E‐cadherin determines Caveolin‐1 tumor suppression or metastasis enhancing function in melanoma cells

The role of caveolin‐1 (CAV1) in cancer is highly controversial. CAV1 suppresses genes that favor tumor development, yet also promotes focal adhesion turnover and migration of metastatic cells. How these contrasting observations relate to CAV1 function in vivo is unclear. Our previous studies implicate E‐cadherin in CAV1‐dependent tumor suppression. Here, we use murine melanoma B16F10 cells, with low levels of endogenous CAV1 and E‐cadherin, to unravel how CAV1 affects tumor growth and metastasis and to assess how co‐expression of E‐cadherin modulates CAV1 function in vivo in C57BL/6 mice. We find that overexpression of CAV1 in B16F10 (cav‐1) cells reduces subcutaneous tumor formation, but enhances metastasis relative to control cells. Furthermore, E‐cadherin expression in B16F10 (E‐cad) cells reduces subcutaneous tumor formation and lung metastasis when intravenously injected. Importantly, co‐expression of CAV1 and E‐cadherin in B16F10 (cav‐1/E‐cad) cells abolishes tumor formation, lung metastasis, increased Rac‐1 activity, and cell migration observed with B16F10 (cav‐1) cells. Finally, consistent with the notion that CAV1 participates in switching human melanomas to a more malignant phenotype, elevated levels of CAV1 expression correlated with enhanced migration and Rac‐1 activation in these cells.     

Gene expression profile favoring phenotypic reversion: a clue for mechanism of tumor suppression by NF-IL6 3'UTR

Transfection of cDNA in 3'untranslated region of human nuclear factor for interleukin-6 (NF-IL6 3'UTR) induced tumor suppression in a human hepatoma cell line. cDNA array analysis was used to reveal changes in gene expression profile leading to tumor suppression The results indicate that this suppression was not due to activation of dsRNA-dependent protein kinase, nor to inactivation of oncogenes; rather, all the changes in expression of known genes, induced by NF-IL6 3'UTR cDNA may be ascribed to the suppression of cellular malignancy. Therefore, our results imply that this 3'untranslated region may have played role of a regulator of gene expression profile.     

p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression

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A nonlinear model with competition between prostate tumor cells and its application to intermittent androgen suppression therapy of prostate cancer

The recurrence of a tumor is a crucial problem in hormonal therapy of prostate cancer. Recent studies suggest that intermittent androgen suppression administration may prolong or hopefully prevent the progression to the recurrence. It was shown that a simple mathematical model is useful to understand how and why intermittent administration can be effective and to seek a better medication scheme. In this paper, we propose a new model for the intermittent androgen suppression therapy. What is central in the new model is that the competitive effect between androgen-dependent and independent cancer cells is assumed to be essential for the decrease of androgen-independent cells under a normal androgen level. In the newly proposed model, the separatrix in the phase space for a normal androgen level plays an important role. There is crucial difference between the previous model and the new one in the phase diagram of success and failure of the permanent tumor control by intermittent androgen suppression administration. That means that the suggestions from the models for clinical problems can be different. We also consider the combined model of the previous and newly proposed models, which can smoothly bridge two models.     

Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer

15-Lipoxygenase-2 (15-LOX2) is a human-specific lipid-peroxidizing enzyme most prominently expressed in epithelial cells of normal human prostate but downregulated or completely lost in > 70% of prostate cancer (PCa) cases. Transgenic expression of 15-LOX2 in the mouse prostate surprisingly causes hyperplasia. Here we first provide evidence that 15-LOX2-induced prostatic hyperplasia does not progress to PCa even in p53^+/− or p53^−/− background. More important, by generating 15-LOX2; Hi-Myc double transgenic (dTg) mice, we show that 15-LOX2 expression inhibits Myc-induced PCa development, such that in the 3-month- and 6-month-old dTg mice, there is a significant reduction in prostate intraneoplasia (PIN) and PCa prevalent in age-matched Hi-Myc prostates. The dTg prostates show increased cell senescence and expression of several senescence-associated molecules, including p27, phosphorylated Rb, and Rb1cc1. We further show that in HPCa, 15-LOX2 and c-Myc manifest reciprocal protein expression patterns. Moreover, RB1CC1 accumulates in senescing normal human prostate (NHP) cells, and in both NHP and RWPE-1 cells, the 15-LOX2 metabolic products 15(S)-HPETE and 15(S)-HETE induce RB1CC1. We finally show that unlike 15-LOX2, RB1CC1 is not lost but rather frequently overexpressed in PCa samples. RB1CC1 knockdown in PC3 cells enhances clonal growth in vitro and tumor growth in vivo. Together, our present studies provide evidence for tumor-suppressive functions for both 15-LOX2 and RB1CC1.     

E6AP AZUL interaction with UBQLN1/2 in cells,condensates, and an AlphaFold-NMR integrated structure

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Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu

Mesenchymal stem cells (MSCs) are a heterogeneous population of non-hematopoietic precursor cells predominantly found in the bone marrow. They have been recently reported to home towards the hypoxic tumor microenvironment in vivo. Interleukin-6 is a multifunctional cytokine normally involved in the regulation of the immune and inflammatory response. In addition to its normal function, IL-6 signaling has been implicated in tumorigenesis. Solid tumors develop hypoxia as a result of inadequate O₂ supply. Interestingly, tumor types with increased levels of hypoxia are known to have increased resistance to chemotherapy as well as increased metastatic potential. Here, we present evidence that under hypoxic conditions (1.5% O₂) breast cancer cells secrete high levels of IL-6, which serve to activate and attract MSCs. We now report that secreted IL-6 acts in a paracrine fashion on MSCs stimulating the activation of both Stat3 and MAPK signaling pathways to enhance migratory potential and cell survival. Inhibition of IL-6 signaling utilizing neutralizing antibodies leads to attenuation of MSC migration. Specifically, increased migration is dependent on IL-6 signaling through the IL-6 receptor. Collectively, our data demonstrate that hypoxic tumor cells specifically recruit MSCs, which through activation of signaling and survival pathways facilitate tumor progression.     

Up-regulation of MELK by E2F1 promotes the proliferation in cervical cancer cells

Cervical cancer is a common gynecologic cancer and a frequent cause of death. In this study, we investigated the role of MELK (maternal embryonic leucine zipper kinase) in cervical cancer. We found that HPV 18 E6/E7 promoted MELK expression by activating E2F1. MELK knockdown blocked cancer cells growth. Furthermore, we used MELK-8A to inhibit the kinase activity of MELK and caused the G2/M phase arrest of cancer cells. Under the treatment of inhibitors, Hela cells formed multipolar spindles and eventually underwent apoptosis. We also found that MELK is involved in protein translation and folding during cell division through the MELK interactome and the temporal proteomic analysis under inhibition with MELK-8A. Altogether, these results suggest that MELK may play a vital role in cancer cell proliferation and indicate a potential therapeutic target for cervical cancer.     

Proteomics strategies to analyze HPV-transformed cells: relevance to cervical cancer

Cervical cancer is the second most common malignant tumor among women worldwide. The initiating event of cervical cancer is the infection with certain types of human papillomavirus (HPV). Interestingly, viral oncogene expression is necessary but not per se sufficient to promote cervical cancer and other factors are involved in neoplastic progression. Thus, major research efforts should be focused to identify novel co-carcinogenic factors and to understand the mechanisms played into tumor development. To reach this goal, proteomics strategies are powerful tools and a number of studies performed by following this approach have contributed to unravel the interplay between viral infection and protein dysfunction that ultimately results in cancer. The present review summarizes the most relevant findings obtained by applying proteomics technologies to both cell culture models and human tissue specimens. The results suggest that viral oncogenes selectively interact with a subset of intracellular proteins mainly involved in apoptosis resistance, cell growth and differentiation and cell transformation.     

Combined genetic polymorphism and risk for development of lung cancer

Susceptibility to lung cancer has been shown to be modulated by host specific factors. Inheritance of different polymorphic cytochrome P450s (CYPs) and the glutathione S-transferases (GSTs) which affect metabolism of environmental toxicants may play a key role in individual susceptibility. Although individual polymorphic genes have been reported to be associated with development of lung cancer, little is known about the combined effects of several genes in carcinogenesis. From our study of 54 lung cancer patients and 50 matched controls, we observed that a combination of several versions of ‘unfavorable' metabolizing genes (CYP2D6, CYP2E1, GSTM1 and GSTT1) is strongly associated with lung cancer. The relative risk for the different combinations of these genotypes ranged between 1.3 and 14, with higher risk involving the activating genes. The duration and intensity of heavy smoking (expressed in pack-years) are the most important determinant for the development of lung cancer. For example, the estimated risk for development of lung cancer associated with smoking >30 pack-years is represented by an odds ratio=6.65; 95% CL=2.3–19.9 irrespective of an individual's genotype, whereas for smoking between >30 and <50 pack-years, odds ratio=4.5; 95% CL=1.37–15; and for smoking >50 pack-years, odds ratio=30; 95% CL=5.7–114. On the other hand, smoking of less than 30 pack-years is associated with an increased risk in the presence of the polymorphic genes (odds ratio=2.5; 95% CL=0.32–54). The results of our study indicate that the inheritance of multiple ‘unfavorable' genotypes, especially activating genes, is a crucial predisposing factor for the development of lung cancer from cigarette smoking. In addition, the genes may cause moderate smokers who would normally outlive the deleterious effects of smoking to develop lung cancer. The information can therefore be used to target individuals for prevention of health problems.