Drosophila homologue of Diaphanous 1 (DIAPH1) controls the metastatic potential of colon cancer cells by regulating microtubule-dependent adhesion

Lin, Yuan-Na; Bhuwania, Ridhirama; Gromova, Kira V.; Failla, Antonio Virgilio; Lange, Tobias; Riecken, Kristoffer; Linder, Stefan; Kneussel, Matthias; Izbicki, Jakob R.; Windhorst, Sabine

doi:10.18632/oncotarget.4094

Cited by 17 publications

(15 citation statements)

References 33 publications

(50 reference statements)

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“…EGF is used as a metastatic inducer and induces tumor cell invasion and metastasis and the downregulation of Focal Adhesion Kinase 26 . Depletion of DIAPH1 strongly inhibits lung metastasis; in contrast to control cells, DIAPH1-depleted cells do not form metastases in other organs 27 . ITGB2 is known to be responsible for the motility-promoting action, it is integral cell-surface proteins that participate in cell adhesion and cell-surface mediated signaling 28 .…”

Section: Resultsmentioning

confidence: 85%

The lichen secondary metabolite atranorin suppresses lung cancer cell motility and tumorigenesis

Zhou

Yang

Park

et al. 2017

Sci Rep

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Lichens are symbiotic organisms that produce various secondary metabolites. Here, different lichen extracts were examined to identify secondary metabolites with anti-migratory activity against human lung cancer cells. Everniastrum vexans had the most potent inhibitory activity, and atranorin was identified as an active subcomponent of this extract. Atranorin suppressed β-catenin-mediated TOPFLASH activity by inhibiting the nuclear import of β-catenin and downregulating β-catenin/LEF and c-jun/AP-1 downstream target genes such as CD44, cyclin-D1 and c-myc. Atranorin decreased KAI1 C-terminal interacting tetraspanin (KITENIN)-mediated AP-1 activity and the activity of the KITENIN 3′-untranslated region. The nuclear distribution of the AP-1 transcriptional factor, including c-jun and c-fos, was suppressed in atranorin-treated cells, and atranorin inhibited the activity of Rho GTPases including Rac1, Cdc42, and RhoA, whereas it had no effect on epithelial-mesenchymal transition markers. STAT-luciferase activity and nuclear STAT levels were decreased, whereas total STAT levels were moderately reduced. The human cell motility and lung cancer RT² Profiler PCR Arrays identified additional atranorin target genes. Atranorin significantly inhibited tumorigenesis in vitro and in vivo. Taken together, our results indicated that E. vexans and its subcomponent atranorin may inhibit lung cancer cell motility and tumorigenesis by affecting AP-1, Wnt, and STAT signaling and suppressing RhoGTPase activity.

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Section: Resultsmentioning

confidence: 85%

The lichen secondary metabolite atranorin suppresses lung cancer cell motility and tumorigenesis

Zhou

Yang

Park

et al. 2017

Sci Rep

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“…BLPAP (Bladder cancer-associated protein) is a highly conserved protein among species displaying tissue-specific expression patterns, but also tissue-specific functions being both a tumor suppressor and a tumor promoting [42]. Recent data revealed that the blockade of DIAPH1-tubulin interaction might be a promising approach to inhibit one of the earliest steps in the metastatic cascade of colon cancer [43]. FGF18 is a pleiotropic growth factor involved in skeletal growth and development [44, 45].…”

Section: Resultsmentioning

confidence: 99%

Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma

et al. 2016

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Understanding the biology and molecular pathogenesis of ovarian epithelial cancer (EOC) is key to developing improved diagnostic and prognostic indicators and effective therapies. Although research has traditionally focused on the hypothesis that high-grade serous carcinoma (HGSC) arises from the ovarian surface epithelium (OSE), recent studies suggest that additional sites of origin exist and a substantial proportion of cases may arise from precursor lesions located in the Fallopian tubal epithelium (FTE). In FTE cells, the transcription factor PAX8 is a marker of the secretory cell lineage and its expression is retained in 96% of EOC. We have recently reported that PAX8 is involved in the tumorigenic phenotype of ovarian cancer cells. In this study, to uncover genes and pathways downstream of PAX8 involved in ovarian carcinoma we have determined the molecular profiles of ovarian cancer cells and in parallel of Fallopian tube epithelial cells by means of a silencing approach followed by an RNA-seq analysis. Interestingly, we highlighted the involvement of pathways like WNT signaling, epithelial-mesenchymal transition, p53 and apoptosis. We believe that our analysis has led to the identification of candidate genes and pathways regulated by PAX8 that could be additional targets for the therapy of ovarian carcinoma.

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“…Because the development of α‐SMA positive stress fibers is known to be regulated by RhoA 43,44 and Diaph1 is an effector of RhoA, it is possible that RhoA‐Diaph1 signaling axis may contribute to HSC activation through modulating the formation of SMA‐positive‐stress fibers. Moreover, the movement of endocytic vesicles within a cell occurs along microtubules 18 and Diaph1 is known to stabilize microtubules so as to target β1‐integrin and membrane type1‐matrix metalloproteinase (MT1‐MMP) to the plasma membrane 15,45 . Thus, in addition to promoting the endocytosis of TβRII at the upstream of the TGFβ signaling, Diaph1 may also participate in and regulate multiple steps of the TGFβ signaling cascade for HSC activation.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the movement of endocytic vesicles within a cell occurs along microtubules 18 and Diaph1 is known to stabilize microtubules so as to target β1-integrin and membrane type1-matrix metalloproteinase (MT1-MMP) to the plasma membrane. 15 , 45 Thus, in addition to promoting the endocytosis of TβRII at the upstream of the TGFβ signaling, Diaph1 may also participate in and regulate multiple steps of the TGFβ signaling cascade for HSC activation.…”

Section: Discussionmentioning

confidence: 99%

“…Diaph1 has been characterized as an oncogenic protein in cancer cells. The gene expression level of Diaph1 was elevated in multiple cancers, including cancer of prostate, breast, lung and lymphocyte, 45 and it correlated with the clinical stage of laryngeal squamous cell carcinoma, 16 metastasis of colorectal cancer, 15 and poor overall survival of patients with high grade (class G3) head and neck cancer. 16 Diaph1 inhibited the apoptosis of cancer cells 16 and promoted cancer cell adhesion, invasion, and metastasis in vitro.…”

Section: Discussionmentioning

confidence: 99%

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Protein diaphanous homolog 1 (Diaph1) promotes myofibroblastic activation of hepatic stellate cells by regulating Rab5a activity and TGFβ receptor endocytosis

Liu

Wang

et al. 2020

FASEB j.

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TGFβ induces the differentiation of hepatic stellate cells (HSCs) into tumor‐promoting myofibroblasts but underlying mechanisms remain incompletely understood. Because endocytosis of TGFβ receptor II (TβRII), in response to TGFβ stimulation, is a prerequisite for TGF signaling, we investigated the role of protein diaphanous homolog 1 (known as Diaph1 or mDia1) for the myofibroblastic activation of HSCs. Using shRNA to knockdown Diaph1 or SMIFH2 to target Diaph1 activity of HSCs, we found that the inactivation of Diaph1 blocked internalization and intracellular trafficking of TβRII and reduced SMAD3 phosphorylation induced by TGFβ1. Mechanistic studies revealed that the N‐terminal portion of Diaph1 interacted with both TβRII and Rab5a directly and that Rab5a activity of HSCs was increased by Diaph1 overexpression and decreased by Diaph1 knockdown. Additionally, expression of Rab5aQ79L (active Rab5a mutant) increased whereas the expression of Rab5aS34N (inactive mutant) reduced the endosomal localization of TβRII in HSCs compared to the expression of wild‐type Rab5a. Functionally, TGFβ stimulation promoted HSCs to express tumor‐promoting factors, and α‐smooth muscle actin, fibronection, and CTGF, markers of myofibroblastic activation of HSCs. Targeting Diaph1 or Rab5a suppressed HSC activation and limited tumor growth in a tumor implantation mouse model. Thus, Dipah1 and Rab5a represent targets for inhibiting HSC activation and the hepatic tumor microenvironment.

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Drosophila homologue of Diaphanous 1 (DIAPH1) controls the metastatic potential of colon cancer cells by regulating microtubule-dependent adhesion

Cited by 17 publications

References 33 publications

The lichen secondary metabolite atranorin suppresses lung cancer cell motility and tumorigenesis

The lichen secondary metabolite atranorin suppresses lung cancer cell motility and tumorigenesis

Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma

Protein diaphanous homolog 1 (Diaph1) promotes myofibroblastic activation of hepatic stellate cells by regulating Rab5a activity and TGFβ receptor endocytosis

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