The hepatocyte growth factor (HGF) along with its receptor (c-MET) are crucial in preserving standard cellular physiological activities, and imbalances in the c-MET signaling pathway can lead to the development and advancement of tumors. It has been extensively demonstrated that immune checkpoint inhibitors (ICIs) can result in prolonged remission in certain patients. Nevertheless, numerous preclinical studies have shown that MET imbalance hinders the effectiveness of anti-PD-1/PD-L1 treatments through various mechanisms. Consequently, clarifying the link between the c-MET signaling pathway and the tumor microenvironment (TME), as well as uncovering the effects of anti-MET treatment on ICI therapy, is crucial for enhancing the outlook for tumor patients. In this review, we examine the impact of abnormal activation of the HGF/c-MET signaling pathway on the control of the TME and the processes governing PD-L1 expression in cancer cells. The review thoroughly examines both clinical and practical evidence regarding the use of c-MET inhibitors alongside PD-1/PD-L1 inhibitors, emphasizing that focusing on c-MET with immunotherapy enhances the effectiveness of treating MET tumors exhibiting elevated PD-L1 expression.

F-box and WD repeat domain-containing 5 (FBXW5), with WD40 repeats, can bind to the PPxY sequence of the large tumor suppressor kinases 1/2 (LATS1/2) kinase domain, resulting in ubiquitination. Ubiquitination and the subsequent degradation of LATS1/2 abrogate the Hippo pathway and worsen gastric cancer (GC). However, the effects and molecular mechanisms of FBXW5 in GC remain unexplored. To elucidate the clinical significance of FBXW5, immunohistochemistry was conducted to reveal the positive correlation between FBXW5 expression and lymph node metastasis (p < 0.001) and TNM stage (training cohort: p = 0.018; validation cohort: p = 0.001). Further, patients with high FBXW5 expression were found to have poor prognosis (training cohort: log-rank p = 0.020; validation cohort: log-rank p = 0.025). Cell experiments revealed the promoting effects of FBXW5 on the proliferation, invasion, metastasis, and chemoresistance of GC cells. Blocking LATS1-YAP1 leads to the loss of FBXW5-mediated regulation of the Hippo pathway and partial functions. Further, co-immunoprecipitation and in vivo ubiquitination assays revealed the interaction between FBXW5 and LATS1, which promoted the ubiquitination and degradation of LATS1. Based on mouse xenograft assays, FBXW5 silencing attenuated the growth of subcutaneous tumor xenografts. Altogether, FBXW5 was found to inactivate the Hippo signaling pathway by enhancing LATS1 ubiquitination and degradation, which promoted the invasion, metastasis, and drug resistance of GC cells.

Chemoresistance is the most significant challenge affecting the clinical efficacy of the treatment of patients with gastric cancer (GC). Here we reported that transmembrane protein 160 (TMEM160) suppressed ferroptosis and induced chemoresistance in GC cells. Mechanistically, TMEM160 recruited the E3 ligase TRIM37 to promote K48-linked ubiquitination and degradation of KEAP1, thereby activating NRF2 and transcriptionally upregulating the target genes GPX4 and SLC7A11 to inhibit ferroptosis. Further in vitro and in vivo experiments demonstrated that the combination of TMEM160 targeting and chemotherapy had a synergistic inhibitory effect on the growth of GC cells, which was partially NRF2-dependent. Moreover, TMEM160 and NRF2 protein levels were markedly overexpressed in GC tissues, and their co-overexpression was an independent factor for poor prognosis. Collectively, these findings indicate that TMEM160, as a pivotal negative regulator of ferroptosis, exerts a crucial influence on the chemoresistance of GC through the TRIM37-KEAP1/NRF2 axis, providing a potential new prognostic factor and combination therapy strategy for patients with GC.

Background: Aberrant long non-coding RNA (lncRNA) expression contributes cancer development and resistance to therapy. This study first assessed expression of lncRNA LINC00958 in a variety of human cancers using GEPIA database data and then associated it with prognosis of head and neck squamous cell carcinoma (HNSCC) and investigated LINC00958 interaction with c-Myc and the c-Myc-related gene interplay in HNSCC cells. Materials and methods: A cohort of 48 HNSCC vs normal tissues was collected for qRT-PCR analysis of LINC00958 and c-Myc expression and statistical analyses. HNSCC cell lines were subjected to transfection with LINC00958 and c-Myc siRNAs or cDNA and their negative control siRNA or empty vector for qRT-PCR, Western blot, cell viability, colony formation, luciferase reporter, chromatin immunoprecipitation, and RNA immunoprecipitation assays. Results: The data showed that LINC00958 expression was upregulated in HNSCC tissues and cell lines, upregulation of which was associated with poor tumor differentiation, advanced tumor stage, and shorter overall survival of patients. In vitro, LINC00958 expression induced HNSCC cell viability and colony formation, whereas knockdown of LINC00958 expression enhanced HNSCC cell sensitivity to ionizing radiation and cisplatin treatment. Mechanistically, LINC00958 is a direct target of c-Myc and can enhance the transcriptional activity of c-Myc, thus to form a positive feedback gene network in HNSCC cells, and in turn to modulate HNSCC cell resistance to chemo- and radiotherapy. Conclusion: This study demonstrated the LINC00958 interplay with c-Myc as a feedback loop facilitated HNSCC development and resistance to chemo- and radiotherapy. Targeting of such a network could be further evaluated as a novel therapeutic strategy for HNSCC patients.