GCF2/LRRFIP1 promotes colorectal cancer metastasis and liver invasion through integrin-dependent RhoA activation

Ariake, Kyohei; Ohtsuka, Hideo; Motoi, Fuyuhiko; Douchi, Daisuke; Oikawa, Masaya; Rikiyama, Toshiki; Fukase, Koji; Katayose, Yu; Egawa, Shinichi; Unno, Michiaki

doi:10.1016/j.canlet.2012.06.012

Cited by 37 publications

(28 citation statements)

References 46 publications

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“…Using Vesiclepdia and Exocarta Databases [47, 48], this protein has already been identified in the cargo of CRC-derived exosomes [49]. The function of LRRFIP1 in cellular polarity/organisation is exemplified by a recent study that demonstrated LRRFIP1-stimulated CRC metastasis and invasion of hepatocytes through integrin-dependent RhoA activation [50]. Interestingly, RhoA can also be activated by Collagen alpha-1(III) chain (COL3A1) [51], another candidate exclusively identified from the cargo of exosomes derived from dTGFBR2 cells.…”

Section: Discussionmentioning

confidence: 99%

TGFBR2-dependent alterations of exosomal cargo and functions in DNA mismatch repair-deficient HCT116 colorectal cancer cells

et al. 2017

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BackgroundColorectal cancers (CRCs) that lack DNA mismatch repair function exhibit the microsatellite unstable (MSI) phenotype and are characterized by the accumulation of frameshift mutations at short repetitive DNA sequences (microsatellites). These tumors recurrently show inactivating frameshift mutations in the tumor suppressor Transforming Growth Factor Beta Receptor Type 2 (TGFBR2) thereby abrogating downstream signaling. How altered TGFBR2 signaling affects exosome-mediated communication between MSI tumor cells and their environment has not been resolved. Here, we report on molecular alterations of exosomes shed by MSI cells and the biological response evoked in recipient cells.MethodsExosomes were isolated and characterized by electron microscopy, nanoparticle tracking, and western blot analysis. TGFBR2-dependent effects on the cargo and functions of exosomes were studied in a MSI CRC model cell line enabling reconstituted and inducible TGFBR2 expression and signaling. Microsatellite frameshift mutations in exosomal and cellular DNA were examined by PCR-based DNA fragment analysis and exosomal protein profiles were identified by mass spectrometry. Uptake of fluorescent-labeled exosomes by hepatoma recipient cells was monitored by confocal microscopy. TGFBR2-dependent exosomal effects on secreted cytokine levels of recipient cells were analyzed by Luminex technology and ELISA.ResultsFrameshift mutation patterns in microsatellite stretches of TGFBR2 and other MSI target genes were found to be reflected in the cargo of MSI CRC-derived exosomes. At the proteome level, reconstituted TGFBR2 expression and signaling uncovered two protein subsets exclusively occurring in exosomes derived from TGFBR2-deficient (14 proteins) or TGFBR2-proficient (five proteins) MSI donor cells. Uptake of these exosomes by recipient cells caused increased secretion (2–6 fold) of specific cytokines (Interleukin-4, Stem Cell Factor, Platelet-derived Growth Factor-B), depending on the TGFBR2 expression status of the tumor cell.ConclusionOur results indicate that the coding MSI phenotype of DNA mismatch repair-deficient CRC cells is maintained in their exosomal DNA. Moreover, we uncovered that a recurrent MSI tumor driver mutation like TGFBR2 can reprogram the protein content of MSI cell-derived exosomes and in turn modulate the cytokine secretion profile of recipient cells. Apart from its diagnostic potential, these TGFBR2-dependent exosomal molecular and proteomic signatures might help to understand the signaling routes used by MSI tumors.Graphical AbstractFricke et al. uncovered coding microsatellite instability-associated mutations of colorectal tumor driver genes like TGFBR2 in MSI tumor cellderived exosomes. Depending on the TGFBR2 expression status of their donor cells, shed exosomes show distinct proteomic signatures and promote altered cytokine secretion profiles in recipient cells. Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-017-0169-y) contains supplementary material, which is avail...

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Section: Discussionmentioning

confidence: 99%

TGFBR2-dependent alterations of exosomal cargo and functions in DNA mismatch repair-deficient HCT116 colorectal cancer cells

et al. 2017

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“…13,15) The RhoA signaling has been reported to be activated in the invasion or metastasis including, but not limited to, colorectal cancer, breast cancer, and prostate cancer. [28][29][30] In order to explore its pro-oncogenic role in cervical carcinoma, we manipulated the RhoA level in Hela cells by overexpressing or knockdowning RhoA. Firstly, we overexpressed RhoA and EGFP with the 2A peptide linker, which is a "self-cleavage" peptide of foot-and-mouth disease virus.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of RhoA promotes the proliferation and migration of cervical cancer cells

Liu

Chen

2014

Bioscience, Biotechnology, and Biochemistry

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The pro-oncogenic role of RhoA has been well identified in other cancers, but rarely in cervical cancer (CC), one of the main causes of cancer-related death in women. In the present study, we identified the overexpression of RhoA and its downstream effectors, ROCK-1 and ROCK-II, in CC specimens using western blotting. Then, we determined the effect of RhoA on the proliferation and migration of Hela cells, one of CC cell lines, by upregulating or downregulating the RhoA expression in Hela cells. We found that there was an overexpression of RhoA, ROCK-I/II in CC, which was associated with the progression of CC. And we confirmed that RhoA promoted the proliferation and migration of CC cells. In conclusion, we found a positive correlation among RhoA with the progression of CC by in vivo and in vitro evidences. A high RhoA expression in CC may predict a high metastatic potential of CC.

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“…A very recent report showed that GCF2/LRRFIP1 regulates pro-survival proteins and pathways in rat astrocytes, including β-catenin, Akt, and mTOR [186]. While still at early stages of investigation, if the effects of GCF2/LRRFIP1 are confirmed, it could become a new therapeutic target to modulate TNF-α expression, although its negative effects must also be studied as another report suggests it may stimulate metastasis in some forms of cancers [187]. …”

Section: Strategies and Challenges Involving Central Tnf-α Signalimentioning

confidence: 99%

Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease

Decourt¹,

Lahiri

Sabbagh

2017

CAR

302

212

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Alzheimer’s disease (AD) affects an estimated 44 million individuals worldwide, yet no therapeutic intervention is available to stop the progression of the dementia. Neuropathological hallmarks of AD are extracellular deposits of amyloid beta (Aβ) peptides into plaques, intraneuronal accumulation of hyperphosphorylated tau protein forming tangles, and chronic inflammation. A pivotal molecule in inflammation is the pro-inflammatory cytokine TNF-α. Several lines of evidence using genetic and pharmacological manipulations indicate that TNF-α signaling exacerbates both Aβ and tau pathologies in vivo. Interestingly, preventive and intervention anti-inflammatory strategies demonstrated a reduction in brain pathology and an amelioration of cognitive function in rodent models of AD. Phase I and IIa clinical trials suggest that TNF-α inhibitors might slow down cognitive decline and improve daily activities in AD patients. In the present review, we summarize the evidence pointing towards a beneficial role of anti-TNF-α therapies to prevent or slow the progression of AD. We also present possible physical and pharmacological interventions to modulate TNF-α signaling in AD subjects along with their limitations.

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GCF2/LRRFIP1 promotes colorectal cancer metastasis and liver invasion through integrin-dependent RhoA activation

Cited by 37 publications

References 46 publications

TGFBR2-dependent alterations of exosomal cargo and functions in DNA mismatch repair-deficient HCT116 colorectal cancer cells

TGFBR2-dependent alterations of exosomal cargo and functions in DNA mismatch repair-deficient HCT116 colorectal cancer cells

Overexpression of RhoA promotes the proliferation and migration of cervical cancer cells

Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease

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