HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia

Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of succinate dehydrogenase C (SDHC), a direct HSF1 target. Forced expression of SDHC largely restores the Hsf1 ablation-induced AML developmental defect. Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML

Overexpression of CARMA3 in Non-Small-Cell Lung Cancer Is Linked for Tumor Progression

We aimed to investigate the clinical significance of the expression of novel scaffold protein CARMA3 in non-small-cell lung cancer (NSCLC) and the biological function of CARMA3 in NSCLC cell lines. We observed moderate to high CARMA3 staining in 68.8% of 141 NSCLC specimens compared to corresponding normal tissues. The overexpression of CARMA3 was significantly correlated with TNM stage (P = 0.022) and tumor status (P = 0.013). CARMA3 upregulation also correlated with a shorter survival rate of patients of nodal status N0 (P = 0.042)as well as the expression of epidermal growth factor receptor (EGFR) (P = 0.009). In EGFR mutation positive cases, CARMA3 expression was much higher (87.5%) compared to non-mutation cases (66.1%). In addition, we observed that knockdown of CARMA3 inhibits tumor cell proliferation and invasion, and induces cell cycle arrest at the boundary between the G1 and S phase. We further demonstrated a direct link between CARMA3 and NF-κB activation. The change of biological behavior in CARMA3 knockdown cells may be NF-κB-related. Our findings demonstrated, for the first time, that CARMA3 was overexpressed in NSCLC and correlated with lung cancer progression, EGFR expression, and EGFR mutation. CARMA3 could serve as a potential companion drug target, along with NF-kB and EGFR in EGFR-mutant lung cancers

Expression of delta-catenin is associated with progression of human astrocytoma

Abstract Background δ-Catenin (CTNND2), which encodes a scaffold protein in humans, has been found in a few malignancies. However, the expression pattern and contribution of δ-catenin to astrocytoma progression are unclear. Methods We investigated δ-catenin expression in human astrocytoma samples and its function in astrocytoma cell lines using immunohistochemistry, siRNA knockdown, transfection, MTT, transwell migration and Rac1 pulldown techniques. Results δ-Catenin protein expression was detected in cytoplasm of astrocytoma cells by immunohistochemistry. Analysis showed that grade I astrocytoma (0%, 0/11) and glial cells from normal brain tissue exhibited negative staining. δ-Catenin expression was significantly higher in grade III-IV (35%, 29/84) compared to grade II astrocytoma cells (18%, 11/61); p CTNND2 overexpression promoted proliferation, invasion and Rac1 activity of U251 astrocytoma cells. Treatment of δ-catenin-transfected cells with a Rac1 inhibitor decreased Rac1 activity and invasion. δ-Catenin knockdown in U87 glioblastoma cell decreased cell proliferation, invasion and Rac1 activity. Conclusion The results suggest that δ-catenin expression is associated with the malignant progression of astrocytoma and promotes astrocytoma cell invasion through upregulation of Rac1 activity. δ-Catenin expression levels may serve as a useful marker of the biological behavior of astrocytoma cells.</p

Diversin is overexpressed in breast cancer and accelerates cell proliferation and invasion.

Diversin was recently reported to play roles in Wnt and JNK pathways. However, the expression pattern and biological roles of diversin in human breast cancer have not been reported. In the present study, we found that diversin was overexpressed in breast cancer specimens by immunohistochemistry and western blot. Significant association was observed between diversin overexpression and TNM stage (p = 0.0036), nodal metastasis (p = 0.0033), negative estrogen receptor expression (p = 0.0012) and triple-negative status (p = 0.0017). Furthermore, colony formation assay and matrigel invasion assay showed that knockdown of diversin expression in MDA-MB-231 cell line with high endogenous expression decreased cell proliferation and cell invasion. Transfection of diversin plasmid in MCF-7 cell line increased cell proliferation and invasion. Further analysis showed that diversin depletion downregulated JNK phosphorylation while its overexpression upregulated JNK phosphorylation. In conclusion, our study demonstrated that diversin was overexpressed in human breast cancers. Diversin could contribute to breast cancer cell proliferation and invasion

Rab11a Is Overexpressed in Gastric Cancer and Regulates FAK/AKT Signaling

Dysregulation of Rab11a has been implicated in the progression of several cancers. However, there have been no such studies for human gastric cancers. In the current study, we examined Rab11a protein expression and found it was upregulated in 49 of 108 gastric cancer tissues and correlated with local invasion, nodal metastasis, and advanced stage. Rab11a protein was higher in gastric cancer cell lines than normal gastric cell line. We transfected Rab11a plasmid and siRNA in both MGC803 and AGS cell lines. Rab11a overexpression increased the cell growth rate, colony numbers, and invasion ability in both MGC803 and AGS cell lines. Downregulation of Rab11a using siRNA decreased the cell proliferation rate, colony numbers, and inhibited invasion. Rab11a overexpression also conferred cisplatin resistance. Annexin V/PI staining showed that Rab11a overexpression suppressed cisplatin-induced apoptosis, while Rab11a depletion promoted cell apoptosis. We also showed that Rab11a overexpression maintained mitochondrial membrane potential. Western blot analysis revealed that Rab11a increased protein expression of MMP2, cyclin D1, Bcl-2, p-FAK, and p-AKT, while Rab11a depletion showed the opposite effects. Blockage of FAK using inhibitor downregulated Bcl-2, cyclin D1, MMP2, and p-AKT expression and abolished the effects of Rab11a on these proteins. In summary, our data demonstrated that Rab11a is upregulated in human gastric cancers. Rab11a facilitated cell proliferation and invasion, as well as cisplatin sensitivity and mitochondrial membrane potential, possibly via the FAK/AKT signaling pathway

Diversin depletion inhibited and its overexpression promoted cell proliferation and invasion and JNK phosphorylation.

<p>A. Colony formation assay showed that diversin knockdown inhibited proliferation in MDA-MB-231 cell line and its overexpression promoted proliferation in MCF-7 cell line. B. Diversin depletion decreased the level of 231 cell invasion and its overexpression facilitated invasion in MCF-7 cells. C. Western blotting revealed that knockdown of diversin decreased the levels of p-JNK and diversin transfection increased p-JNK, without significant changes of total JNK, p-p38 and p38. Scale bar, 200 µm.</p

Diversin expression in breast cancer cell lines.

<p>A. Western blot analysis of diversin expression in breast cancer cell lines Her-18, MDA-MB-231, MDA-MB-435, T46D, MCF-7 and normal breast cell line MCF-10A. B. Western blot and realtime PCR analysis showed that diversin siRNA treatment markedly decreases diversin mRNA and protein levels in MDA-MB-231 (p<0.05). Transfection of diversin plasmid significantly upregulated its expression in MCF-7 cell line (p<0.05).</p

Distribution of diversin status in breast cancer according to clinicopathological characteristics.

<p>Distribution of diversin status in breast cancer according to clinicopathological characteristics.</p