Thioredoxin-interacting protein (TXNIP) is a thioredoxin-binding protein that can mediate oxidative stress, inhibit cell proliferation, and induce apoptosis by inhibiting the function of the thioredoxin system. TXNIP is important because of its wide range of functions in cardiovascular diseases, neurodegenerative diseases, cancer, diabetes, and other diseases. Increasing evidence has shown that TXNIP expression is low in tumors and that it may act as a tumor suppressor in various cancer types such as hepatocarcinoma, breast cancer, and lung cancer. TXNIP is known to inhibit the proliferation of breast cancer cells by affecting metabolic reprogramming and can affect the invasion and migration of breast cancer cells through the TXNIP-HIF1α-TWIST signaling axis. TXNIP can also prevent the occurrence of bladder cancer by inhibiting the activation of ERK, which inhibits apoptosis in bladder cancer cells. In this review, we find that TXNIP can be regulated by binding to transcription factors or other binding proteins and can also be downregulated by epigenetic changes or miRNA. In addition, we also summarize emerging insights on TXNIP expression and its functional role in different kinds of cancers, as well as clarify its participation in metabolic reprogramming and oxidative stress in cancer cells, wherein it acts as a putative tumor suppressor gene to inhibit the proliferation, invasion, and migration of different tumor cells as well as promote apoptosis in these cells. TXNIP may therefore be of basic and clinical significance for finding novel molecular targets that can facilitate the diagnosis and treatment of malignant tumors.

Previous studies have shown that dysregulation of microRNA-150 (miR-150) is associated with aberrant proliferation of human non-small cell lung cancer (NSCLC) cells. However, whether miR-150 has a critical role in NSCLC cell metastasis is unknown. Here, we reveal that the critical pro-metastatic role of miR-150 in the regulation of epithelial-mesenchymal-transition (EMT) through down-regulation of FOXO4 in NSCLC. In vitro, miR-150 targets 3′UTR region of FOXO4 mRNA, thereby negatively regulating its expression. Clinically, the expression of miR-150 was frequently up-regulated in metastatic NSCLC cell lines and clinical specimens. Contrarily, FOXO4 was frequently down-regulated in NSCLC cell lines and clinical specimens. Functional studies show that ectopic expression of miR-150 enhanced tumor cell metastasis in vitro and in a mouse xenograft model, and triggered EMT-like changes in NSCLC cells (including E-cadherin repression, N-cadherin and Vimentin induction, and mesenchymal morphology). Correspondingly, FOXO4 knockdown exhibited pro-metastatic and molecular effects resembling the effect of miR-150 over-expression. Moreover, NF-κB/snail/YY1/RKIP circuitry regulated by FOXO4 were likely involved in miR-150-induced EMT event. Simultaneous knockdown of miR-150 and FOXO4 abolished the phenotypic and molecular effects caused by individual knockdown of miR-150. Therefore, our study provides previously unidentified pro-metastatic roles and mechanisms of miR-150 in NSCLC.

The deregulation of Annexin A1 (ANXA1), a regulator of inflammation and immunity, leads to cancer growth and metastasis. However, whether ANXA1 is involved in cancer immunosuppression is still unclear. Here, we report that ANXA1 knockdown (i) dramatically downregulates programmed cell death-ligand 1 (PD-L1) expression in breast cancer, lung cancer, and melanoma cells; (ii) promotes T cell–mediated killing of cancer cells in vitro; and (iii) inhibits cancer immune escape in immune-competent mice via downregulating PD-L1 expression and increasing the number and killing activity of CD8+ T cells. Mechanistically, ANXA1 functioned as a sponge molecule for interaction of PARP1 and Stat3. Specifically, binding of ANXA1 to PARP1 decreased PARP1’s binding to Stat3, which reduced poly(ADP-ribosyl)ation and dephosphorylation of Stat3 and thus, increased Stat3’s transcriptional activity, leading to transcriptionally upregulated expression of PD-L1 in multiple cancer cells. In clinical samples, expression of ANXA1 and PD-L1 was significantly higher in breast cancer, non–small cell lung cancer, and skin cutaneous melanoma compared with corresponding normal tissues and positively correlated in cancer tissues. Moreover, using both ANXA1 and PD-L1 proteins for predicting efficacy of anti–PD-1 immunotherapy and patient prognosis was superior to using individual proteins. Our data suggest that ANXA1 promotes cancer immune escape via binding PARP1 and upregulating Stat3-induced expression of PD-L1, that ANXA1 is a potential new target for cancer immunotherapy, and combination of ANXA1 and PD-L1 expression is a potential marker for predicting efficacy of anti–PD-1 immunotherapy in multiple cancers.

The biological functions of exosomes and microRNAs (miRs) in nasopharyngeal carcinoma (NPC) remain largely unexplored. Here, miR-197-3p was screened and identified, and whose level was reduced in serum and exosomes of patients with NPC. MiR-197-3p might be a good diagnostic and prognostic indicator. Our data showed that miR-197-3p expression was closely related to radioresistance, apoptosis, proliferation, migration, and survival of NPC. Inhibition of miR-197-3p expression in vitro could promote the proliferation and migration of NPC cells, while promotion of miR-197-3p expression in vivo could significantly inhibit the growth and enhance the radiosensitivity of NPC cells. From the perspective of mechanism, miR-197-3p could inhibit AKT/mTOR phosphorylation activation, inhibit an activated pathway of AKT/mTOR, target Heat Shock 70-kDa Protein 5(HSPA5) related to endoplasmic reticulum homeostasis, inhibit HSPA5-mediated autophagy, and reverse the radioresistance of NPC. Interestingly, exosomal miR-197-3p (EXO-miR-197-3p) reduced the proliferation and migration potential of NPC cells in vitro, and tumor growth and radioresistance of NPC cells in vivo. EXO-miR-197-3p inhibited NPC progression and radioresistance by regulating AKT/mTOR phosphorylation activation and HSPA5-mediated autophagy. In conclusion, our results highlight the potential of EXO-miR-197-3p as an effective radiosensitizer and therapeutic agent for refractory NPC.

Breast cancer is the most common malignancy among women worldwide. Kynureninase (KYNU) located in 2q22.2, which was associated with tryptophan utilization and metabolic diseases including cardiac, renal and limb defects syndrome 2. However, the role of KYNU in breast cancer (BC) development remains unclear. The expression of KYNU was examined by immunohistochemistry (IHC) in 137 primary BC tissues, and the correlation of KYNU expression with clinical pathological characteristics and the biomarkers (ER, PR, HER2, E‐cad and Ki‐67) was analysed. The role of KYNU in cancer cell proliferation, tumour growth and development was evaluated by MTT assay, soft agar colony formation assay and xenograft mouse models. Among 137 primary BC tissues, 46.7% (64/137) had high KYNU expression (IHC scores >4) while 53.3% (73/137) had low KYNU expression (IHC scores ≤4). The expression of KYNU was positively correlated with the expressions of ER ( P = .002), PR ( P = .007) and E‐cad ( P = .03), while negatively associated with tumour grade ( P = .008), tumour stage ( P < .001) and the expressions of HER2 ( P = .04) and Ki‐67 ( P = .019). Overexpression of KYNU significantly inhibited cell proliferation in cell culture, colony formation in soft agar and xenograft BC development in NOD/SCID mice. Kynureninase suppresses BC cell proliferation, tumour growth and development. Kynureninase may function as a tumour suppressor in BC.

Glucose‑regulated protein 78 (GRP78) was revealed to be associated with the radioresistance of nasopharyngeal carcinoma (NPC) in our previous study. GRP78 is a highly expressed cell surface protein, and holds great promise as a cancer specific target. Its expression may be impacted by the regulation of miRNAs, which may be involved in the radioresistance of NPC. A better understanding of the mechanisms of radioresistance may generate new targets of therapy for NPC patients. The present study was designed to investigate the effect of microRNA targeting GRP78 on the radiosensitivity of NPC. First, we used miRWalk software to predict miRNAs that may interact with GRP78. Subsequently, analysis of miR‑495 and GRP78 expression was performed in the primary tissues of 92 NPC tissues and cell lines by immunohistochemistry and real‑time PCR and the results revealed that miR‑495 expression was lower in radioresistant NPC tissues in comparison to chronic rhinitis tissues, and also lower in radioresistant 5‑8F cells (5‑8F‑IR) in comparison to its parental 5‑8F cells. Notably, we observed an inverse association between the expression miR‑495 and GRP78. Our bioinformatics analysis led to the identification of miR‑495 as the optimal miRNA interacting with GRP78 mRNA. Furthermore, miR‑495 targeting the 3'untranslated region (UTR) of GRP78 was detected by a Dual‑Glo Luciferase Assay system. Finally, we observed that miR‑495 inhibition led to a significant increase in the radioresistance of 5‑8F cells and higher GRP78 expression, which may be involved in epithelial‑mesenchymal transition (EMT) phenotype. miR‑495 targeted the 3'UTR of GRP78 and contributed to the efficacy of radiation therapy in NPC.