Significance of positive and inhibitory regulators in the TGF-β signaling pathway in colorectal cancers

Coates, Ryan F.; Gardner, Juli-Anne; Gao, Yuan; Cortright, Valerie; Mitchell, Jeannette; Ashikaga, Takamaru; Skelly, Joan M.; Yang, Michelle

doi:10.1016/j.humpath.2017.05.021

Cited by 11 publications

(6 citation statements)

References 17 publications

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“…PPM1A is a member of the protein phosphatase 2C family of Ser/Thr protein phosphatases. 18 PPM1A has been shown to regulate TGF-beta/Smad 19–21 and mitogen activated protein kinase 22 cellular signaling pathways. PPM1A has been shown to regulate proliferation, 22 cell invasion, 23 and migration, 23 but how PPM1A regulates these activities is not understood.…”

Section: Introductionmentioning

confidence: 99%

The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression

et al. 2019

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Estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and HER2-negative, or “triple negative,” breast cancer (TNBC) is a poor prognosis clinical subtype that occurs more frequently in younger women and is commonly treated with toxic chemotherapy. Effective targeted therapy for TNBC is urgently needed. Our previous studies have identified several kinases critical for TNBC growth. Since phosphatases regulate the function of kinase signaling pathways, we sought to identify critical growth-regulatory phosphatases that are expressed differentially in ER-negative, as compared to ER-positive, breast cancers. In this study, we examined the role of one of these differentially expressed phosphatases, the protein phosphatase Mg + 2/Mn + 2 dependent 1A ( PPM1A ) which is underexpressed in ER-negative breast cancer as compared to ER-positive breast cancers, in regulating TNBC growth. We found that PPM1A is deleted in ~40% of ER-negative breast cancers, and that induced expression of PPM1A suppresses in vitro and in vivo growth of TNBC cells. This study demonstrates that induction of PPM1A expression blocks the cell cycle and reduces CDK and Rb phosphorylation. These results suggest PPM1A is a crucial regulator of cell cycle progression in triple negative breast cancer. Our results also suggest that PPM1A loss should be explored as a predictive biomarker of CDK inhibitor sensitivity.

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Section: Introductionmentioning

confidence: 99%

The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression

et al. 2019

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“…Besides, qRT‐PCR proofed that depletion of miR‐522 promoted the messenger RNA (mRNA) and protein levels of PPM1A, and vice versa (Figure F,G). PPM1A has been proven to function as a pivotal regulator of TGF‐β/Smad pathway . Therefore, we measured the expression of related markers and identified that miR‐522 repression decreased the level of TGF‐β1 and blocked the phosphorylation of Smad2 and Smad3, implying that suppression of miR‐522 blunted TGF‐β/Smad pathway (Figure H).…”

Section: Resultsmentioning

confidence: 94%

“…PPM1A has been proven to function as a pivotal regulator of TGFβ/Smad pathway. 18 Therefore, we measured the expression of related markers and identified that miR-522 repression decreased the level of TGF-β1 and blocked the phosphorylation of Smad2 and Smad3, implying that suppression of miR-522 blunted TGF-β/Smad pathway (Figure 3H). Taken together, we validate that miR-522 targets PPM1A and further stimulates TGF-β/Smad pathway.…”

Section: Discussionmentioning

confidence: 99%

miR‐522 stimulates TGF‐β/Smad signaling pathway and promotes osteosarcoma tumorigenesis by targeting PPM1A

Liu

2019

J of Cellular Biochemistry

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Osteosarcoma (OS) is identified as an aggressive malignancy of the skeletal system and normally occurs among young people. It is well accepted that microRNAs are implicated in biological activities of diverse tumors. Although miR‐522 has been proved to elicit oncogenic properties in a wide range of human cancers, the physiological function and latent mechanism of miR‐522 in OS tumorigenesis remain largely to be probed. In the current study, we certified that miR‐522 was highly expressed in OS cells and presented carcinogenic function by contributing to cell proliferation, migration, and EMT progression whereas dampening cell apoptosis. In addition, miR‐522 provoked TGF‐β/Smad pathway through targeting PPM1A. Finally, the results of mechanism experiments elucidated that miR‐522 stimulated TGF‐β/Smad pathway to induce the development of OS via targeting PPM1A, which exposed that miR‐522 may become a promising curative target for OS patients.

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“…SMAD4, which is a CRC suppressor, is an important factor in TGF-β signaling. SMAD4 mutation or loss can strongly affect TGF-β/SMAD signaling and promote CRC cell metastasis (17,(39)(40)(41)(42). There is evidence to indicate that the loss of SMAD4 promotes CRC cell metastasis (43,44).…”

Section: Discussionmentioning

confidence: 99%

HLTF suppresses the migration and invasion of colorectal cancer cells via TGF‑β/SMAD signaling in vitro

Liu

Zhou

et al. 2018

Int J Oncol

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Helicase-like transcription factor (HLTF) has been identified as a tumor suppressor gene. The hypermethylation of HTLF is frequently observed in various types of cancer, including colorectal cancer (CRC). However, the mechanisms through which HLTF suppresses CRC progression remain unclear. Thus, the aim of the present study was to explore the biological function of HLTF in CRC cells and the underlying mechanisms. CRC tissues and cells were used to detect the expression of HLTF. Wound-healing and Transwell assays were performed to assess the motility of CRC cells. The results revealed that HLTF expression was significantly associated with the differentiation status, invasion depth, lymph node metastasis and distant metastasis. A low HLTF expression was significantly associated with a poor survival. Furthermore, HTLF knockdown or ectopic overexpression significantly promoted or suppressed the motility of CRC cells, respectively. With regard to the underlying molecular mechanisms, the protein expression of HTLF was upregulated when the CRC cells were stimulated with transforming growth factor (TGF)-β, and HLTF upregulation induced an increase in SMAD4 and p-SMAD2/3 expression and a decrease in levels of the TGF-β/SMAD pathway downstream genes, Vimentin and zinc finger e-box binding homeobox 1 (ZEB1). On the whole, the findings of this study suggest that HLTF is negatively associated with the progression of CRC, and its overexpression suppresses the migration and invasion of CRC cells by targeting the TGF-β/SMAD pathway.

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Significance of positive and inhibitory regulators in the TGF-β signaling pathway in colorectal cancers

Cited by 11 publications

References 17 publications

The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression

The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression

miR‐522 stimulates TGF‐β/Smad signaling pathway and promotes osteosarcoma tumorigenesis by targeting PPM1A

HLTF suppresses the migration and invasion of colorectal cancer cells via TGF‑β/SMAD signaling in vitro

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