Journal of Bioenergetics and Biomembranes

N6-methyladenosine (m6A) reader HNRNPA2B1 accelerates the cervical cancer cells aerobic glycolysis

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Hypoxia-induced HIF1α dependent COX2 promotes ovarian cancer progress

Hypoxia can promote the progression and metastasis of ovarian cancer, while the underlying mechanisms are still unclear. Hypoxia culture or CoCl2 induced-oxygen deprivation condition could promote SKOV3 cells to express cyclooxygenase-2 (COX2). Luciferase assay indicates that hypoxia-inducible factor 1α (HIF1α) could bind directly with the promoter region of COX2 to promote the transcription. COX2 over-expressed SKOV3 cells show up-regulated stemness-related markers expression, proinflammatory gene expression, and increased tumor sphere formation. The inflammatory molecules (interleukin-6, C-X-C motif chemokine ligand 12, interleukin-1B, interleukin-10, and C-C motif chemokine ligand 2) and COX2 expression show positive correlations in the Cancer Genome Atlas data. COX2 over-expression could promote SKOV3 cell proliferation in the subcutaneous tumor model and metastasis in the transfer model. In conclusion, hypoxia-induced HIF-1α mediated COX2 expression could promote the proliferation, inflammation, and metastasis of ovarian cancer.

Interference with MTHFD2 induces ferroptosis in ovarian cancer cells through ERK signaling to suppress tumor malignant progression

Ovarian cancer (OC) is a deadliest gynecological cancer with the highest mortality rate. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a crucial tumor-promoting factor, is over-expressed in several malignancies including OC. The present study aimed to explore the role and mechanisms of MTHFD2 in OC malignant progression. Thus, cell proliferation, cycling, apoptosis, migration, and invasion were evaluated by CCK-8 assay, EdU assay, flow cytometry, wound healing, transwell assay and western blotting. Additionally, glycolysis was assessed by measuring the level of glucose and lactate production, as well as the expressions of GLUT1, HK2 and PKM2. Then the expression of ferroptosis-related proteins and ERK signaling was detected using western blotting. Ferroptosis was detected through the measurement of iron level, GSH, MDA and ROS activities. The results revealed that MTHFD2 was highly expressed in OC cells. Besides, interference with MTHFD2 induced ferroptosis, promoted ROS accumulation, destroyed mitochondrial function, reduced ATP content and inhibited glycolysis in OC cells. Subsequently, we further found that interference with MTHFD2 affected mitochondrial function and glycolysis in OC cells through ERK signaling. Moreover, interference with MTHFD2 affected ferroptosis to inhibit the malignant progression of OC cells. Collectively, our present study disclosed that interference with MTHFD2 induced ferroptosis in OC to inhibit tumor malignant progression through regulating ERK signaling.

KIFC1 promotes aerobic glycolysis in endometrial cancer cells by regulating the c-myc pathway

Endometrial cancer (EC) is a common gynecological malignant tumor worldwide. It is imperative to study pathogenesis and therapeutic targets for improving the prognosis of EC. The present study aimed to explore the function and mechanism of kinesin family member C1 (KIFC1) in EC. EC tumor and adjacent normal tissues were collected from 68 pairs of patients. The expression of KIFC1 in tissues and EC cells was analyzed by immunohistochemistry, qRT-PCR or western blot. MTT assay was used to test the cell viability. Flow cytometry was used to determine apoptosis and the cell cycle. Glucose uptake, lactate production, ATP contents and lactate dehydrogenase (LDH) activity were evaluated by a glucose metabolism kit. The expression of HMGA1, c-myc and glycolytic genes was assessed using western blot or qRT-PCR. A mouse xenograft model was established in BALB/c mice to detect tumor growth in vivo. KIFC1 was significantly upregulated in EC tumor tissues compared to adjacent normal control tissues. The upregulated expression of KIFC1 was correlated with poor prognosis in patients. Lentiviral-mediated overexpression of KIFC1 observably enhanced cell viability and reduced the apoptotic rate of Ishikawa and HEC-1B cells. Cell cycle progression was also expedited in the KIFC1 vector group. Moreover, overexpression of KIFC1 elevated glucose uptake, lactate production, ATP contents and LDH activity. However, knockdown of KIFC1 by short hairpin RNA (shRNA) showed the reverse effect on cellular functions. In addition, the expression of c-myc, GLUT1, LDHA and HK2 was increased by the KIFC1 vector. Moreover, HMGA1 regulated the expression of c-myc and glycolytic genes. Upregulated HMGA1 could rescue the effect of KIFC1 knockdown on cellular functions and the expression of glycolytic genes. Finally, KIFC1 knockdown inhibits tumor growth in vivo. The upregulation of KIFC1 was correlated with poor prognosis in EC. KIFC1 promoted aerobic glycolysis in endometrial cancer cells by regulating the HMGA1/c-myc pathway. KIFC1 may be a potential target for the diagnosis and therapy of EC.

Key factors mediated by PI3K signaling pathway and related genes in endometrial carcinoma

By analyzing the gene expression of endometrial carcinoma (EC) patients, the key factors in PI3K signaling pathway and its related genes mediating EC were explored. The EC samples and normal endometrial samples were downloaded from TCGA database and GTEx database. The R language "limma" package was used for differential analysis, and the expression level of genes in each tissue was analyzed by "gganatogram" package. Functional enrichment analysis of differential genes was carried out by KOBAS, an online bioinformatics website. The correlation between key genes and differential genes was evaluated using TCGA data and GTEx combined gene expression data. The corresponding clinical data were downloaded from TCGA database and GTEx database, and the R language "survival" package was used to assess the potential of candidate differential genes as a key factor of EC. Based on the combined differential analysis of TCGA and GTEx databases, 299 genes with significant differential in expression were finally got. Functional enrichment analysis revealed that genes were predominantly enriched in the entry of "Pathways in cancer", including RAC2 and PIK3R3 genes which were related with the abnormal PI3K pathway in cancer. PIK3R3, a key gene in the PI3K signaling pathway, was highly-expressed in EC. SPDEF, GCNT2, KIAA1324, C9orf152, MARVELD3, and APEX2 genes were found to be positively correlated with PIK3R3 in EC, all of which were highly expressed in EC. KM survival analysis showed that SPDEF, GCNT2, KIAA1324 and C9orf152 were significantly correlated with patients' survival. ROC analysis showed that SPDEF, GCNT2, KIAA1324 and C9orf152 gene could be used as potential markers for prognosis and survival of EC patients. It was found that PIK3R3, a key gene in the PI3K signaling pathway, was highly expressed in EC. The SPDEF, GCNT2, KIAA1324 and C9orf152 genes were also highly expressed in EC, and were positively correlated with PIK3R3 in EC. Moreover, they are significantly correlated with the patients' survival, suggesting that they may be potential markers for the prognosis of patients with EC.