LHPP suppresses colorectal cancer cell migration and invasion in vitro and in vivo by inhibiting Smad3 phosphorylation in the TGF-β pathway

Hou, Bin; Li, Wenhan; Xia, Peng; Zhao, Fengyu; Zhao, Lei; Zeng, Qingnuo; Wang, Shilong; Chang, Dongdong

doi:10.1038/s41420-021-00657-z

Cited by 35 publications

(35 citation statements)

References 33 publications

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“…TGF-β is a multifunctional cytokine, and its receptors play a crucial role in cancer initiation and progression through a range of activities in the regulation of cell proliferation, differentiation, apoptosis, and migration ( Gencer et al, 2017 ). After activation of TGF-β signaling, TGF-β-associated ligands bind to corresponding receptors I and II ( de la Cruz-Merino et al, 2009 ) and then transfer extracellular signals to nuclear components through canonical TGF-β pathways, such as the TGF-β/Smad pathway, and noncanonical TGF-β pathways, such as the p38/mitogen-activated protein kinase (MAPK) pathway, GTP pathway, PI3K/AKT pathway, and NF-κB pathway ( Patil et al, 2011 ; Bataller et al, 2019 ; Chang and Pauklin, 2021 ; Choi et al, 2021 ; Hou et al, 2021 ). TGF-β has often been implicated in carcinogenesis, and studies have demonstrated that TGF-β has both oncogenic and tumor-suppressive functions in cancer regulation mechanisms ( Yu and Feng, 2019 ; Belitškin et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

TGF-β Signaling Pathway-Based Model to Predict the Subtype and Prognosis of Head and Neck Squamous Cell Carcinoma

Guan

Xue

2022

Front. Genet.

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Background: Although immunotherapy with immune checkpoint therapy has been used to treat head and neck squamous cell carcinoma (HNSCC), response rates and treatment sensitivity remain limited. Recent studies have indicated that transforming growth factor-β (TGF-β) may be an important target for novel cancer immunotherapies.Materials and methods: We collected genomic profile data from The Cancer Genome Atlas and Gene Expression Omnibus. The least absolute shrinkage and selection operator method and Cox regression were used to establish a prognostic model. Gene set enrichment analysis was applied to explore biological functions. Tracking of indels by decomposition and subclass mapping algorithms were adopted to evaluate immunotherapy efficiency.Result: We established a seven TGF-β pathway-associated gene signature with good prediction efficiency. The high-risk score subgroup mainly showed enrichment in tumor-associated signaling such as hypoxia and epithelial-mesenchymal transition (EMT) pathways; This subgroup was also associated with tumor progression. The low-risk score subgroup was more sensitive to immunotherapy and the high-risk score subgroup to cisplatin, erlotinib, paclitaxel, and crizotinib.Conclusion: The TGF-β pathway signature gene model provides a novel perspective for evaluating effectiveness pre-immunotherapy and may guide further studies of precision immuno-oncology.

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Section: Discussionmentioning

confidence: 99%

TGF-β Signaling Pathway-Based Model to Predict the Subtype and Prognosis of Head and Neck Squamous Cell Carcinoma

Guan

Xue

2022

Front. Genet.

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“…The transforming growth factor‐β (TGF‐β) represents a structurally‐related protein family that comprises bone morphogenic proteins, activins/inhibins, and TGF‐β, while the latter controls various cellular functions such as apoptosis, proliferation, migration, epithelial–mesenchymal transition (EMT), and differentiation 14 . Interestingly, attenuation of the TGF‐β/Smad signalling was previously associated with repression of cancer cell EMT in hepatocellular carcinoma, in addition to diminishing cell invasion and migration in GC 15,16 . On the other hand, up‐regulation of the key proteins of the TGF‐β/Smad pathway has been documented in GC and further reported to exhibit a significant positive correlation with the degree of differentiation, lymph node metastasis, and Tumour–Node–Metastasis stage of GC 17 .…”

Section: Introductionmentioning

confidence: 99%

“…14 Interestingly, attenuation of the TGF-β/Smad signalling was previously associated with repression of cancer cell EMT in hepatocellular carcinoma, in addition to diminishing cell invasion and migration in GC. 15,16 On the other hand, up-regulation of the key proteins of the TGF-β/Smad pathway has been documented in GC and further reported to exhibit a significant positive correlation with the degree of differentiation, lymph node metastasis, and Tumour-Node-Metastasis stage of GC. 17 Ginsenoside Rb2 was previously indicated to inhibit EMT of colorectal cancer cells via blockade of the TGF-β1/Smad signalling.…”

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confidence: 99%

Ginsenoside Rh1 regulates gastric cancer cell biological behaviours and transplanted tumour growth in nude mice via the TGF‐β/Smad pathway

Yang

Shen

et al. 2022

Clin Exp Pharma Physio

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Gastric cancer (GC) is one of the most prevalent malignancies of the digestive tract.Ginsenoside Rh1 was reported to exert effects on GC. The current study set out to explore the mechanism underlying Ginsenoside Rh1 effects on GC. With oxaliplatin (OXA) serving as the positive control, human GC cells AGS were treated with 0, 10, 25, 50, 74, or 100 μM of ginsenoside Rh1 for 48 h. Proliferation, migration, invasion, and apoptosis were subsequently assessed by means of MTT, scratch test, Transwell, and TUNEL, respectively. AGS cells were further jointly treated with Rh1 and the TGF-β/Smad pathway activator Kartogenin, followed by detection of TGF-β/Smad pathway effects on AGS biological behaviours. Moreover, TGF-β/Smad pathway activation was detected with a Western blot assay. Furthermore, xenograft tumour models were established and tumour growth was recorded. Ki-67 expression patterns and apoptosis were detected with immunohistochemistry and TUNEL, respectively. In vitro, Ginsenoside Rh1 repressed AGS cell proliferation, migration, and invasion, and further promoted apoptosis, with a concentration of 50 μM Rh1 exerting the equivalent effects as OXA. In vivo, Ginsenoside Rh1 inhibited GC proliferation and induced tumour cell apoptosis. Mechanistically, Ginsenoside Rh1 reduced TGF-β1 and TGF-β2 levels and Smad2 and Smad3 phosphorylation levels. Collectively, our findings highlighted that ginsenoside Rh1 inhibited GC cell growth and tumour growth in xenograft tumour models via inhibition of the TGF-β/Smad pathway.

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“…Our previous study also demonstrated that LHPP could repress the proliferation and progression of colorectal cancer cells by inhibiting PI3K/AKT pathway [ 15 ]. In addition, our team suggested that LHPP protein might impede the metastasis of colorectal cancer by mediating the phosphorylation of Smad3 in TGF-β/Smad canonical pathway [ 16 ]. Based on these results and references, we hypothesized that LHPP might be involved in the development of pancancer and play a common role in the progression of different cancer types.…”

Section: Introductionmentioning

confidence: 99%

Does the LHPP gene share a common biological function in pancancer progression?

et al. 2022

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Although emerging evidence has revealed that LHPP, a histidine phosphatase protein, suppresses the progression of different cancers, a pan-cancer analysis still remains unavailable. Therefore, we first utilized different bioinformatics tools to explore the tumor inhibitory role of LHPP protein across 33 tumor types based on the TCGA project. Additionally, HGC-27 gastric cancer cells were used to evaluate the biological functions of LHPP after stable transfection with lentiviruses. Consequently, LHPP mRNA and protein expression were down-regulated in the most cancer tissues corresponding to normal tissues. The data showed that patients with higher LHPP performance had a better prognosis of overall survival (OS) and disease-free survival (DFS) in brain glioma and renal carcinoma. In addition, we found that enhancement of LHPP expression attenuated the proliferation, migration and invasion of gastric cancer cells. The expression levels of cell-cycle-related and EMT-related molecules, such as CDK4, CyclinD1, Vimentin and Snail, were clearly reduced. Moreover, a genetic alteration analysis showed that the most frequent mutation types in LHPP protein was amplification. The patients without LHPP mutation showed a better tendency of prognosis in UCEC, STAD and COAD. Cancer-associated fibroblast infiltration was also observed in head and neck squamous cell carcinoma, stomach adenocarcinoma and testicular germ cell tumors. In summary, our pancancer analysis among various tumor types could provide a comprehensive understanding of LHPP biological function in the progression of malignant diseases and promote the development of novel therapeutic targets.

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LHPP suppresses colorectal cancer cell migration and invasion in vitro and in vivo by inhibiting Smad3 phosphorylation in the TGF-β pathway

Cited by 35 publications

References 33 publications

TGF-β Signaling Pathway-Based Model to Predict the Subtype and Prognosis of Head and Neck Squamous Cell Carcinoma

TGF-β Signaling Pathway-Based Model to Predict the Subtype and Prognosis of Head and Neck Squamous Cell Carcinoma

Ginsenoside Rh1 regulates gastric cancer cell biological behaviours and transplanted tumour growth in nude mice via the TGF‐β/Smad pathway

Does the LHPP gene share a common biological function in pancancer progression?

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