High expression of PTPRM predicts poor prognosis and promotes tumor growth and lymph node metastasis in cervical cancer

Liu, Pan; Zhang, Chunyu; Liao, Yuandong; Liu, Junxiu; Huang, Jiaming; Xia, Meng; Chen, Ming; Tan, Hao; He, Weipeng; Xu, Manman; Li, Tianyu; Ooi, Shiyin; Du, Qiqiao; Qin, Shengmei; Zhu, Yuan; Zou, Qiaojian; Wang, Wei; Yao, Shuzhong

doi:10.1038/s41419-020-02826-x

Cited by 23 publications

(25 citation statements)

References 44 publications

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“…These findings indicate that the EMT phenotypes are context dependent [ 39 ] and CCa cells may not go through a full EMT, but rather adopt some qualities of mesenchymal cells and keep some epithelial characteristics during LN metastasis. Furthermore, the EMT phenotype often accompanied with increased lymphangiogenesis [ 40 , 41 ]. We observed that LNMAS exerted an inhibitory effect on lymphangiogenesis in vitro and in vivo (Fig.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of LNMAS orchestrates partial EMT and immune escape from macrophage phagocytosis to promote lymph node metastasis of cervical cancer

et al. 2022

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Epithelial-mesenchymal transition (EMT) is an essential step to drive the metastatic cascade to lymph nodes (LNs) in cervical cancer cells. However, few of them metastasize successfully partially due to increased susceptibility to immunosurveillance conferred by EMT. The precise mechanisms of cancer cells orchestrate EMT and immune evasion remain largely unexplored. In this study, we identified a lncRNA termed lymph node metastasis associated suppressor (LNMAS), which was downregulated in LN-positive cervical cancer patients and correlated with LN metastasis and prognosis. Functionally, LNMAS suppressed cervical cancer cells metastasis in vitro and in vivo. Mechanistically, LNMAS exerts its metastasis suppressive activity by competitively interacting with HMGB1 and abrogating the chromatin accessibility of TWIST1 and STC1, inhibiting TWIST1-mediated partial EMT and STC1-dependent immune escape from macrophage phagocytosis. We further demonstrated that the CpG sites in the promoter region of LNMAS was hypermethylated and contributed to the downregulation of LNMAS. Taken together, our results reveal the essential role of LNMAS in the LN metastasis of cervical cancer and provide mechanistic insights into the regulation of LNMAS in EMT and immune evasion.

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Section: Discussionmentioning

confidence: 99%

Downregulation of LNMAS orchestrates partial EMT and immune escape from macrophage phagocytosis to promote lymph node metastasis of cervical cancer

et al. 2022

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“…The process involves several steps, including tumour secretion of lymphangiogenic factors [ 27 – 29 ], tumour lymphangiogenesis [ 28 ], lymph node lymphangiogenesis [ 30 ], and lymphatic vessel activation of metastatic tumour cells [ 31 ]. For example, PTPRM upregulation is relevant to LNM of CCa through VEGF-C-dependent lymphangiogenesis and Src-AKT signalling pathway-mediated EMT [ 32 ]. RACK1 promotes the invasive activities and LNM of CCa via galectin 1 [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

FABP4 is an independent risk factor for lymph node metastasis and poor prognosis in patients with cervical cancer

Gong

et al. 2021

Cancer Cell Int

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Background Pelvic lymph node metastasis (LNM) is a crucial independent prognostic factor in cervical cancer (CCa) and serves as an indicator for radiation therapy as the primary or an adjuvant treatment option. However, preoperative diagnosis of LNM remains challenging. Thus, we aimed to identify biomarkers of LNM in patients with presumed early-stage CCa. Methods The differentially expressed genes (DEGs) between tumours with different lymph node statuses were identified by using The Cancer Genome Atlas database. Then, univariate Cox regression analysis and Kaplan–Meier analyses were utilized to screen overall survival (OS)-associated genes. Multivariate Cox analysis and logistical analysis were utilized to evaluate independent risk factors for OS and LNM, respectively. Subsequently, the protein level of fatty acid binding protein 4 (FABP4) was detected in normal cervical and CCa tissues by immunohistochemistry assays. EdU assays were performed to determine whether FABP4 altered the proliferation of cervical cancer cells. Wound healing and Transwell assays were conducted to explore the effects of FABP4 depletion on migratory and invasive abilities of cervical cancer cells. F-actin fluorescence staining were performed to investigate morphological change and Western blotting analyses were performed to determine epithelial mesenchymal transition-related marker expression and downstream signalling pathways. Results A total of 243 DEGs, including 55 upregulated and 188 downregulated DEGs, were found in CCa patients with LNM versus those without LNM. Among these, FABP4 was found to be closely associated with poor OS. Multivariate analysis uncovered that FABP4 was an independent risk factor for OS and LNM in patients with CCa. The immunohistochemical results verified dramatically increased FABP4 expression in CCa tissues compared to normal cervical epithelia and its association with poor OS and LNM. In vitro, The proliferation, migration and invasion of cervical cancer cells were significantly inhibited after knocking down of FABP4, which was accompanied by elevated expression of E-cadherin and downregulated expression of N-cadherin, Vimentin and p-AKT. Conclusions FABP4 might be a promising biomarker of LNM and survival in patients with early-stage CCa and therefore could significantly contribute to the development of personalized prognosis prediction and therapy optimization.

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“…Lipid rafts have been reported to be essential platforms for signaling regulation [ 19 ]. Thus, for a detailed mechanistic study, we first chose to clarify whether various signaling pathways, mTOR, ROCK, PI3K/AKT, and c-Src, which have been found to be related to cervical cancer tumorigenesis or progression [ 20 – 22 ], were involved. We intended to explore the upstream signaling pathway in regulating p-FAK.…”

Section: Resultsmentioning

confidence: 99%

FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis

Liu

Zhang

et al. 2022

Cell Death Dis

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Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC.

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High expression of PTPRM predicts poor prognosis and promotes tumor growth and lymph node metastasis in cervical cancer

Cited by 23 publications

References 44 publications

Downregulation of LNMAS orchestrates partial EMT and immune escape from macrophage phagocytosis to promote lymph node metastasis of cervical cancer

Downregulation of LNMAS orchestrates partial EMT and immune escape from macrophage phagocytosis to promote lymph node metastasis of cervical cancer

FABP4 is an independent risk factor for lymph node metastasis and poor prognosis in patients with cervical cancer

FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis

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