Chronic psychologic stress is often associated with manifestations of malignant diseases. Identification of modulators regulating the interaction between stress and tumorigenesis could provide potential strategies to ameliorate cancer progression. In this study, we observed that chronic stress markedly promoted lung cancer progression. Analysis of the landscape of long noncoding RNA expression indicated that long noncoding RNA HIF1A-AS3 was upregulated in the stressed group and in lung cancer specimens compared with normal tissues. HIF1A-AS3 promoted the proliferation and invasion of lung cancer cells both in vitro and in vivo. Mechanistically, HIF1A-AS3 translationally activated hypoxia-inducible factor-1α (HIF1α) via direct interaction with YBX1, stimulating downstream signaling cascades. HIF1α inversely stimulated HIF1A-AS3 transcription by directly binding to its promoter region. Investigation of the immune microenvironment revealed that macrophage depletion could efficiently abolish the tumor-promoting effects of chronic stress. Both chronic stress and HIF1A-AS3 overexpression induced M2-like macrophage polarization in tumor tissues in mice. Conditioned medium from HIF1A-AS3–overexpressing lung cancer cells enhanced the macrophages mobility. Macrophages exhibited suppressed phagocytic activity against HIF1A-AS3-overexpressing tumor cells. Targeting HIF1A-AS3/HIF1α signaling, which was aberrantly upregulated in human lung cancer specimens and predictive of poor prognosis, counteracted chronic stress–induced lung cancer progression in vivo. In conclusion, the HIF1A-AS3/HIF1α positive feedback loop mediates chronic stress–induced lung cancer growth through functional reprogramming of tumor-associated macrophages, suggesting that this axis may serve as a promising diagnostic and therapeutic target for patients with lung cancer suffering from psychologic stress. Significance: Chronic stress facilitates lung cancer immune evasion by inducing M2-like macrophage polarization, supporting the potential of combination therapies targeting both tumor cells and the immune microenvironment for treating stress-related cancers.

Background: That breast carcinoma is the most common malignant lesion in women. This study aimed to differentiate benign from malignant breast lesions and to predict grading of the latter by comparing the diagnostic value of different parameters in intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). Materials and methods: Retrospective analysis was performed utilizing imaging and pathological data from 112 patients with 124 breast lesions that underwent IVIM-DWI examination with 3.0 T MRI. Out of 124, 47 benign and 77 malignant lesions were confirmed by pathological diagnosis. The diagnostic performance of f, D, and D* value to distinguish benign from malignant breast lesions, was evaluated using pathological results as the gold standard. Correlation between D value and Ki-67 index was evaluated to predict grading of malignant breast lesions. Results: The D value (0.99 ± 0.21) of patients with malignant lesions was significantly lower than that (1.34 ± 0.18) of patients harboring benign lesions (P = .00). The D* value (7.60 ± 2.10) in malignant lesion group was higher than that (6.83 ± 2.13) of the benign lesion group (P = .113). The f value (8.50 ± 2.13) in malignant lesion group was remarkably higher than that (7.68 ± 1.98) of benign lesion group (P = .035). For differential diagnosis of benign from malignant breast lesions, optimal diagnostic threshold of D value and f value were 1.21 and 7.86, respectively. The areas of D and f values under the ROC curve were 0.883 and 0.601, respectively. The sensitivity, specificity, and accuracy of D value were 83.0%, 86.7%, and 85.5%, respectively. Accordingly, those indexes of f value were 64.9%, 57.4%, and 62.1%, respectively. Furthermore, the Ki-67 staining index of malignant lesions was robustly negatively correlated with D value (r = −0.395, P < .01). Conclusion: Concrete parameters of IVIM-DWI can help to improve the specificity and accuracy in differential diagnosis of breast benign and malignant lesions. D value is most relevant and valuable in predicting the grading of malignant breast lesions.

Despite the advent of precision medicine and immunotherapy, mortality due to lung cancer remains high. The sonic hedgehog (SHH) cascade and its key terminal factor, glioma-associated oncogene homolog 1 (GLI1), play a pivotal role in the stemness and drug resistance of lung cancer. Here, we investigated the molecular mechanism of non-canonical aberrant GLI1 upregulation. The SHH cascade was upregulated in stem spheres and chemo-resistant lung cancer cells and was accountable for drug resistance against multiple chemotherapy regimens. GLI1 and the long non-coding RNA SOX2OT were positively regulated, and the GLI1-SOX2OT loop mediated the proliferation of parental and stem-like lung cancer cells. Further mechanistic investigation revealed that SOX2OT facilitated METTL3/14/IGF2BP2-mediated m6A modification and stabilization of the GLI1 mRNA. Additionally, SOX2OT upregulated METTL3/14/IGF2BP2 by sponging miR-186-5p. Functional analysis corroborated that GLI1 acted as a downstream target of METTL3/14/IGF2BP2, and GLI1 silencing could block the oncogenicity of lung cancer stem-like cells. Pharmacological inhibition of the loop remarkably inhibited the oncogenesis of lung cancer cells in vivo. Compared with paired adjacent normal tissues, lung cancer specimens exhibited consistently upregulated GLI1/SOX2OT/METTL3/14/IGF2BP2. The m6A-modified GLI1-SOX2OT loop may serve as a potential therapeutic target and prognostic predictor for lung cancer therapy and diagnosis in the clinic.

The development of drug resistance in cancer is associated with multiple malignant properties, including proliferative progression, metastasis, and stemness. Long noncoding RNAs (lncRNAs) reportedly contribute to multidrug resistance in lung cancer. However, functional and mechanistic studies of key lncRNAs associated with lung cancer are lacking. Candidate lncRNA IGFL2-AS1 and its downstream target, the HSPA1A and RAP1 cascade, were identified using RNA sequencing. In vitro functional assays, including proliferation, clonal formation, Transwell migration, sphere formation, and drug sensitivity test, were conducted to explore the function of the IGFL2-AS1/HSPA1A axis in lung cancer. For in vivo functional validation, subcutaneous implantation and tail vein injection of luciferase-tagged lung cancer cells were performed in mouse models. Moreover, RNA pulldown, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and point/truncated mutations were utilized to dissect the mechanisms underlying the activation of the YBX1-mediated IGFL2-AS1/HSPA1A axis. Pharmacological inhibition of HSPA1A was performed to restore chemotherapy sensitivity and attenuate lung cancer cell metastasis in vivo. Finally, tissue microarray staining was employed to evaluate the expression of the YBX1/IGFL2-AS1/HSPA1A/RAP1 axis in lung cancer specimens and its correlation with prognosis. IGFL2-AS1, stimulated by C/EBPβ, was aberrantly upregulated in chemoresistant cell lines and lung cancer specimens. IGFL2-AS1 promoted lung cancer proliferation, metastasis, drug resistance, and stemness by upregulating HSPA1A expression both in vitro and in vivo. Mechanistically, IGFL2-AS1 recruited YBX1 to the HSPA1A promoter, facilitating its transcription. Pharmacological inhibition of HSPA1A restored the sensitization of A549 cells resistant to cisplatin and 5-fluorouracil via the downstream RAP1 signaling cascade. Notably, the YBX1/IGFL2-AS1/HSPA1A axis was consistently activated in lung cancer specimens and correlated with poor patient prognosis. This study demonstrated that the YBX1-modulated IGFL2-AS1/HSPA1A/RAP1 axis is aberrantly activated in lung cancer cells and is associated with unfavorable prognosis, highlighting its potential as a novel therapeutic target in clinical settings.

Non-coding RNAs are responsible for oncogenesis and the development of stemness features, including multidrug resistance and metastasis, in various cancers. Expression of lncRNA MIR31HG in lung cancer tissues and peripheral sera of lung cancer patients were remarkably higher than that of healthy individuals and indicated a poor prognosis. Functional analysis showed that MIR31HG fosters stemness-associated malignant features of non-small cell lung cancer cells. Further mechanistic investigation revealed that MIR31HG modulated GLI2 expression via WDR5/MLL3/P300 complex-mediated H3K4me and H3K27Ace modification. In vivo MIR31HG repression with an antisense oligonucleotide attenuated tumor growth and distal organ metastasis, whereas MIR31HG promotion remarkably encouraged cellular invasion in lung and liver tissues. Our data suggested that MIR31HG is a potential diagnostic indicator and druggable therapeutic target to facilitate multiple strategic treatments for lung cancer patients.