LIMK1 promotes peritoneal metastasis of gastric cancer and is a therapeutic target

Xi, Kang; Li, Weilin; Liu, Weixin; Liang, Han; Deng, Jingyu; Yu, Jun; Zhao, Suisheng; Kang, Wei; To, Ka Fai; Chiu, Philip Wai Yan; Wang, Guiying; Ng, Enders Kwok Wai

doi:10.1038/s41388-021-01656-1

Cited by 32 publications

(26 citation statements)

References 43 publications

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“…Gene expression was calculated as fragments per kilobase of transcript per million mapped reads) by DESeq2. 9 Statistical analysis Data are presented as mean±SD. Differences between two groups were compared using Student's t-test.…”

Section: Rna Sequencingmentioning

confidence: 99%

Loss of YTHDF1 in gastric tumors restores sensitivity to antitumor immunity by recruiting mature dendritic cells

Bai

Pan

Chen

et al. 2022

J Immunother Cancer

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BackgroundGastric cancer (GC) is one of the most common cancer worldwide. We analyzed the expression of m6A regulatory genes in GC cohorts and revealed that YTHDF1 was uniquely upregulated in GC as compared with adjacent normal tissues. In this study, we analyzed the role of YTHDF1 in GC cells and modulation of the tumor immune microenvironment.MethodsThree GC cohorts (cohort 1, n=101; cohort 2, n=278, and the Cancer Genome Atlas cohort, n=375) were analyzed for YTHDF1 expression. Function of YTHDF1 in GC was determined in GC cell lines. Role of YTHDF1 in antitumor immunity was investigated in allograft models.ResultsYTHDF1 is upregulated in GC compared with adjacent normal tissues, and high YTHDF1 expression was correlated with poor survival of patients with GC at mRNA (p=0.016) and protein levels (p=0.039). Loss of YTHDF1 in human (AGS, BGC823, MKN74) or mouse (YTN16) GC cell lines inhibited cell growth and colony formation in vitro. Strikingly, syngeneic YTN16 tumors with loss of YTHDF1 underwent complete remission in immunocompetent mice, while a lesser effect was found in immunodeficient mice. Consistently, YTHDF1 loss in GC tumors led to recruitment of mature dendritic cells (DCs) with increased MHCII expression and interleukin-12 (IL-12) secretion, which in turn, promoted CD4+ and CD8+ T cells infiltration with increased interferon-γ (IFN-γ) secretion. Loss of YTHDF1 mediated the overexpression of IFN-γ receptor 1 and JAK/STAT1 signaling pathway in tumor cells, which might contribute to restored sensitivity to antitumor immunity. In addition, pre-emptive exposure of YTN16 tumors with YTHDF1 loss triggered a potent antitumor immune response on rechallenge with wild-type YTN16 cells, implying that YTHDF1 loss induced a lasting systemic antitumor immunity.ConclusionsYTHDF1 is overexpressed in GC and promotes GC by inducing cell proliferation and repression of DCs-mediated antitumor immune response. YTHDF1 is a promising therapeutic target for GC treatment.

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Section: Rna Sequencingmentioning

confidence: 99%

Loss of YTHDF1 in gastric tumors restores sensitivity to antitumor immunity by recruiting mature dendritic cells

Bai

Pan

Chen

et al. 2022

J Immunother Cancer

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“…LIM domain kinase (LIMK) is a class of serine/threonine protein kinases (3); previous studies indicated that LIMK1 was highly expressed in numerous malignant tumors and correlated with patients' poor prognoses (4)(5)(6)(7)(8). However, there is little research on the role of LIMK2 in malignant tumors.…”

Section: Introductionmentioning

confidence: 99%

LIMK2 Is a Novel Prognostic Biomarker and Correlates With Tumor Immune Cell Infiltration in Lung Squamous Cell Carcinoma

Shen

et al. 2022

Front. Immunol.

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Previous research found that LIM domain kinase 2 (LIMK2) expression correlated with a poor prognosis in many cancers. However, its role in lung squamous cell carcinoma (LUSC) has not yet been clarified. Our study aimed to clarify the role of LIMK2 in LUSC prognosis prediction and explore the relationship between LIMK2 and immune infiltration in LUSC. In this study, we first analyzed the expression level and prognostic value of LIMK2 across cancers. Subsequently, we explored the association of LIMK2 expression with immune infiltrating cells and immune checkpoints. our study found that LIMK2 was highly expressed and positively associated with the overall survival of LUSC. Moreover, our study further indicated that LIMK2 expression was significantly negatively correlated with immune cell infiltration and immune checkpoints in LUSC. Finally, we confirmed upstream regulatory noncoding RNAs (ncRNAs) of LIMK2, and the PVT1 and DHRS4-AS1/miR-423-5p/LIMK2 regulatory axes were successfully constructed in LUSC. Put together, LIMK2 is a novel prognostic biomarker and correlates with tumor immune cell infiltration in LUSC, and the expression of LIMK2 is regulated by the PVT1 and DHRS4-AS1/miR-423-5p axes.

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“…Evidence showed that PM is one of the most frequent types of metastasis in GC and up to 14% of newly diagnosed GC patients ( Kang et al, 2021 ). Furthermore, the peritoneum is considered the most common site of recurrence upon radical surgery in GC patients ( Sugarbaker et al, 2003 ; Thomassen et al, 2014 ).…”

Section: Peritoneal Metastasis Of Gastric Cancermentioning

confidence: 99%

Oncolytic Virotherapy in Peritoneal Metastasis Gastric Cancer: The Challenges and Achievements

Shao

Yang

Zhang

et al. 2022

Front. Mol. Biosci.

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Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death globally. Although the mortality rate in some parts of the world, such as East Asia, is still high, new treatments and lifestyle changes have effectively reduced deaths from this type of cancer. One of the main challenges of this type of cancer is its late diagnosis and poor prognosis. GC patients are usually diagnosed in the advanced stages of the disease, which is often associated with peritoneal metastasis (PM) and significantly reduces survival. This type of metastasis in patients with GC poses a serious challenge due to limitations in common therapies such as surgery and tumor resection, as well as failure to respond to systemic chemotherapy. To solve this problem, researchers have used virotherapy such as reovirus-based anticancer therapy in patients with GC along with PM who are resistant to current chemotherapies because this therapeutic approach is able to overcome immune suppression by activating dendritic cells (DCs) and eventually lead to the intrinsic activity of antitumor effector T cells. This review summarizes the immunopathogenesis of peritoneal metastasis of gastric cancer (PMGC) and the details for using virotherapy as an effective anticancer treatment approach, as well as its challenges and opportunities.

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LIMK1 promotes peritoneal metastasis of gastric cancer and is a therapeutic target

Cited by 32 publications

References 43 publications

Loss of YTHDF1 in gastric tumors restores sensitivity to antitumor immunity by recruiting mature dendritic cells

Loss of YTHDF1 in gastric tumors restores sensitivity to antitumor immunity by recruiting mature dendritic cells

LIMK2 Is a Novel Prognostic Biomarker and Correlates With Tumor Immune Cell Infiltration in Lung Squamous Cell Carcinoma

Oncolytic Virotherapy in Peritoneal Metastasis Gastric Cancer: The Challenges and Achievements

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