// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Yueyu Cao1, 3, Mengdan Wei2, 3, Bing Li2, 3, Yali Liu2, 3, Ying Lu2, 3, Zhipeng Tang1, 3, Tianbao Lu3, Yujiao Yin1, 3, Zhiqiang Qin1, 2, 3, 4, Zengguang Xu2, 3 1Department of Oncology, Shanghai East Hospital, Dalian Medical University, Shanghai 200120, China 2Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China 3Research Center for Translational Medicine and Key Laboratory of Arrhythmias, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China 4Departments of Microbiology/Immunology/Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA 70112, USA Correspondence to: Zhiqiang Qin, e-mail: zqin@lsuhsc.edu Zengguang Xu, e-mail: xuzg1998@163.com Keywords: EIF4G1, USP10, NSCLC, lung cancer Received: January 26, 2016 Accepted: March 02, 2016 Published: March 18, 2016

Background: The amino acid transporter SLC6A14, which transports 18 of the 20 proteinogenic amino acids, is too low to be detected in healthy normal tissues but is significantly increased in some solid cancers. However, little is known about the roles of SLC6A14 in colorectal cancer (CRC). Methods: The mRNA and protein levels of SLC6A14 were detected using TCGA database, real-time polymerase chain reaction, western blot, and tissue microarrays, respectively. Amino acids concentration was determined by LC-MS/MS. Cell proliferation and apoptosis were determined using MTT assay and flow cytometry. Transwell invasion assay and wound healing assay were employed to analyze cell migration and invasion. The protein levels of Akt-mTOR signaling pathway and MMPs proteins were detected by western blot. Results: Both of the mRNA and protein levels of SLC6A14 were upregulated in CRC tissues, and the protein levels of SLC6A14 were closely related to the tumor cells differentiation: the higher the expression of SLC6A14 was, the poorer the differentiation of the tumor cells was. Further knockdown SLC6A14 with siRNA or treatment with α-MT in CRC cell lines reduced cell proliferation and migration in vitro and inhibited xenograft tumor growth in vivo. Mechanistically, SLC6A14 was demonstrated to regulate the expression and phosphorylation of Akt-mTOR, which mediates the promoting tumor growth function of SLC6A14. Blockade of SLC6A14 with α-MT inhibited the activation of mTOR signaling. Conclusion: SLC6A14 was upregulated in CRC and could promote tumor progression by activating the Akt-mTOR signaling pathway, which may serve as an effective molecular target for the treatment of CRC.

Background: Abnormal proliferation of fibroblast-like synoviocytes (FLSs) in the synovial lining layer is the primary cause of synovial hyperplasia and joint destruction in rheumatoid arthritis (RA). Currently, the relationship between metabolic abnormalities and FLS proliferation is a new focus of investigation. However, little is known regarding the relationship between amino acid metabolism and RA. Methods: The concentrations of amino acids and cytokines in the synovial fluid of RA (n = 9) and osteoarthritis (OA, n = 9) were detected by LC–MS/MS and CBA assay, respectively. The mRNA and protein expression of cationic amino acid transporter-1 (CAT-1) were determined in FLSs isolated from RA and OA patients by real-time PCR and western blotting. MTT assay, cell cycle, apoptosis, invasion, and cytokine secretion were determined in FLSs knocked down of CAT-1 using siRNA or treated with D-arginine under normoxic and hypoxic culture conditions. A mouse collagen-induced arthritis (CIA) model was applied to test the therapeutic potential of blocking the uptake of L-arginine in vivo. Results: L-rginine was upregulated in the synovial fluid of RA patients and was positively correlated with the elevation of the cytokines IL-1β, IL-6, and IL-8. Further examination demonstrated that CAT-1 was the primary transporter for L-arginine and was overexpressed on RA FLSs compared to OA FLSs. Moreover, knockdown of CAT-1 using siRNA or inhibition of L-arginine uptake using D-arginine significantly suppressed L-arginine metabolism, cell proliferation, migration, and cytokine secretion in RA FLSs under normoxic and hypoxic culture conditions in vitro but increased cell apoptosis in a dose-dependent manner. Meanwhile, in vivo assays revealed that an L-arginine-free diet or blocking the uptake of L-arginine using D-arginine suppressed arthritis progression in CIA mice. Conclusion: CAT-1 is upregulated and promotes FLS proliferation by taking up L-arginine, thereby promoting RA progression.

Ubiquitin-specific peptidase 10 (USP10) can sustain cellular functions and regulate cellular processes. It plays an essential role in cancer inhibition or facilitation by reversing ubiquitin-proteasome degradation. Studies have identified USP10 to be involved in tumor progression in various cancers. However, the pan-cancer expression pattern of USP10, its prognostic value, and the association between tumor immune cell infiltration and USP10 expression remain to be discussed and thus comprised the aims of the present study. Based on clinical samples and bioinformatic analyses, high USP10 expression was observed in most cancer tissues except for ovarian cancer. High USP10 expression correlated with pathological stage and node metastasis and predicted poor patient prognosis. In addition, further analyses at the TIMER and GEPIA databases showed that USP10 is involved in the infiltration of multiple immune cells and regulated the infiltration levels of specific immune cell subpopulations, particularly in pancreatic adenocarcinoma (PAAD) and liver hepatocellular carcinoma (LIHC). Importantly, USP10 might influence survival by modulating immune infiltration in patients with PAAD and LIHC. These results identified USP10 as a potential biomarker for pan-cancer prognosis, and in certain cancers, USP10 could identify clinical prognosis linked to tumor immune infiltration.

Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1), as the key component of the transcription initiation factor complex EIF4F, is significantly upregulated in multiple solid tumours, including lung cancer. However, the function and mechanism of EIF4G1 in the regulation of non‐small‐cell lung cancer (NSCLC) remain unclear. Here, using the clinical samples and the comprehensive survival analysis platforms Kaplan‐Meier plotter, we observed aberrant upregulation of EIF4G1 in NSCLC tissues; furthermore, high expression of EIF4G1 showed association with low differentiation of lung cancer cells and poor overall survival in NSCLC patients. Non‐small‐cell lung cancer cell line A549 and H1703 stably infected with EIF4G1 shRNA were used to determine the function of EIF4G1 in regulating cell proliferation and tumorigenesis in vitro and in vivo. The results demonstrated that EIF4G1 promoted the G1/S transition of the cell cycle and tumour cell proliferation in non‐small cell lung cancer. Mechanistically, EIF4G1 was found to regulate the expression and phosphorylation of mTOR (Ser2448), which mediates the tumorigenesis‐promoting function of EIF4G1. The inhibition of mTOR attenuated the EIF4G1‐induced development and progression of tumours. These findings demonstrated that EIF4G1 is a new potential molecular target for the clinical treatment of non‐small cell lung cancer.

Targeting EIF4F complex in non-small cell lung cancer cells Targeting EIF4F complex in non–small cell lung cancer cells