Tumor necrosis factor (TNF)-α is a pleiotropic cytokine that triggers cell proliferation, cell death, or inflammation. Besides its cytotoxic effect on cancer cells, TNF-α exerts tumor promoting activity. Aberrant TNF-α signaling promotes cancer cell motility, invasiveness, and enhances cancer metastasis. Exaggerated tumor cell migration, invasion, and metastasis by TNF-α has been attributed to the activation of NF-κB signaling. It is yet to be elucidated if other signaling pathways and effector molecules are involved in TNF-α-induced cancer cell migration and metastasis. Expression of C/EBPβ, a transcription factor involved in metabolism, inflammation, and cancer, is increased upon TNF-α treatment. TNF-α induces C/EBPβ expression by enhancing its transcription and protein stability. Activation of p38 MAPK, but not NF-κB or JNK, is responsible for TNF-α-induced stabilization of C/EBPβ protein. C/EBPβ is involved in TNF-α-induced cancer cell migration. Knockdown of C/EBPβ inhibits TNF-α-induced cell migration, while overexpression of C/EBPβ increases migration of cancer cells. C/EBPβ is translated into transcriptional activator LAP1 and LAP2 and transcriptional repressor LIP utilizing alternative in-frame translation start sites. Despite TNF-α induces expression of all three isoforms, LAP1/2, but not LIP, promote cancer cell migration. TNF-α induced MMP1/3 expression, which was abrogated by C/EBPβ knockdown or p38 MAPK inhibition. MMP inhibitor or knockdown of MMP1/3 diminished TNF-α- and C/EBPβ-induced cell migration. Thus, C/EBPβ mediates TNF-α-induced cancer cell migration by inducing MMP1/3 expression, and may participate in the regulation of inflammation-associated cancer metastasis.
The correlation of genetic alterations with response to neoadjuvant chemotherapy (NAC) has not been fully revealed. In this study, we enrolled 247 breast cancer patients receiving anthracycline‐taxane‐based NAC treatment. A next generation sequencing (NGS) panel containing 36 hotspot breast cancer‐related genes was used in this study. Two different standards for the extent of pathologic complete response (pCR), ypT0/isypN0 and ypT0/is, were used as indicators for NAC treatment. TP53 mutation (n = 149, 60.3%), PIK3CA mutation (n = 109, 44.1%) and MYC amplification (n = 95, 38.5%) were frequently detected in enrolled cases. TP53 mutation ( P = 0.019 for ypT0/isypN0 and P = 0.003 for ypT0/is) and ERBB2 amplification ( P < 0.001 for both ypT0/isypN0 and ypT0/is) were related to higher pCR rates. PIK3CA mutation ( P = 0.040 for ypT0/isypN0) and CCND2 amplification ( P = 0.042 for ypT0/is) showed reduced sensitivity to NAC. Patients with MAPK pathway alteration had low pCR rates ( P = 0.043 for ypT0/is). Patients with TP53 mutation (−) PIK3CA mutation (−) ERBB2 amplification (+) CCND1 amplification (−), TP53 mutation (+) PIK3CA mutation (−) ERBB2 amplification (+) CCND1 amplification (−) or TP53 mutation (+) PIK3CA mutation (+) ERBB2 amplification (+) CCND1 amplification (−)had significantly higher pCR rates ( P < 0.05 for ypT0/isypN0 and ypT0/is) than wild type genotype tumors. Some cancer genetic alterations as well as pathway alterations were associated with chemosensitivity to NAC treatment. Our study may shed light on the molecular characteristics of breast cancer for prediction of NAC expectations when breast cancer is first diagnosed by biopsy.
Background Complex kinase rearrangement, a mutational process involving one or two chromosomes with clustered rearrangement breakpoints, interferes with the accurate detection of kinase fusions by DNA-based next-generation sequencing (NGS). We investigated the characteristics of complex ALK rearrangements in non-small cell lung cancers using multiple molecular tests. Methods Samples of non-small cell lung cancer patients were analyzed by targeted-capture DNA-based NGS with probes tilling the selected intronic regions of fusion partner genes, RNA-based NGS, RT-PCR, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Results In a large cohort of 6576 non-small cell lung cancer patients, 343 (5.2%) cases harboring ALK rearrangements were identified. Fourteen cases with complex ALK rearrangements were identified by DNA-based NGS and classified into three types by integrating various genomic features, including intergenic (n = 3), intragenic (n = 5) and “bridge joint” rearrangements (n = 6). All thirteen cases with sufficient samples actually expressed canonical EML4-ALK fusion transcripts confirmed by RNA-based NGS. Besides, positive ALK IHC was detected in 13 of 13 cases, and 9 of 11 cases were positive in FISH testing. Patients with complex ALK rearrangements who received ALK inhibitors treatment (n = 6), showed no difference in progression-free survival (PFS) compared with patients with canonical ALK fusions n = 36, P = 0.9291). Conclusions This study firstly reveals the molecular characteristics and clinical outcomes of complex ALK rearrangements in NSCLC, sensitive to ALK inhibitors treatment, and highlights the importance of utilizing probes tilling the selected intronic regions of fusion partner genes in DNA-based NGS for accurate fusion detection. RNA and protein level assay may be critical in validating the function of complex ALK rearrangements in clinical practice for optimal treatment decision.
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