PTHrP increases xenograft growth and promotes integrin α6β4 expression and Akt activation in colon cancer

Shen, Xiaoli; Rychahou, Piotr G.; Evers, B. Mark; Falzon, Miriam

doi:10.1016/j.canlet.2007.09.010

Cited by 22 publications

(29 citation statements)

References 38 publications

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“…Indeed, the ability of PTHrP to regulate mammary bud development through paracrine interactions with the mesenchyme is established (Hens and Wysolmerski, 2005), but the ability of a specific integrin to control this paracrine mechanism is novel. Interestingly, it was reported previously that PTHrP can regulate β4 expression based on in vitro data (Mula et al, 2010; Shen et al, 2007), a result contrary to our finding. It may be possible, however, that a feedback loop exists between β4 and PTHrP.…”

Section: Resultscontrasting

confidence: 99%

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Sun

Feltri³

et al. 2015

Developmental Biology

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The integrin α6β4 (referred to as β4) is expressed in epithelial cells where it functions as a laminin receptor. Although in vitro studies have implicated β4 in the biology of mammary epithelial cells, its contribution to mammary gland development has not been settled. To address this problem, we generated and analyzed itgb4flox/flox MMTV-Cre− and itgb4flox/flox MMTV-Cre+ mice. The salient features of embryonic mammary tissue from itgb4flox/flox MMTV-Cre+ mice were significantly smaller mammary buds and increased apoptosis in the surrounding mesenchyme. Also, compared to control glands, the itgb4-deleted mammary buds lacked expression of the progenitor cell marker CK14 and they were unable to generate mammary glands upon transplantation into cleared fat pads of recipient mice. Analysis of mammary glands at puberty and during pregnancy revealed that itgb4-diminished mammary tissue was unable to elongate and undergo branching morphogenesis. Micro-dissection of epithelial cells in the mammary bud and of the surrounding mesenchyme revealed that loss of β4 resulted in a significant decrease in the expression of parathyroid hormone related protein (PTHrP) in epithelial cells and of target genes of the PTHrP receptor in mesenchymal cells. Given that the phenotype of the itgb4-deleted mammary tissue mimicked that of the PTHrP knockout, we hypothesized that β4 contributes to mammary gland development by sustaining PTHrP expression and enabling PTHrP signaling. Indeed, the inability of itgb4-deleted mammary buds to elongate was rescued by exogenous PTHrP. These data implicate a critical role for the β4 integrin in mammary gland development and provide a mechanism for this role.

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Section: Resultscontrasting

confidence: 99%

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Sun

Feltri³

et al. 2015

Developmental Biology

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“…In HT29 and HCT116 colon cancer cells the appearance of parathyroid nuclear G-protein coupled receptor is responsible for a direct nuclear action for PTH (Shen et al 2007). We observed that PTH inhibited the splicing of CYP24, however this suppression of CYP24 splicing was overcome in the presence of 1,25(OH) 2 D 3 .…”

Section: Discussionmentioning

confidence: 70%

Regulation of CYP24 splicing by 1,25-dihydroxyvitamin D3 in human colon cancer cells

Xiang

Tiwari²,

Roy³

et al. 2011

Journal of Endocrinology

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In addition, alteration of multiple signaling pathways also affected CYP24 splicing and cellular sensitivity in response to vitamin D appeared to correlate with the induction of CYP24 splicing. These results suggest that 1,25(OH) 2 D 3 not only regulates CYP24 transcription, but also plays an important role in posttranscriptional modulation of CYP24 by inducing its splicing. Our findings reveal an additional regulatory step that makes the vitamin D mediated action more prompt and efficient.

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“…Protein concentrations were estimated using the Bio-Rad protein assay. Protein levels were analyzed by Western blot analysis as previously described [41]. GAPDH was used as loading control.…”

Section: Methodsmentioning

confidence: 99%

Role of parathyroid hormone-related protein in the pro-inflammatory and pro-fibrogenic response associated with acute pancreatitis

Bhatia

Kim

Aronson

et al. 2012

Regulatory Peptides

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Pancreatitis is a common and potentially lethal necro-inflammatory disease with both acute and chronic manifestations. Current evidence suggests that the accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic disease, which is associated with an increased risk of pancreatic cancer. While parathyroid hormone-related protein (PTHrP) exerts multiple effects in normal physiology and disease states, its function in pancreatitis has not been previously addressed. Here we show that PTHrP levels are transiently elevated in a mouse model of cerulein-induced AP. Treatment with alcohol, a risk factor for both AP and chronic pancreatitis (CP), also increases PTHrP levels. These effects of cerulein and ethanol are evident in isolated primary acinar and stellate cells, as well as in the immortalized acinar and stellate cell lines AR42J and irPSCc3, respectively. Ethanol sensitizes acinar and stellate cells to the PTHrP-modulating effects of cerulein. Treatment of acinar cells with PTHrP (1-36) increases expression of the inflammatory mediators interleukin-6 (IL-6) and intracellular adhesion protein (ICAM-1), suggesting a potential autocrine loop. PTHrP also increases apoptosis in AR42J cells. Stellate cells mediate the fibrogenic response associated with pancreatitis; PTHrP (1-36) increases procollagen I and fibronectin mRNA levels in both primary and immortalized stellate cells. The effects of cerulein and ethanol on levels of IL-6 and procollagen I are suppressed by the PTH1R antagonist, PTHrP (7-34). Together these studies identify PTHrP as a potential mediator of the inflammatory and fibrogenic responses associated with alcoholic pancreatitis.

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PTHrP increases xenograft growth and promotes integrin α6β4 expression and Akt activation in colon cancer

Cited by 22 publications

References 38 publications

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Regulation of CYP24 splicing by 1,25-dihydroxyvitamin D3 in human colon cancer cells

Role of parathyroid hormone-related protein in the pro-inflammatory and pro-fibrogenic response associated with acute pancreatitis

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