PTEN suppresses renal cell carcinoma proliferation and migration via inhibition of the PI3K/AKT pathway.

Renal cell carcinoma (RCC) is a frequent and aggressive type of kidney cancer with limited therapeutic options. Although phosphatase and tensin homolog (PTEN) have been recognized as a potential tumor suppressor in all kinds of cancers, its function in RCC remains to be thoroughly elucidated. This article was recruited to examine the PTEN's role in managing the PI3K/AKT pathway and its impact on the RCC cell proliferation and migration. This study collected renal cancer and adjacent non-cancerous tissue samples from our hospital. HK-2 and 786-O cells were used, with 786-O cells divided into control, vector, and oe-PTEN groups. PTEN and related protein levels were detected using RT-qPCR and Western blot. Statistical analyses were performed using the Mann-Whitney U test and Kruskal-Wallis H test. Cell viability and migration were assessed using the CCK-8 assay and wound healing assay. All analyses were conducted with SPSS 22.0 software, with statistical significance defined as p < 0.05. RT-qPCR results showed that PTEN expression was significantly increased in RCC tumor tissues compared to normal tissues (p < 0.01). However, PTEN mRNA levels were significantly reduced in 786-O cells compared to HK-2 cells (p < 0.01). In 786-O cells with low PTEN expression, further induction of PTEN overexpression significantly inhibited PI3K/AKT signaling activity (p < 0.01), accompanied by decreased cell viability and migration ability. These results indicate that the expression pattern of PTEN in RCC is complex, but its overexpression can exert tumor-suppressive effects by inhibiting the PI3K/AKT signaling pathway. Our findings demonstrate that PTEN overexpression in RCC cells leads to decreased PI3K/AKT signaling, decreasing cell viability and migration. This study highlights the critical role of PTEN in RCC progression and suggests potential therapeutic targets for intervention.

Xu X ，Tang YY ，Liang X ，Luo W ，Jiang DM ，Chen J ... -  《World Journal of Surgical Oncology》

MYBL2 promotes proliferation of clear cell renal cell carcinoma by regulating TOP2A and activating AKT/mTOR signaling pathway.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system, and clear cell renal cell carcinoma (ccRCC) is the most common subtype. MYBL2 has been reported to be overexpressed in various tumors and associated with poor prognosis in patients, but its biological role in ccRCC remains unclear. In this study, we investigated the mRNA and protein expression levels of MYBL2 in ccRCC samples and evaluated the prognostic value of MYBL2 using TCGA dataset. In vitro functional assays were performed using CCK-8, EdU, colony formation, cell scratch, and transwell assays, as well as in vivo tumorigenesis assays to investigate the biological functions of MYBL2 in ccRCC. Additionally, gene set enrichment analysis (GSEA) was used to explore the downstream pathways of MYBL2, which were further validated. Finally, we predicted the target genes of MYBL2 using bioinformatics and validated them using ChIP and dual-luciferase reporter gene assays. MYBL2 expression was significantly higher in ccRCC than in adjacent normal tissues and was associated with poor prognosis. MYBL2 expression was positively correlated with the pathological tumor grade and clinical TNM stage of ccRCC patients. Knockdown of MYBL2 significantly inhibited the proliferation of renal cancer cells in vitro and in vivo, and knockdown of MYBL2 could inhibit cell invasion and migration, while overexpression of MYBL2 had the opposite effect. GSEA revealed that MYBL2 was associated with the mTOR signaling pathway and cell cycle pathway, which was confirmed by our study. Finally, we found that TOP2A was a target gene of MYBL2, and MYBL2 could bind to the TOP2A promoter to regulate its transcriptional activity, promoting the proliferation of clear cell renal cell carcinoma cells. MYBL2 emerges as a highly expressed factor that significantly correlates with adverse patient prognosis in ccRCC. Mechanistically, MYBL2 transcriptionally upregulates TOP2A, thereby modulating the proliferation of ccRCC cells. Furthermore, MYBL2 activates the mTOR signaling pathway, a critical node in the progression of ccRCC. Collectively, these findings position MYBL2 as a promising candidate for both a biological marker and a therapeutic target in the management of ccRCC.

Huang Y ，Xi X ，Ye Z ，Zhang C ，Jiang Y ，Yu F ，Huang G ... -  《-》

Rosmarinic acid attenuates glioblastoma cells and spheroids' growth and EMT/stem-like state by PTEN/PI3K/AKT downregulation and ERK-induced apoptosis.

Glioblastoma (GB) is a highly malignant type of brain cancer with a poor prognosis. Therapeutic strategies for GB are still limited. Rosmarinic acid (RA), a polyphenolic compound, is a promising experimental anticancer agent, but its specific protein targets for GB remain unclear. This study aimed to elucidate the anticancer effects of RA in 2D- and 3D-GB cells and the underlying mechanisms. 3D-tumor spheroids (mimics in vivo tumors) were obtained by the hanging-drop/agarose method. RA's anti-glioma activity on U-87MG (p53-wt/PTEN-mt) and LN229 (p53-mt/PTEN-wt) cells was evaluated through cell viability, colony-formation, migration/invasion/angiogenesis assays, fluorescence imaging, and spheroid growth analysis. The underlying mechanism of the anticancer effects of RA was investigated by Western blot and immunofluorescence analysis. The MEK inhibitor U0126 was used to block ERK phosphorylation. RA treatments exerted anti-proliferative and pro-apoptotic effects on human GB cells. RA dose-dependently reduced angiogenesis and intracellular ROS levels, suppressed glioma growth, and migration/invasion in 2D-culture and cancer stem cell (CSC)-like 3D-spheroid culture (SPC). Repeated therapy in SPC was more effective by leading to disrupted structure than a single treatment. Treatments in SPC also suppressed epithelial-mesenchymal transition (EMT) and CSC-like properties. Strikingly, RA downregulated the SIRT1/FOXO1/NF-κB axis independently of p53 or PTEN function in both gliomas. Immunofluorescence labeling revealed decreased SIRT1 and NF-κB-p65 and increased FOXO1 and GAPDH proteins in nuclear location (associated with apoptosis). Surprisingly, RA increased p-ERK1/2 levels, but priming with U0126 abolished RA-mediated p-ERK upregulation; thus, autophagy and apoptosis induction in GB cells were prevented, and the growth of GB spheroids accelerated. Specifically, RA also inhibited the PTEN/PI3K/AKT pathway in U-87MG cells. Due to genetic differences in cells, U-87MG cells were more sensitive to RA treatments than LN229 cells. Meanwhile, our positive control drug trial results with FDA-approved temozolomide (TMZ) used in GB treatment showed that our test compound rosmarinic acid exhibited higher therapeutic effects than TMZ at lower doses. Suppression of EMT, downregulation of SIRT1/FOXO1/NF-κB axis, inhibition of PTEN/PI3K/AKT signaling pathway, and ERK-induced apoptosis and autophagy were determined to be involved in stopping glioma progression. Our findings for the first time, revealed that RA may have potential therapeutic use by having multiple targets in human brain cancer with further clinical studies.

Şengelen A ，Önay-Uçar E 《-》

[GINS1 Enhances Glycolysis, Proliferation and Metastasis in Lung Adenocarcinoma Cells by Activating the Notch/PI3K/AKT/mTORC1 Signaling Pathway].

Huo Y ，Xu X ，Ma X ，Feng Y ... -  《-》

HTR1D regulates the PI3K/Akt signaling pathway to impact hepatocellular carcinoma development and resistance to sorafenib.

Hepatocellular carcinoma (HCC) has a poor prognosis, partly due to resistance to treatments like sorafenib. The 5-hydroxytryptamine receptor 1D (HTR1D) is involved in cancer progression through the PI3K/Akt pathway, but its role in HCC is not well understood. This study investigates HTR1D's expression, function, and potential as a prognostic marker in HCC. First, the correlation between HTR1D and hepatocellular carcinoma was analyzed using the TCGA database, and the expression level of HTR1D in clinical samples was detected by qPCR. Then the siRNA was transfected into Huh-7 and Hep3B cells, and the cell proliferation ability, colony formation ability, migration and invasion ability were detected with or without sorafenib. And the expression of the PI3K/Akt pathway was detected by Western Blot. Finally, the potential of HTR1D as a predictive marker for patient prognosis was evaluated by immunohistochemistry. Analysis of TCGA data showed that methylation of the HTR1D gene was associated with cancer status. Clinical samples confirmed significant differences in HTR1D expression between HCC and adjacent tissues, with higher expression correlating with poorer patient prognosis. Interference with HTR1D gene expression demonstrated its role in promoting HCC proliferation, migration, and drug resistance through the PI3K/Akt pathway. These findings were validated in a mouse model. Immunohistochemical analysis of clinicopathological samples suggested that HTR1D could be a valuable prognostic marker for HCC. HTR1D is highly expressed in hepatocellular carcinoma tissues, and it can influence hepatocellular carcinoma development and resistance to sorafenib by regulating the PI3K/Akt signaling pathway. In addition, HTR1D has potential as a prognostic indicator.

Zhang Y ，Zhang Y ，Zhou S ，Rehman MU ，Lin F ，Zhang J ，Zhou H ... -  《BMC CANCER》