scholarly journals CUB domain-containing protein 1 controls HGF responses by integrating Src and Met–STAT3 signaling

2019 ◽  
Author(s):  
Kentaro Kajiwara ◽  
Atsuya Sugihara ◽  
Kazuhiro Aoki ◽  
Daisuke Okuzaki ◽  
Kunio Matsumoto ◽  
...  
Keyword(s):  
Breast Cancer Cells ◽  
Renal Growth ◽  
Compensatory Renal Growth ◽  
Stat3 Signaling ◽  
Biological Responses ◽  
Organ Regeneration ◽  
Cub Domain ◽  
Hepatocyte Growth ◽  
Invasive Cell

AbstractHepatocyte growth factor (HGF) controls various biological responses, including morphogenesis, organ regeneration, and cancer invasion, by activating its receptor, Met. However, the mechanisms that precisely control diverse Met signaling remain unclear. Here, we identified CUB domain-containing protein 1 (CDCP1) as a crucial element of HGF signaling. In MDCK cysts, HGF induced Src activation via CDCP1 upregulation, and CDCP1 ablation abrogated HGF responses, i.e., extended invasive cell protrusions and promoted cell growth/proliferation. Mechanistically, CDCP1 upregulation promoted Src recruitment into lipid rafts to activate Met-associated STAT3. In breast cancer cells in which Met and CDCP1 were co-upregulated, CDCP1 knockdown suppressed HGF-induced cell invasion. Furthermore, in vivo analysis showed that CDCP1 ablation suppressed compensatory renal growth by attenuating Met–STAT3 signaling. These findings demonstrate that CDCP1 plays a crucial role in controlling HGF responses by integrating Src and Met-STAT3 signaling, and provide new insights into the regulatory mechanisms underlying the multifaceted functions of HGF.

scholarly journals CDCP1 promotes compensatory renal growth by integrating Src and Met signaling

2021 ◽  
Vol 4 (4) ◽  
pp. e202000832
Author(s):  
Kentaro Kajiwara ◽  
Shotaro Yamano ◽  
Kazuhiro Aoki ◽  
Daisuke Okuzaki ◽  
Kunio Matsumoto ◽  
...  
Keyword(s):  
Compensatory Growth ◽  
Morphological Changes ◽  
Renal Tubules ◽  
Kidney Cells ◽  
Renal Growth ◽  
Compensatory Renal Growth ◽  
Stat3 Signaling ◽  
Cub Domain ◽  
Hepatocyte Growth ◽  
Canine Kidney

Compensatory growth of organs after loss of their mass and/or function is controlled by hepatocyte growth factor (HGF), but the underlying regulatory mechanisms remain elusive. Here, we show that CUB domain-containing protein 1 (CDCP1) promotes HGF-induced compensatory renal growth. Using canine kidney cells as a model of renal tubules, we found that HGF-induced temporal up-regulation of Src activity and its scaffold protein, CDCP1, and that the ablation of CDCP1 robustly abrogated HGF-induced phenotypic changes, such as morphological changes and cell growth/proliferation. Mechanistic analyses revealed that up-regulated CDCP1 recruits Src into lipid rafts to activate STAT3 associated with the HGF receptor Met, and activated STAT3 induces the expression of matrix metalloproteinases and mitogenic factors. After unilateral nephrectomy in mice, the Met-STAT3 signaling is transiently up-regulated in the renal tubules of the remaining kidney, whereas CDCP1 ablation attenuates regenerative signaling and significantly suppresses compensatory growth. These findings demonstrate that CDCP1 plays a crucial role in controlling compensatory renal growth by focally and temporally integrating Src and Met signaling.

scholarly journals Atrial natriuretic peptide suppresses compensatory renal growth in rats.

1994 ◽  
Vol 4 (12) ◽  
pp. 2016-2022
Author(s):  
J L Logan ◽  
U F Michael
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Mesangial Cells ◽  
Cell Types ◽  
Renal Growth ◽  
Compensatory Renal Growth ◽  
Intact Rats ◽  
Atrial Natriuretic

Atrial natriuretic peptide (ANP) inhibits the growth of a variety of cell types in vitro including mesangial cells. The effects of ANP on the growth of the kidney in vivo were evaluated. A 2-h infusion of 0.2 microgram/250 g body wt per minute of ANP suppressed the subsequent uptake of [3H]thymidine into the renal DNA of uninephrectomized but not intact rats. This treatment also depressed the ratio of RNA/DNA in kidneys undergoing compensatory growth. Correlative physiologic studies revealed enhanced GFR in rats with two kidneys infused with ANP, but no increase in the GFR of uninephrectomized rats. It was concluded that ANP may oppose the growth factor(s) mediating compensatory renal growth.

scholarly journals HMGN5 escorts oncogenic STAT3 signaling by regulating chromatin landscape in tumorigenesis of breast cancer

2022 ◽  
Author(s):  
Jiahui Mou ◽  
Meijun Huang ◽  
Feifei Wang ◽  
Xiaoding Xu ◽  
Hanqi Xie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epigenetic Alterations ◽  
Stat3 Signaling ◽  
Specific Manner ◽  
A Cell ◽  
Nucleosome Binding

Epigenetic alterations are widely linked with carcinogenesis, therefore becoming emerging therapeutic targets in the treatment of cancers, including breast cancer. HMGNs are nucleosome binding proteins, which regulate chromatin structures in a cell type- and disease-specific manner. However, the roles of HMGNs in the tumorigenesis of breast cancer are less known. In this study, we report that HMGNs are highly expressed in 3D-cultured breast cancer cells. HMGN5, a member of HMGNs, controls the proliferation, invasion and metastasis of breast cancer cells in vitro and in vivo. Clinically, HMGN5 is an unfavorable prognostic marker in patients. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape oncogenic chromatin landscape and transcriptional program. Lastly, we provide evidence that interference of HMGN5 by nanoparticle-packaged siRNA is potentially an effective approach in breast cancer treatment. Taken together, our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic-target in STAT3-hyperactive breast cancer.

Incorporation of 32P into phospholipids in vivo during compensatory renal growth

1985 ◽  
Vol 833 (2) ◽  
pp. 223-228 ◽  
Author(s):  
Hrvoje Banfić ◽  
Nikša Pokrajac ◽  
Robin F. Irvine
Keyword(s):  
Renal Growth ◽  
Compensatory Renal Growth

scholarly journals In VitroandIn VivoEffects of Suppressor of Cytokine Signalling 7 Knockdown in Breast Cancer: The Influence on Cellular Response to Hepatocyte Growth Factor

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Walid Sasi ◽  
Lin Ye ◽  
Wen G. Jiang ◽  
Anup K. Sharma ◽  
Kefah Mokbel
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Xenograft Growth ◽  
And Migration ◽  
Hepatocyte Growth

Purpose. Suppressor of cytokine signaling 7 (SOCS7) is a member of the SOCS family and is known to interact with phospholipase Cγ-1 (PLCγ-1), a key downstream mediator of the hepatocyte growth factor (HGF)/C-MET axis. Here, we report our observations of the effect of knocking down SOCS7 gene on the behaviour of breast cancer cells bothin vitroandin vivoand to elucidate whether this involves HGF/C-MET pathway using the PLCγ-1 blocker U73122.Methods. MCF7 and MDA-MB-231 breast cancer cells were transfected with anti-SOCS7 ribozymal transgene, to create sublines with SOCS7 knockdown. Thein vitrogrowth and migration of the cells were evaluated in basic conditions and with HGF and U73122 treatment using growth assays, scratch-wound, and electrical cell impedance sensing (ECIS) migration assays. MCF7 and MDA-MB-231in vivotumour xenograft growth were also studied.Results. Basalin vitrogrowth and migration of both cellular lines and thein vivoMCF7 xenograft growth were significantly enhanced with SOCS7 knockdown.In vitroHGF treatment has further influenced the growth and migration when SOCS7 gene was knocked-down in both cellular lines(P<0.05). PLCγ-1 pharmacological inhibition of the HGF/C-MET cascade during theirin vitrogrowth and migration seemed to only occur when SOCS7 gene was knocked down.Conclusions. We report a unique regulatory role for SOCS7 in controlling the malignant behaviour of breast cancer lines MCF7 and MDA-MB-231in vitroand the MCF7 tumour xenograftsin vivo. We also report a regulatory role for SOCS7 during thein vitroHGF-induced growth and migration in these cells as HGF treatment and SOCS7 loss have synergistically enhanced these functions. This SOCS7 knockdown-attributed effect could be due to a precise anti-PLCγ-1 role.

Early increase in pulsatile growth hormone release after unilateral nephrectomy in adult rats

1994 ◽  
Vol 266 (4) ◽  
pp. F628-F632 ◽  
Author(s):  
A. Haramati ◽  
M. D. Lumpkin ◽  
S. E. Mulroney
Keyword(s):  
Growth Hormone ◽  
Early Time ◽  
Peak Level ◽  
Unilateral Nephrectomy ◽  
Sham Operation ◽  
Renal Growth ◽  
Adult Rats ◽  
Compensatory Renal Growth ◽  
Jugular Veins ◽  
Hypertrophic Response

Removal of one kidney results, within days, in accelerated growth of the remaining kidney. However, the mechanisms that underlie this compensatory renal hypertrophic response, particularly in the early time period following nephrectomy, are not understood. In this study we tested the hypothesis that removal of one kidney leads to a change in the pulsatile release of growth hormone (GH), which facilitates compensatory renal growth. Adult Wistar rats were implanted with Silastic cannulas in jugular veins and underwent either unilateral nephrectomy (UNX) or sham operation. Plasma levels of GH were determined 24 and 48 h after sham operation or UNX. Blood samples were taken every 20 min over a 6-h period from conscious, unrestrained animals. Pulsatile GH release was markedly elevated 24 h after UNX in both the amplitude of the surges as well as in the duration of release. Peak GH levels after 24 h were three- to fourfold higher in UNX rats compared with sham controls (417 +/- 75 vs. 119 +/- 23 ng/ml, P < 0.05). However, this enhanced release of GH appeared to be of short duration and began declining by 48 h post-UNX (peak level of 227 +/- 37 ng/ml, P < 0.05 vs. both 24 h UNX and sham controls). To examine whether this rise in GH release post-UNX contributed to the compensatory renal growth, rats underwent UNX and were immediately treated with an antagonist to GH-releasing factor (GRF-AN; i.e., [N-Ac-Tyr1,D-Arg2]GRF-(1-29) amide, 200 micrograms/kg twice daily), and the effects on GH release and renal growth were determined. Administration of GRF-AN significantly suppressed the increase in GH release post-UNX and was associated with a significant attenuation in renal growth 48 h post-UNX in GRF-AN-treated rats (8.7 +/- 2.6% vs. 22.7 +/- 3.0% in UNX controls, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

scholarly journals Controllable Drug Delivery by Na+/K+ ATPase α1 Targeting Peptide Conjugated DSPE-PEG Nanocarriers for Breast Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382110278
Author(s):  
Yayan Yang ◽  
Qian Feng ◽  
Chuanfeng Ding ◽  
Wei Kang ◽  
Xiufeng Xiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Click Reaction ◽  
Chemotherapy Drugs ◽  
Targeting Peptide ◽  
And Migration

Although Epirubicin (EPI) is a commonly used anthracycline for the treatment of breast cancer in clinic, the serious side effects limit its long-term administration including myelosuppression and cardiomyopathy. Nanomedicines have been widely utilized as drug delivery vehicles to achieve precise targeting of breast cancer cells. Herein, we prepared a DSPE-PEG nanocarrier conjugated a peptide, which targeted the breast cancer overexpression protein Na+/K+ ATPase α1 (NKA-α1). The nanocarrier encapsulated the EPI and grafted with the NKA-α1 targeting peptide through the click reaction between maleimide and thiol groups. The EPI was slowly released from the nanocarrier after entering the breast cancer cells with the guidance of the targeting NKA-α1 peptide. The precise and controllable delivery and release of the EPI into the breast cancer cells dramatically inhibited the cells proliferation and migration in vitro and suppressed the tumor volume in vivo. These results demonstrate significant prospects for this nanocarrier as a promising platform for numerous chemotherapy drugs.

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