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Clinicopathological Significance and Antitumor Effect of MPHOSPH1 in Testicular Germ Cell Tumor.

ABSTRACT: MPHOSPH1, which is one of the kinesin superfamily proteins, has been reported to play an essential role in the carcinogenesis and progression of several kinds of cancers. MPHOSPH1 has also been suggested to be involved in STAT3 phosphorylation in hepatocellular carcinoma. However, the biological behavior of MPHOSPH1 in testicular germ cell tumors (TGCTs) is unclear at present. The purposes of this study were to investigate the correlation between the expression of MPHOSPH1 and clinicopathological factors and to examine the efficacy of MPHOSPH1 target therapy in TGCTs. We investigated 75 formalin-fixed paraffin-embedded TGCT samples, containing a total of 86 germ cell tumor components, by immunohistochemistry and 12 frozen samples by Western blotting. Moreover, we carried out in vitro studies to clarify the antitumor effect of MPHOSPH1 knockdown in embryonal carcinoma cell lines, NEC8 and NEC14, using small interference RNA (siRNA). A significantly high expression of MPHOSPH1 was recognized in embryonal carcinoma and yolk sac tumor components compared to the seminoma component (p<0.001, respectively). Clinically, non-seminoma cases are known to have worse prognosis than pure-seminoma cases. Interestingly, high MPHOSPH1 expression was associated with distant metastasis (p=0.001), and thus with advanced-stage disease in this study. High expression of MPHOSPH1 interacted with high expression of phosphorylated STAT3 (p=0.01). The in vitro experiments demonstrated that MPHOSPH1 interruption by siRNA resulted in a significant reduction of cell migration, invasion, proliferation and colony formation in both embryonal carcinoma cell lines (p<0.001, respectively). In conclusion, MPHOSPH1 may be a potential treatment option for TGCTs, and its expression may be a novel biomarker of poor prognosis.

SUBMITTER: Abe T

PROVIDER: S-EPMC6277652 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Clinicopathological Significance and Antitumor Effect of MPHOSPH1 in Testicular Germ Cell Tumor.

Abe Tatsuro T Kohashi Kenichi K Takemoto Junkichi J Kinoshita Fumio F Eto Masatoshi M Oda Yoshinao Y

Journal of Cancer 20181031 23

MPHOSPH1, which is one of the kinesin superfamily proteins, has been reported to play an essential role in the carcinogenesis and progression of several kinds of cancers. MPHOSPH1 has also been suggested to be involved in STAT3 phosphorylation in hepatocellular carcinoma. However, the biological behavior of MPHOSPH1 in testicular germ cell tumors (TGCTs) is unclear at present. The purposes of this study were to investigate the correlation between the expression of MPHOSPH1 and clinicopathologica ...[more]

PMID: 30519350

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Project description:Testicular Germ Cell Tumors (TGCTs) are a rare group of neoplasms and the most common solid malignancy arising in young male adults. Despite the good response of these tumors to platinum-based chemotherapy, some patients are refractory to treatment and present poor clinical outcomes. During carcinogenesis and tumor development, cancer cells reprogram energy metabolism toward a hyper-glycolytic phenotype, an emerging hallmark of cancer. This phenomenon, known as the Warburg effect or aerobic glycolysis, involves overexpression of metabolism-related proteins, like glucose and monocarboxylate transporters, pH regulators and intracellular glycolytic enzymes. The metabolic profile of TGCTs is very little explored and, recently, this metabolic rewiring of cancer cells has been associated with aggressive clinicopathological characteristics of these tumors. The overexpression of monocarboxylate transporter 4 (MCT4) in TGCTs has been pointed out as a poor prognostic factor, as well as a promising therapeutic target. As a result, the main aim of the present study was to evaluate the prognostic value of key metabolism-related proteins in TGCTs. The immunohistochemical expressions of CD44 (as a monocarboxylate transporter chaperone), glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), hexokinase II (HKII) and lactate dehydrogenase V (LDHV) were evaluated in a series of 148 adult male patients with TGCTs and associated with clinicopathological parameters. In addition, paired normal tissues were also evaluated. The sample included 75 seminoma and 73 non-seminoma tumors. GLUT1 and CD44 expression was significantly increased in malignant samples when compared to paired normal samples. Conversely, HKII and LDHV expressions were significantly decreased in malignant samples. Concerning the clinicopathological values, CAIX expression was significantly associated with disease recurrence, while HKII expression was significantly associated with aggressive characteristics of TGCTs, including higher staging and non-seminoma histology. In conclusion, this study brings new insights on the metabolic characteristics of TGCTs, showing alterations in the expression of proteins related with the Warburg effect, as well as associations of the hyper-glycolytic and acid-resistant phenotype with aggressive clinicopathological parameters.

Project description:BACKGROUND:Treatment for cancer may lead to development of cognitive difficulties in cancer survivors. This study aimed to evaluate long-term cognitive functioning (CogF) in germ-cell tumor (GCT) survivors. SUBJECTS, MATERIALS, AND METHODS:GCT survivors (n = 155) from the National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function at a median of 10 years of follow-up (range: 5-32). The study group consisted of survivors receiving a cisplatin-based chemotherapy, radiotherapy to the retroperitoneal lymph nodes, or both, whereas the control group included survivors treated with orchiectomy only. RESULTS:Of the total survivors, 138 received treatment beyond orchiectomy and 17 controls had orchiectomy alone. Any treatment resulted in significantly greater cognitive difficulties on the overall cognitive function score. Treatment with radiotherapy was associated with cognitive declines in overall cognitive functioning and in subscales for perceived cognitive impairment and cognitive impairment perceived by others (both p < .05). The burden of chemotherapy plus radiotherapy or radiotherapy versus controls resulted in the impairment in all cognitive functioning domains (all p < .05). Overall long-term cognitive impairment was independent of age in the multivariable analysis. CONCLUSION:This prospective study shows that GCT survivors suffer from a long-term CogF impairment. These results may help guide clinicians' decisions in treatment and follow-up of GCTs. IMPLICATIONS FOR PRACTICE:In this study, long-term survivors of germ-cell tumors have reported cognitive impairment after curative treatment with radiotherapy and chemotherapy compared with controls who had treatment with orchiectomy only. These data provide an argument against the use of adjuvant radiotherapy for stage I seminoma. Unnecessary overtreatment with chemotherapy and additional radiotherapy after chemotherapy should be avoided.

Dataset Information

Clinicopathological Significance and Antitumor Effect of MPHOSPH1 in Testicular Germ Cell Tumor.

Publications

Clinicopathological Significance and Antitumor Effect of MPHOSPH1 in Testicular Germ Cell Tumor.

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