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Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)–mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3′UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC. Significance: This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.

Nicotine addiction and the occurrence of lymph node spread are two major significant factors associated with esophageal cancer’s poor prognosis; however, nicotine’s role in inducing lymphatic metastasis of esophageal cancer remains unclear. Here we show that OTU domain-containing protein 3 (OTUD3) is downregulated by nicotine and correlates with poor prognosis in heavy-smoking esophageal cancer patients. OTUD3 directly interacts with ZFP36 ring finger protein (ZFP36) and stabilizes it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 binds with the VEGF-C 3-‘UTR and recruits the RNA degrading complex to induce its rapid mRNA decay. Downregulation of OTUD3 and ZFP36 is essential for nicotine-induced VEGF-C production and lymphatic metastasis in esophageal cancer. This study establishes that the OTUD3/ZFP36/VEGF-C axis plays a vital role in nicotine addiction-induced lymphatic metastasis, suggesting that OTUD3 may serve as a prognostic marker, and induction of the VEGF-C mRNA decay might be a potential therapeutic strategy against human esophageal cancer., The mechanism of how VEGF-C is regulated to promote lymphatic metastasis of oesophageal cancer is unclear. Here the authors show that nicotine prevents the mRNA decay of VEGF-C mRNA and promotes lymphatic metastasis by downregulating deubiquitinase OTUD3 and RNA binding protein ZFP36.

The majority of clinical deaths among patients with triple-negative breast cancer (TNBC) are caused by uncontrolled cell proliferation and aggressive metastases, which is regulated by hyperactive glycogen synthase kinase 3 beta (GSK3β); however, the underlying mechanisms remain largely unknown. In the present study, we found that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) was specifically upregulated in TNBC, compared with that in normal tissues and non-TNBC. High PPP1R14C expression correlated significantly with shorter 5-year relapse-free survival and overall survival in patients with TNBC. Overexpressing PPP1R14C promoted, while suppression of PPP1R14C decreased the cell proliferation and the aggressive phenotype of TNBC cells, in vitro and in vivo. Importantly, we revealed that PPP1R14C interacted with and inactivated type 1 Ser/Thr protein phosphatase (PP1) to sustain GSK3β phosphorylation at S9, and induced the ubiquitylation and degradation of non-phosphorylated GSK3β (S9A) via recruiting E3 ligase, TRIM25. Furthermore, treating with C2 ceramide (C2), which recovered kinase activity of GSK3β, resulted in tumor growth inhibition in PPP1R14C-overexpressing TNBC cells. Our findings reveal a novel mechanism whereby PPP1R14C sustains inactive GSK3β, which might lead to targeted therapy for TNBC.

Balancing mRNA nuclear export kinetics with its nuclear decay is critical for mRNA homeostasis control. How this equilibrium is aberrantly disrupted in esophageal cancer to acquire cancer stem cell properties remains unclear. Here we find that the RNA-binding protein interleukin enhancer binding factor 2 (ILF2) is robustly upregulated by nicotine, a major chemical component of tobacco smoke, via activation of JAK2/STAT3 signaling and significantly correlates with poor prognosis in heavy-smoking patients with esophageal cancer. ILF2 bound the THO complex protein THOC4 as a regulatory cofactor to induce selective interactions with pluripotency transcription factor mRNAs to promote their assembly into export-competent messenger ribonucleoprotein complexes. ILF2 facilitated nuclear mRNA export and inhibited hMTR4-mediated exosomal degradation to promote stabilization and expression of SOX2, NANOG, and SALL4, resulting in enhanced stemness and tumor-initiating capacity of esophageal cancer cells. Importantly, inducible depletion of ILF2 significantly increased the therapeutic efficiency of cisplatin and abrogated nicotine-induced chemoresistance in vitro and in vivo. These findings reveal a novel role of ILF2 in nuclear mRNA export and maintenance of cancer stem cells and open new avenues to overcome smoking-mediated chemoresistance in esophageal cancer. Significance: This study defines a previously uncharacterized role of nicotine-regulated ILF2 in facilitating nuclear mRNA export to promote cancer stemness, suggesting a potential therapeutic strategy against nicotine-induced chemoresistance in esophageal cancer.

Background Aberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2–8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC). Methods The deletion frequency and expression of NKX2–8 in 144 EOC specimens were assayed using Fluorescence in situ hybridization and immunochemical assays. The effects of NKX2–8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2–8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays. Findings NKX2–8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2–8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPT1A and CPT2. Loss of NKX2–8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2–8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC. Interpretation Our results demonstrate that NKX2–8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2–8-deleted EOC. Fund This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities.

Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor‐alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt‐like transcription factor 2 (SALL2) expression was significantly reduced during tamoxifen therapy through transcription profiling analysis of 9 paired primary pre‐tamoxifen‐treated and relapsed tamoxifen‐resistant breast cancer tissues. SALL2 transcriptionally upregulated ESR1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL2 induced downregulation of ERα and PTEN and activated the Akt/mTOR signaling, resulting in estrogen‐independent growth and tamoxifen resistance in ERα‐positive breast cancer. Furthermore, hypermethylation of SALL2 promoter was found in tamoxifen‐resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor‐mediated SALL2 restoration resensitized tamoxifen‐resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL2 in regulation of ER and represent a potential clinical signature that can be used to categorize breast cancer patients who may benefit from co‐therapy with tamoxifen and DNMT inhibitor., Resistance to tamoxifen is a clinically important challenge for breast cancer treatment. This study uncovers a mechanism by which the transcription factor SALL2 regulates ERα, and identifies a subset of breast cancer patients who might benefit from tamoxifen/DNMTs inhibitor co‐therapy.

Background: Aberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2-8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC). Methods: The deletion frequency and expression of NKX2-8 in 144 EOC specimens were assayed using Fluorescence in situ hybridization and immunochemical assays. The effects of NKX2-8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2-8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays. Findings: NKX2-8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2-8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPT1A and CPT2. Loss of NKX2-8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2-8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC. Interpretation: Our results demonstrate that NKX2-8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2-8-deleted EOC. Funding Statement: This work was supported by Natural Science Foundation of China (No. 81830082, 91740119, 91529301, 81621004, 91740118, 81773106 and 81530082); Guangzhou Science and Technology Plan Projects (201803010098); Natural Science Foundation of Guangdong Province (2018B030311009 and 2016A030308002); The Fundamental Research Funds for the Central Universities [No. 17ykjc02]. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Prior donor consent and approval were obtained from the Institutional Research Ethics Committee. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University