Targeting SHP-1–STAT3 signaling: a promising therapeutic approach for the treatment of cholangiocarcinoma

Hu, Meiru; Chen, L.J.; Chen, Y.L.; Tsai, Ming-Hsien; Shiau, Chung‐Wai; Chao, Tzu I.; Kao, Jia‐Horng; Chen, K.F.

doi:10.1016/s0959-8049(17)30363-5

Cited by 3 publications

(5 citation statements)

References 29 publications

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“…With increased expression of SHP-1 protein, phosphorylated STAT3 levels were significantly decreased in decitabine-treated (2 and 5 mmol/L) cells, suggesting that SHP-1 protein also dephosphorylates STAT3 in MDS skm-1 cells, similar to other types of cancer. 26,27 To investigate the effect of STAT3 dephosphorylation on the skm-1 cell biological response, possible changes in cell viability and apoptosis were assessed. A higher concentration of 5-Aza was associated with decreased cell viability and increased apoptosis, which is consistent with other reports.…”

Section: Discussionmentioning

confidence: 99%

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The role of Src homology region 2 domain-containing phosphatase-1 hypermethylation in the classification of patients with myelodysplastic syndromes and its association with signal transducer and activator of transcription 3 phosphorylation in skm-1 cells

et al. 2021

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Introduction Myelodysplastic syndromes (MDS) are a group of heterogeneous bone marrow clonal diseases characterized by the abnormal differentiation and development of bone marrow cells. Src homology region 2 domain-containing phosphatase (SHP)-1 is an important tumor suppressor gene that regulates the signal transducer and activator of transcription (STAT) pathway. Methods Survival analysis was performed to evaluate the function of decitabine (5-Aza) in treating MDS patients with and without SHP-1 methylation. The effects of 5-Aza treatment on SHP-1 expression and methylation and STAT3 phosphorylation were investigated in MDS cells by methylation-specific PCR, reverse transcription PCR, and western blotting. Cell viability and apoptosis were similarly evaluated by MTT assay and flow cytometry. Results High-risk MDS patients showed significant SHP-1 hypermethylation compared with low-risk patients, and patients with no SHP-1 methylation had longer overall survival. SHP-1 expression was significantly increased at mRNA and protein levels following 5-Aza treatment, while the phosphorylation of STAT3 protein was significantly decreased. Apoptosis increased significantly in MDS cells treated with higher doses of 5-Aza while cell viability decreased significantly. Conclusion SHP-1 hypermethylation was associated with poor prognosis in HR patients with MDS, suggesting it could be used as a prognostic indicator.

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Section: Discussionmentioning

confidence: 99%

“…With increased expression of SHP-1 protein, phosphorylated STAT3 levels were significantly decreased in decitabine-treated (2 and 5 µmol/L) cells, suggesting that SHP-1 protein also dephosphorylates STAT3 in MDS skm-1 cells, similar to other types of cancer. 26,27…”

Section: Discussionmentioning

confidence: 99%

The role of Src homology region 2 domain-containing phosphatase-1 hypermethylation in the classification of patients with myelodysplastic syndromes and its association with signal transducer and activator of transcription 3 phosphorylation in skm-1 cells

et al. 2021

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“…However, many compounds in experimental cancer trials exert at least some of their tumour suppressing action by inhibiting the activation of STAT3, instead of directly targeting IL‐6 and its receptors. For example, the EGFR inhibitor afatinib reduces proliferation of iCCA cell lines and sensitizes them to cell death signals concomitantly with pSTAT3 reduction; SC‐43, a sorafenib derivative, inhibits STAT3 phosphorylation by a Src homology region 2 domain‐containing phosphatase‐1 (SHP1)‐dependent mechanism, inducing cell cycle arrest/apoptosis in cultured CCA cell lines and growth inhibition of CCA xenografts in the mouse . Other drug candidates with similar outcome are metformin, natural compounds from plants (berberine, cryptotanshinone, xanthohumol, matrine), genestein and the synthetic sphingosine immunosuppressant FTY720 .…”

Section: Targeted Therapiesmentioning

confidence: 99%

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

Fouassier

Marzioni

Afonso

et al. 2019

Liver International

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Cholangiocarcinoma (CCA) is a deadly disease. While surgery may attain cure in a minor fraction of cases, therapeutic options in either the adjuvant or advanced setting are limited. The possibility of advancing the efficacy of therapeutic approaches to CCA relies on understanding its molecular pathogenesis and developing rational therapies aimed at interfering with oncogenic signalling networks that drive and sustain cholangiocarcinogenesis. These efforts are complicated by the intricate biology of CCA, which integrates not only the driving force of tumour cell‐intrinsic alterations at the genetic and epigenetic level but also pro‐tumorigenic cues conveyed to CCA cells by different cell types present in the rich tumour stroma. Herein, we review our current understanding of the mechanistic bases underpinning the activation of major oncogenic pathways causative of CCA pathogenesis. We subsequently discuss how this knowledge is being exploited to implement rationale‐based and genotype‐matched therapeutic approaches that predictably will radically transform CCA clinical management in the next decade. We conclude by highlighting the mechanisms of therapeutic resistance in CCA and reviewing innovative approaches to combat resistance at the preclinical and clinical level.

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“…We therefore hypothesized that the interaction of sorafenib (or its derivatives SC-43 and SC-60) and the N-SH2 domain might lead to a release of the D61 catalytic site and activation of SHP-1 activity. Currently, the hypothesized mechanism was supported by using ectopic expressing dN1 (deleted N-SH2) and D61A mutant SHP-1 in cholangiocarcinoma [ 71 ], HCC [ 72 ], CRC [ 73 ], and triple-negative breast cancer (TNBC) [ 69 ] cells. Compared to wild-type SHP-1-expressing cells, SC-43 [ 71 , 73 ] and SC-60 [ 69 , 72 ] exerted less p-STAT3 downregulation and apoptosis-promoting effects on these mutant SHP-1-expressing cells.…”

Section: Shp-1/stat3 Pathway Is a Target In The Treatment Of Humanmentioning

confidence: 99%

“…Currently, the hypothesized mechanism was supported by using ectopic expressing dN1 (deleted N-SH2) and D61A mutant SHP-1 in cholangiocarcinoma [ 71 ], HCC [ 72 ], CRC [ 73 ], and triple-negative breast cancer (TNBC) [ 69 ] cells. Compared to wild-type SHP-1-expressing cells, SC-43 [ 71 , 73 ] and SC-60 [ 69 , 72 ] exerted less p-STAT3 downregulation and apoptosis-promoting effects on these mutant SHP-1-expressing cells. Compared with sorafenib, SC-1 and SC-43 induced more potent apoptosis in association with downregulation of p-STAT3 and its downstream molecules (cyclin D1 and survivin) in breast cancer cell lines [ 68 ].…”

Section: Shp-1/stat3 Pathway Is a Target In The Treatment Of Humanmentioning

confidence: 99%

Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

Huang

Su²,

Liu

et al. 2017

IJMS

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The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p-STAT3 signaling and combined strategies that were/are discovered in our and our colleagues’ laboratories.

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Targeting SHP-1–STAT3 signaling: a promising therapeutic approach for the treatment of cholangiocarcinoma

Cited by 3 publications

References 29 publications

The role of Src homology region 2 domain-containing phosphatase-1 hypermethylation in the classification of patients with myelodysplastic syndromes and its association with signal transducer and activator of transcription 3 phosphorylation in skm-1 cells

The role of Src homology region 2 domain-containing phosphatase-1 hypermethylation in the classification of patients with myelodysplastic syndromes and its association with signal transducer and activator of transcription 3 phosphorylation in skm-1 cells

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

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