Induction of cardiac fibroblast lysyl oxidase by TGF-β1 requires PI3K/Akt, Smad3, and MAPK signaling

Voloshenyuk, Tetyana G; Landesman, Elizabeth S.; Khoutorova, Elena; Hart, Andrew; Gardner, Jason D.

doi:10.1016/j.cyto.2011.03.024

Cited by 166 publications

(150 citation statements)

References 39 publications

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“…Furthermore, HIFIA knockdown might downregulate the expression of LOX. In contrast, it has been reported that LOX is regulated by TGFb signaling [55] which is upreglated in hypoxic conditions [36], which suggests that TGFb is also associated with LOX mRNA expression in hypoxic conditions.…”

Section: Discussionmentioning

confidence: 61%

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

et al. 2015

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Purpose It has been reported that lysyl oxidase (LOX) is a hypoxia-responsive factor and is associated with the malignant progression of carcinoma. The aim of this study was to clarify the relationship between the epithelialmesenchymal transition (EMT) and LOX in gastric cancer cells under hypoxia. Methods Two gastric cancer cell lines, OCUM-2MD3 and OCUM-12, were used in an in vitro study. The effect of LOX small interfering RNA (siRNA) on the EMT and motility of gastric cancer cells under hypoxic condition was analyzed by reverse transcription PCR, Western blot, a wound-healing assay, and an invasion assay. Correlations between LOX expression and the clinicopathological features of 544 patients with gastric carcinoma were examined immunohistochemically.Results Hypoxic conditions increased the number of polygonal or spindle-shaped cells resulting from EMT in gastric cancer cells. The EMT of cancer cells induced by hypoxia was inhibited by treatment with LOX siRNA. The number of migrating and invading gastric cancer cells in hypoxia was significantly decreased by LOX knockdown. LOX siRNA significantly increased the E-cadherin level and decreased the vimentin level of gastric cancer cells. LOX expression was significantly associated with invasion depth, tumor differentiation, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal metastasis. Multivariable analysis revealed that LOX was an independent parameter for overall survival. Conclusion LOX affects the EMT of gastric cancer cells in hypoxic conditions. LOX expression is a useful prognostic factor for patients with gastric cancer.

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Section: Discussionmentioning

confidence: 61%

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

et al. 2015

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“…Furthermore, signaling studies have found that both SMAD-dependent and -independent (e.g. JNK/AP-1, PI3K/Akt, and MAPK) signaling pathways were involved in the regulation of LOX induced by TGFB1 in cardiac fibroblasts and human trabecular meshwork cells (Sethi et al 2011, Voloshenyuk et al 2011. A recent study revealed that LOX mRNA and enzyme activities were induced by TGFB1 in a dose-dependent manner in rat granulosa cells (Harlow et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β1 increases lysyl oxidase expression by downregulating MIR29A in human granulosa lutein cells

et al. 2016

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“…The clinical targeting of HREs, such as hypoxia-inducible factor, has shown relative promise in recent years (23,24). However, it has been shown that LOX expression can be induced by cross-talk from other signaling pathways including TGFb (25)(26)(27)(28)(29). At present it is too early to determine whether the success of hypoxia-inducible factor inhibitors is in part attributed to depleting LOX expression.…”

Section: Therapeutic Potential and Clinical Implications For Future Tmentioning

confidence: 98%

Lysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis

2016

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Secondary metastatic cancer remains the single biggest cause of mortality and morbidity across most solid tumors. In breast cancer, 100% of deaths are attributed to metastasis. At present, there are no "cures" for secondary metastatic cancer of any form and there is an urgent unmet clinical need to improve the tools available in our arsenal against this disease, both in terms of treatment, but also prevention. Recently, we showed that hypoxic induction of the extracellular matrix modifying enzyme lysyl oxidase (LOX) correlates with metastatic dissemination to the bone in estrogen receptor negative breast cancer and is essential for the formation of premetastatic osteolytic lesions. We showed that in models of breast cancer metastasis, targeting LOX, or its downstream effects, significantly inhibited premetastatic niche formation and the resulting metastatic burden, offering preclinical validation of this enzyme as a therapeutic target for metastatic breast cancer. Our work is the latest in an emerging body of work supporting the targeting of LOX and calls for greater efforts in developing therapeutics against this extracellular secreted factor in the prevention of cancer progression across multiple solid tumor types. Cancer Res; 76(2); 188-92. Ó2016 AACR. Cancer Metastasis and the Importance of the Cellular MicroenvironmentThe spread of primary tumors to nonadjacent unrelated organs has proven to be a complex and difficult problem for researchers to tackle. This is because metastasis is a systemic process involving not only primary tumor cells, but also contributions from a vast and diverse range of nonmalignant host cells at both primary and secondary sites over varying timescales.Over the last two decades, it has become increasingly apparent in the field of cancer research that the genetic aberrations once seen as the primary drivers of cancer initiation and metastasis, can account for only a subset of the necessary steps required for progression. Additional contributions from the tumor microenvironment, dictated by both the tumor cells themselves, but more importantly by resident nonmalignant cells, provide an enormous repertoire of both soluble and insoluble cues, which facilitate metastasis. The dissemination of an isolated (and often surgically resectable) primary tumor to full-blown metastatic disease is a complex and reciprocal process, and it is currently unclear whether tumor cells or the microenvironment drives progression or they act equally. The deposition and posttranslational modification, as well as remodeling of the local extracellular matrix (ECM) has been shown to be critically important in metastasis both at primary and secondary sites. Similarly, the secretomes of cancer cells (and recruited host cells) have also been shown to be key in controlling the recruitment and response of nonmalignant host cells within the primary tumor microenvironment generating both feed-forward and feed-back signaling loops.The idea that a tumor can modulate not only the behavior of local cells and the re...

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Induction of cardiac fibroblast lysyl oxidase by TGF-β1 requires PI3K/Akt, Smad3, and MAPK signaling

Cited by 166 publications

References 39 publications

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

Transforming growth factor-β1 increases lysyl oxidase expression by downregulating MIR29A in human granulosa lutein cells

Lysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis

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