Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis

Li, Jingjing; Yin, Hongkun; Guan, Dongxian; Zhao, Jiang-Sha; Feng, Yuxiong; Deng, Yuezhen; Wang, Xiang; Li, Nan; Wang, Xiaofan; Cheng, Shuqun; Bao, Ying; Xie, Dong

doi:10.1038/s41416-018-0077-y

Cited by 63 publications

(124 citation statements)

References 26 publications

(33 reference statements)

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“…These results are consistent with previous studies of augmented PTEN expression on the PI3k/Akt/mTOR pathway and its signaling constituents 25,27,28,33,35,55 .…”

Section: Chemerin Inhibits Pakt and Ps6 Signaling Leading To Decreasesupporting

confidence: 93%

“…Our group was the first to show that augmented chemerin in the TME -often downregulated in human tumors -resulted in recruitment of anti-tumor immune effector cells and significantly reduced tumor growth 23 . Several other groups have now shown similar findings both in preclinical and clinical scenarios 6,55,82 , supporting the robustness of these data. Our studies elucidate a novel axis between chemerin, CMKLR1, PTEN, and PD-L1 while simultaneously confirming chemerin's impact on PTEN/PI3k pathway expression 55 , extending this to additional tumor types (ie prostate, sarcoma).…”

Section: Discussionsupporting

confidence: 71%

“…Importantly, a recent study showed that chemerin could suppress hepatocellular carcinoma (HCC) growth and metastases via the PTEN-Akt signaling axis in a mouse model 55 . Using human HCC cell lines, Li et al showed that chemerin overexpression resulted in upregulation of PTEN and suppression of the PI3K/Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

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Chemerin increases T-cell mediated cytotoxicity of human tumors via modulation of a novel CMKLR1/PTEN/PD-L1 axis

Rennier

Krug

Virdi

et al. 2019

Preprint

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Chemerin (RARRES2) is an endogenous leukocyte chemoattractant known to recruit innate immune cells through its chemotactic receptor, CMKLR1. RARRES2 is often downregulated in prostate cancer and across multiple tumor types compared to normal tissue. Additionally, a methylome-wide analysis identified RARRES2 as one of the most hypermethylated genes in sarcoma. Recent studies have shown that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, at least in part by recruitment of immune effector cells. However, as tumor cells have been shown to express functional chemokine receptors that can impact their phenotype, we hypothesized that chemerin might have additional, tumor-intrinsic effects. Here, we show for the first time that human cancer cells exposed to exogenous chemerin significantly upregulate PTEN expression and activity. Additionally, chemerin-induced PTEN expression correlated with a concomitant reduction in PD-L1 mRNA and protein expression. Chemerin treatment of tumor cells led to significantly reduced tumor cell migration/invasion, as well as significantly increased cytotoxicity by T cells. siRNA knockdown of tumor expressed CMKLR1 abrogated chemerin-induced modulation of PTEN and PD-L1 expression and activity, supporting the presence of a CMKLR1/PTEN/PD-L1 signaling cascade. We then compared chemerin treatment to PD-L1 inhibition by siRNA knockdown or the antagonistic antibody atezolizumab in T cell cytotoxicity assays and surprisingly found chemerin treatment was as effective as both Chemerin modulates PTEN/PD-L1 via CMKLR1 in human tumors Page 2 of 29 PD-L1 knockdown and atezolizumab treatment in mediating tumor lysis. Collectively, our data show a novel link between chemerin, PTEN and PD-L1 in human tumor lines, with functional consequences that may have a role in improving T cell-mediated immunotherapies. Runnning Title: Chemerin modulates PTEN/PD-L1 via CMKLR1 in human tumors Word Counts: Abstract -250

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“…These results are consistent with previous studies of augmented PTEN expression on the PI3k/Akt/mTOR pathway and its signaling constituents 25,27,28,33,35,55 .…”

Section: Chemerin Inhibits Pakt and Ps6 Signaling Leading To Decreasesupporting

confidence: 93%

Section: Discussionsupporting

confidence: 71%

See 1 more Smart Citation

Chemerin increases T-cell mediated cytotoxicity of human tumors via modulation of a novel CMKLR1/PTEN/PD-L1 axis

Rennier

Krug

Virdi

et al. 2019

Preprint

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“…11 Down-regulated chemerin expression was detected in most tumor types, including melanoma and liver cancer, [11][12][13] and overexpression of chemerin could inhibit tumor growth and metastasis through different mechanisms including direct inhibition of the proliferation and migration of tumor cells or modulation of the tumor microenvironment. [12][13][14][15] For example, our previous study demonstrated that chemerin inhibits the progression of orthotopic murine liver cancer by reducing tumor-promoting inflammation, and others found that chemerin inhibits the invasion of human liver cancer cells. 13,14 Melanoma is a highly aggressive skin cancer, representing only 4% of skin cancers but accounting for 80% of deaths from dermatological cancer.…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14][15] For example, our previous study demonstrated that chemerin inhibits the progression of orthotopic murine liver cancer by reducing tumor-promoting inflammation, and others found that chemerin inhibits the invasion of human liver cancer cells. 13,14 Melanoma is a highly aggressive skin cancer, representing only 4% of skin cancers but accounting for 80% of deaths from dermatological cancer. 16 Melanoma has been recognized as one of the most immunogenic malignancies with abundant infiltration of various immune cells.…”

Section: Introductionmentioning

confidence: 99%

Chemerin partly mediates tumor‐inhibitory effect of all‐trans retinoic acid via CMKLR1‐dependent natural killer cell recruitment

et al. 2019

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Summary Down‐regulated chemerin expression has been reported to correlate with poor prognosis of several types of cancer including melanoma. All‐trans retinoic acid (atRA) is a potent inducer of chemerin, and we previously reported that atRA inhibited murine melanoma growth through enhancement of anti‐tumor T‐cell immunity. Here, we aimed to investigate whether loss of endogenous chemerin accelerated melanoma growth and whether chemerin was involved in the melanoma‐inhibitory effect of atRA. We demonstrated that chemerin was constitutively expressed in the skin, which was down‐regulated during murine melanoma growth. Rarres2−/− mice, which are deficient in chemerin, exhibited aggravated tumor growth and impaired tumor‐infiltrating natural killer (NK) cells that express CMKLR1, the functional receptor of chemerin. Topical treatment with atRA up‐regulated skin chemerin expression, which was primarily derived from dermal cells. Moreover, atRA treatment significantly enhanced tumor‐infiltrating NK cells, which was completely abrogated in Rarres2−/− mice and Cmklr1−/− mice, suggesting a dependency of NK cell recruitment on the chemerin–CMKLR1 axis in melanoma. Despite comparable melanoma growth detected in wild‐type mice and Cmklr1−/− mice, lack of CMKLR1 partially abrogated the melanoma‐inhibitory effect of atRA. This may be due to the inability to enhance tumor‐infiltrating NK cells in Cmklr1−/− mice following atRA treatment. Collectively, our study suggests that down‐regulation of chemerin could be a strategy used by cancers such as melanoma to impair anti‐tumor NK cell immunity and identifies a new anti‐tumor mechanism of atRA by up‐regulating chemerin to enhance CMKLR1‐dependent NK cell recruitment.

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Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma

Vachher

Bansal

Kumar

et al. 2022

J of Cellular Biochemistry

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Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%–90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.

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Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis

Abstract: Our study has revealed the suppressive role and therapeutic potential of chemerin in HCC metastasis, providing both a prognostic marker and drug candidate for HCC.

Cited by 63 publications

References 26 publications

Chemerin increases T-cell mediated cytotoxicity of human tumors via modulation of a novel CMKLR1/PTEN/PD-L1 axis

Chemerin increases T-cell mediated cytotoxicity of human tumors via modulation of a novel CMKLR1/PTEN/PD-L1 axis

Chemerin partly mediates tumor‐inhibitory effect of all‐trans retinoic acid via CMKLR1‐dependent natural killer cell recruitment

Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma

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