HOXD9 contributes to the Warburg effect and tumor metastasis in non-small cell lung cancer via transcriptional activation of PFKFB3.

Warburg effect is associated with the progression of various tumors, leading to the development of drugs targeting the phenomenon. PFKFB3 is an isoform of 6-phosphofructo-2-kinase (PFK2) that modulates the Warburg effect and has been implicated in most common types of cancer, including non-small cell lung cancer (NSCLC). However, the mechanisms underlying the upstream regulation of PFKFB3 in NSCLC remain poorly understood. This study reported that the transcription factor HOXD9 is upregulated in NSCLC patient samples relative to adjacent normal tissue. Elevated HOXD9 levels are primarily associated with poor prognosis in patients with NSCLC. Functionally, HOXD9 knockdown impaired the metastatic capacity of NSCLC cells, whereas its over-expression accelerated the metastasis and invasion of NSCLC cells in an orthotopic tumor mouse model. In addition, HOXD9 promoted metastasis by increasing cellular glycolysis. Further mechanistic studies revealed that HOXD9 directly binds to the promoter region of PFKFB3 to enhance its transcription. The recovery assay confirmed that the capability of HOXD9 to promote NSCLC cells metastasis was significantly weakened upon PFKFB3 inhibition. These data suggest that HOXD9 may exert as a novel biomarker in NSCLC, indicating that blocking the HOXD9/PFKFB3 axis may be a potential therapeutic strategy for NSCLC treatment.

Heat shock protein 47 promotes cell migration and invasion through AKT signal in non-small cell lung cancer.

Lung cancer is one of the most lethal malignancies, with the highest number of cases and deaths. Non-small cell lung cancer (NSCLC) is the most ordinary type of pathology in lung cancer. Meanwhile, various researchers have reported that heat shock protein 47 (HSP47) plays a vital regulatory role in cancer. However, the role of HSP47 in NSCLC is not clear. Consequently, the current study set out to investigate the role of HSP47 in the pathogenesis of NSCLC. First, we evaluated the expression patterns of HSP47 in NSCLC cell lines related to human normal lung epithelial cells, and HSP47 was found to be highly expressed in NSCLC cell lines. In addition, inhibiting the expression of HSP47 brought about marked repression in cell proliferation, migration and invasion in PC-9 cells. On the contrary, cell proliferation, migration and invasion were all elevated after over-expression of HSP47. Mechanistical experimentation further illustrated that protein kinase B (AKT) signal was repressed after inhibition of HSP47, and the influence of sh-HSP47 on cell proliferation, migration and invasion was countered by epidermal growth factor. Lastly, in-vivo animal models demonstrated that inhibition of HSP47 repressed cell tumorigenesis and AKT signal. Collectively, our findings illustrated that HSP47 was highly expressed in NSCLC cell lines, whereas inhibition of HSP47 repressed cell migration and invasion by diminishing the AKT signal. Inhibition of HSP47 also exhibited strong therapeutic effects on NSCLC in vivo.

Clinical observation of Yiqi Qingdu prescription on the treatment of intermediate-stage and advanced non-small-cell lung cancer.

OBJECTIVE: To observe the effects of the Yiqi Qingdu prescription () on intermediate-stage and advanced non-small-cell lung cancer (NSCLC). METHODS: In total, 300 patients with intermediate-stage or advanced NSCLC were randomly and equally divided into three groups using computer-generated random numbers as follows: Western medicine (WM), Chinese medicine (CM), and integrated Traditional Chinese and Western Medicine (IM). After 3 months of treatment, the overall response rate (ORR); disease control rate (DCR); symptom score (SS); Karnofsky performance status (KPS); adverse event score; counts of CD3 + , CD4 + , and CD8 + cells; CD4 + /CD8 + ratio; and carcinoembryonic antigen (CEA) level were compared among the groups. RESULTS: The ORRs were 30.36% , 20.24% , and 7.87% in the IM, CM, and WM groups, respectively, whereas the DCRs were 85%, 75%, and 73%, respectively. Compared to the CM group, the ORR was significantly higher in the WM and IM groups, whereas the DCR was significantly higher in the IM group (all P < 0.05). SS was obviously higher in the WM group than in the other two groups (both P < 0.01). KPS was significantly lower in the WM group after treatment (P = 0.005). The mean number of adverse events was significantly lower in the CM (2.2 ± 1.3) and IM (2.4 ± 1.3) groups than in the WM group (4.6 ± 1.7, both P < 0.05). CD3 + cell counts were significantly decreased in the WM group (P = 0.031). In the IM group, CD8+ cell counts were increased after treatment, whereas the CD4 + /CD8 + ratio was decreased (both P < 0.01). Compared with the WM group, CD3 + (P = 0.01), CD4 + (P = 0.044), and CD8 + (P = 0.009) cell counts were significantly higher in the IM group, whereas the CD4+ /CD8+ ratio was significantly lower (P = 0.011). Relative to the CM group, CD8 + cell counts were significantly higher (P = 0.001) and the CD4+ /CD8+ ratio was significantly lower in the IM group (P = 0.001). CEA levels were significantly increased in the CM group (P = 0.023). CONCLUSION: The Yiqi Qingdu prescription can improve the outcomes of WM in patients with NSCLC.

CircRNA hsa_circ_0087862 Acts as an Oncogene in Non-Small Cell Lung Cancer by Targeting miR-1253/RAB3D Axis.

PURPOSE: Circular RNAs (circRNAs) have been found to regulate several human tumors. The present study was to explore the mechanism of hsa_circ_0087862 in regulating non-small cell lung cancer (NSCLC). METHODS: Totally 102 NSCLC cases were enrolled. NCI-H1359 and A549 cells were transfected. Cells viability, apoptosis, migration and invasion were determined by CCK-8 assay, flow cytometry, scratch test and transwell experiment, respectively. Luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay were performed. Xenograft tumor experiments were performed using nude mice. hsa_circ_0087862, miR-1253 and RAB3D expression in tissues/cells were detected by qRT-PCR. RAB3D and Ki67 protein expressions in cells/tissues were researched by Western blot and immunohistochemistry. Apoptosis of xenograft tumor tissue cells was detected using Tunel assay. RESULTS: hsa_circ_0087862 was significantly up-regulated in NSCLC patients, which was associated with poor prognosis (P < 0.05). hsa_circ_0087862 down-regulation prominently weakened NSCLC cells viability, migration, invasion and enhanced apoptosis (P < 0.01). hsa_circ_0087862 overexpression exhibited the opposite results in NSCLC cells. miR-1253 was sponged by hsa_circ_0087862. miR-1253 expression in NSCLC tissues was negatively correlated with hsa_circ_0087862 (P < 0.001). RAB3D expression in NSCLC was directly inhibited by miR-1253. miR-1253 down-regulation or RAB3D overexpression dramatically reversed NSCLC cells phenotype induced by hsa_circ_0087862 down-regulation. hsa_circ_0087862 down-regulation markedly inhibited tumor growth in vivo (P < 0.01). In xenograft tumor tissues, hsa_circ_0087862 down-regulation obviously decreased expression of RAB3D, Ki67 and increased apoptosis. CONCLUSION: hsa_circ_0087862 acted as an oncogene in NSCLC by targeting miR-1253/RAB3D.