisplatin with autophagosome-lysosome fusion may be partly responsible for cisplatin-induced neurotoxicity.

Data on the involvement of Meox1 in balloon-injury-induced neointima formation of rats.

In the previous report, Meox1 was found to promote SMCs phenotypic modulation and injury-induced vascular remodeling by regulating the FAK-ERK1/2-autophagy signaling cascade (Wu et al., 2017) [1]. Here, we presented new original data on the involvement of Mesoderm/mesenchyme homeobox gene l (Meox1) in balloon-injury-induced neointima formation of rat. In rat carotid artery balloon injury model to induce vascular remodeling, Meox1 was induced in vascular smooth muscle cell (SMCs) of rat carotid arteries. Most proliferating cell nuclear antigen (PCNA)-positive cells also expressed Meox1. These data suggested that Meox1 may be involved in SMCs proliferation during injury-induced neointima formation. Furthermore, knocked down its expression in injured arteries by adenoviral delivery of Meox1 short hairpin RNA (shRNA) (shMeox1), neointima formation was significantly inhibited. Elastin staining also confirmed the reduction of neointima in Meox1 shRNA-transduced arteries. Moreover, knockdown of Meox1 decreased the collagen production/deposition that was significantly increased in neointima induced by balloon injury.